[
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Peritoneal dialysis is not a risk factor for primary vascular graft thrombosis after renal transplantation.",
        "key_reference_abstract": "## OBJECTIVE\nTo find out if patients undergoing peritoneal dialysis (PD) have an increased risk of primary vascular thrombosis of the renal allograft, compared with patients on hemodialysis (HD).\n## DESIGN\nObservational, retrospective cohort study.\n## SETTING\nTertiary care hospital, covering an approximate population of 2,000,000. Extensive use of suboptimal donors for renal transplantation.\n## PATIENTS AND METHODS\nThe study included 827 patients receiving a cadaveric renal transplantation (RTx) in our center between 1988 and 1997 (700 on HD and 127 on PD). We searched for a potential difference in the incidence of graft thrombosis, according to the pretransplant dialysis modality and taking into consideration the main reported risk factors for this complication of RTx.\n## RESULTS\nThe accumulated incidence of primary graft thrombosis was 4.7% in PD patients, and 6.1% in HD patients (NS). Arterial and venous thrombosis were also similar in both groups. Logistic regression analysis demonstrated that extremes of age of the donor, use of the right kidney, protracted cold ischemia, delayed graft function, and transplantation to a hypersensitized recipient independently predicted graft thrombosis. Peritoneal dialysis was not independently associated with the complication under study (adjusted odds ratio HD/PD = 2.5, 95% CI = 0.8-7.7).\n## CONCLUSIONS\nPeritoneal dialysis is not associated with an increased risk of primary vascular thrombosis of the renal allograft.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Dialysis modality and delayed graft function after cadaveric renal transplantation.",
        "key_reference_abstract": "The purpose of this investigation was to compare outcomes in the immediate posttransplant period for hemodialysis (HD) and peritoneal (PD) dialysis patients who received cadaveric renal transplantation. Data were obtained from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation between April 1994 and December 1995. Baseline characteristics were compared between groups, and multivariate logistic regression was performed with outcome measures including urine production in the first 24 h posttransplantation (U24), requirement for dialysis in the first week posttransplant (FWDIAL), and treatment for acute rejection during the initial hospitalization. The odds of oliguria (not producing urine in the first 24 h) were 1.49 (1.28 to 1.74) times higher in HD versus PD patients. After adjustment for other comorbid conditions including age, gender, race, HLA mismatch, time on dialysis, panel-reactive antibodies, and cold and warm ischemia time, the odds of oliguria were 1.60 (1.14 to 2.25) times higher in black HD patients compared with PD patients and 1.29 (1.06 to 1.57) times higher in white HD patients. In a similar manner, after adjustment for significant comorbid conditions, the odds of requiring dialysis in the first week were 1.56 (1.22 to 2.0) times higher in black HD patients versus PD patients and 1.40 (1.21 to 1.60) times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. These results suggest that there is an association between hemodialysis and delayed graft function. Differences in biocompatibility between the two modalities could potentially be responsible.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.",
        "key_reference_abstract": "## BACKGROUND\nRenal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients.\n## METHODS\nRenal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression.\n## RESULTS\nForty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs).\n## CONCLUSIONS\nThe strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis.",
        "key_reference_abstract": "## BACKGROUND\nDelayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF.\n## METHODS\nThe records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed.\n## RESULTS\nDGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01).\n## CONCLUSION\nPD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "A comparison of transplant outcomes in peritoneal and hemodialysis patients.",
        "key_reference_abstract": "## BACKGROUND\nStudies examining the effect of pre-transplant dialysis modality on graft and patient survival after kidney transplantation have produced conflicting results. Therefore, we studied the effects of pre-transplant dialysis modality on outcomes in a large United States cohort.\n## METHODS\nWe compared rates of transplantation between peritoneal dialysis and hemodialysis patients from the years 1995 to 1998 in the United States (N = 252,402) and outcomes after transplantation (N = 22,776), using data from the Centers for Medicare and Medicaid Services.\n## RESULTS\nIn a Cox proportional hazards analysis that was adjusted for multiple patient characteristics, kidney transplantation was 1.39 (95% CI = 1.35 to 1.43) times more likely in peritoneal dialysis vs. hemodialysis patients (P < 0.0001). Over the entire follow-up period, the adjusted risk for death-censored graft failure was 1.15 (1.04 to 1.26) times higher in peritoneal dialysis vs. hemodialysis (P < 0.05), but mortality and overall graft failure rates were not different. Pre-transplant dialysis modality did not affect outcomes for patients who survived with a functioning kidney for at least 3 months. However, in adjusted Cox analyses restricted to the first 3 months, peritoneal dialysis was associated with a 1.23 (1.09 to 1.39) times higher risk for early graft failure (P < 0.001) and a 1.33 (1.16 to 1.53) times higher risk for death-censored graft failure (P < 0.001). Peritoneal dialysis patients, however, were seen to have a lower incidence of delayed graft function. In a smaller sample of patients with data on causes of early graft failure, graft thrombosis was more commonly listed as a cause of graft failure among peritoneal dialysis patients, 41% (64/156), compared to hemodialysis patients, 30% (106/349), P < 0.05.\n## CONCLUSIONS\nKidney transplantation is more frequent in peritoneal dialysis than in hemodialysis patients, and transplantation in peritoneal dialysis patients is more frequently associated with early, but not late, graft failure. Delayed graft function was less common in peritoneal dialysis patients but this potential benefit appears to be offset by other factors which are associated with early graft loss. Additional studies are needed to determine what factors may help understand this early risk of graft failure.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Access to, and outcome of, renal transplantation according to treatment modality of end-stage renal disease in France.",
        "key_reference_abstract": "## BACKGROUND\nAlthough peritoneal dialysis (PD) is recognized as one of the methods of treatment of end-stage renal disease (ESRD), there have been recurrent concerns about the access of patients treated by this modality to kidney transplantation (KTx), as well as reports showing increased complications of KTx in such patients, such as graft thrombosis and infections.\n## METHODS\nThe aim of this study was to provide a comprehensive view of the impact on transplantation of pretransplant modality of treatment of ESRD using a multivariate analysis of the French database. From 1997 to 2000, after exclusion of pediatric patients, multiple transplantations, and living donors, 6420 were patients registered on the waiting list, and 3464 were transplanted.\n## RESULTS\nUsing a Cox proportional hazard analysis, we found a shorter waiting time for PD patients (RR 0.71, P < 0.0001), which became equivalent to hemodialysis (HD) patients when taking into account the transplant center as a variable (RR 1.0, P= 0.95). Concerning graft survival, only preemptive transplantation had a significant impact, being associated to a decreased risk of graft failure (RR 0.46, P= 0.005). Conclusion. Our study supports the concept that the choice of any pretransplant dialysis modality does not influence waiting time for transplant or the results of transplantation.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Impact of pretransplant dialysis on early graft function in pediatric kidney recipients.",
        "key_reference_abstract": "Delayed graft function (DGF) is a frequent complication of kidney transplantation (KT) that may affect both short- and long-term graft outcome. It has been reported that pretransplantation peritoneal dialysis was correlated with a better recovery of graft function than hemodialysis in adult kidney recipients. However, the effect of pretransplantation dialysis mode (PDM) seemed to be unclear on the early outcome of KT in pediatric recipients. In this study, the potential impact of PDM on early graft function was evaluated in 174 pediatric patients who underwent KT by using cadaveric donors. The primary outcome parameter was the time to reach a serum creatinine (SCr) level 50% of the pretransplantation value [T(1/2(SCr))], while DGF was defined as a T(1/2(SCr)) >3 days after KT (n = 40). By stratifying kidney recipients for normal function graft or DGF, this latter group showed a significantly higher body weight (BW) on the day of KT (P = 0.014), body surface area (BSA) (P = 0.005), warm ischemia time (WIT) (P = 0.022), early SCr on the day 1 after KT (P < 0.001), and T(1/2(SCr)) (P < 0.001), whereas lower urine volume (UV) collected in the first 24 h after KT (P < 0.001) and fluid load (P < 0.001) occurred. Univariate exponential correlation that was carried out between T(1/2(SCr)) and all the other variables had shown a better value than the linear correlation for BW (R(2) = 0.28 vs. R(2) = 0.04), BSA (R(2) = 0.29 vs. R(2) = 0.03), and SCr (R(2) = 0.51 vs. R(2) = 0.28). In a multivariate regression analysis performed by entering T(1/2(SCr)) as dependent variable and following a forward stepwise method, cold ischemia time (CIT) (P = 0.027) but not PDM (P = 0.195) reached significance. In a Cox regression analysis carried out with T(1/2(SCr)) as dependent variable, neither CIT nor PDM gained significance. This study suggests that PDM does not affect early graft function in pediatric kidney recipients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival.",
        "key_reference_abstract": "## BACKGROUND\nThe effect of pretransplantation renal replacement therapy (RRT) modality on allograft and recipient survival outcome is not well understood.\n## METHODS\nWe studied allograft and recipient survival by using US Renal Data System records from January 1, 1990, to December 31, 1999, with a follow-up period through December 31, 2000 (n = 92,844; 60% males; 70% white; 23% black). Pretransplantation and predominant RRT modality during the end-stage renal disease (ESRD) period and number and specific combinations of RRT modalities were evaluated.\n## RESULTS\nCompared with hemodialysis (HD), a Cox model showed that peritoneal dialysis (PD) immediately before transplantation predicts a 3% lower risk for graft failure (P < 0.05) and 6% lower risk for recipient death (P < 0.001). When predominant RRT modality was analyzed (modality used for > 50% of the ESRD time), PD (hazard ratio [HR], 0.97; P < 0.05) had a protective effect for graft survival compared with HD. Better recipient survival also was associated with PD (HR, 0.96; P < 0.05). Increased number of RRT modalities during the ESRD course was associated with increased risk for graft failure (HR, 1.04 per additional modality used; P < 0.005) and recipient death (HR, 1.11 per additional modality used; P < 0.001). Any combination or any single modality (except for PD + HD for graft survival and PD + HD and PD + HD + transplantation for recipient survival) had protective effects on graft and recipient survival compared with HD.\n## CONCLUSION\nOur results suggest that compared with PD, HD as an RRT modality immediately before transplantation or as a predominant RRT modality during the ESRD course, used alone or in combination with other RRT modalities, is associated with increased risks for graft failure and recipient death. Increased number of RRT modalities used during the ESRD course is associated with worsening of graft and recipient survival.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Influence of dialysis duration and modality on kidney transplant outcomes.",
        "key_reference_abstract": "## BACKGROUND\nThe influence of pretransplantation dialysis on kidney transplant outcomes has been the subject of longstanding interest. Although increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survivals, analyses of the impact of dialysis modality on kidney allograft outcome have produced conflicting results.\n## OBJECTIVE\nThe objective of this study was to evaluate the influence of dialysis duration and modality on the function and survival of renal allografts.\n## PATIENTS\nWe retrospectively reviewed the clinical data of 421 adults who received first kidney transplantations from cadaveric heart-beating donors performed in our unit from May 1989 to May 2007. Three hundred seventy-four patients (88.8%) were on hemodialysis (HD) prior to kidney transplantation, including 247 patients (58.7%) on treatment for at least 24 months.\n## RESULTS\nPatients with a dialysis duration > or =24 months were significantly older (45.9 vs 42.8 years; P = .013). Renal function at 3, 12, 60, and 96 months was similar between the 2 groups. Longer duration on dialysis was associated with poorer overall graft and patient survivals. No differences were observed in renal function or graft and patient survivals comparing HD or peritoneal dialysis (PD). Multivariate analysis confirmed the lack of correlation between dialysis duration or modality and allograft failure.\n## CONCLUSION\nLonger dialysis duration influenced overall graft and patient survival. However, dialysis modality showed no influence on graft function or survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Impact of pre-transplant dialysis modality on post-transplant diabetes mellitus after kidney transplantation.",
        "key_reference_abstract": "Post-transplant diabetes mellitus (PTDM) is a well-known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre-transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti-diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre-transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p\u2003=\u20030.85). In the multivariate analysis, age (p\u2003<\u20030.001), body mass index (BMI) (p\u2003<\u20030.001), use of tacrolimus (p\u2003=\u20030.002), and rejection episodes (p\u2003<\u20030.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p\u2003=\u20030.004), had lower BMI (p\u2003=\u20030.07), and were less likely to have a history of hepatitis C (p\u2003=\u20030.007) and autosomal dominant polycystic kidney disease (p\u2003=\u20030.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre-transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients.",
        "key_reference_abstract": "## BACKGROUND\nPost-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD).\n## METHODS\nThree hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model.\n## RESULTS\nIn the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 \u00b1 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007).\n## CONCLUSIONS\nTreatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "The role of pretransplant dialysis modality on renal allograft outcome.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe pretransplant dialysis modality might influence renal allograft and patient survival after transplantation. Studies published to date yielded conflicting results.\n## METHODS\nDeceased-donor allograft recipients reported to the 'Collaborative Transplant Study' were analysed, using multivariate Cox regression analysis, considering potential confounders which included pretransplant patient cardiovascular risk evaluation as well as immunological and treatment parameters. Primary end points were all-cause graft survival, death-censored graft survival and patient survival.\n## RESULTS\nIn total, 60,008 recipients were analysed. Patients who were on peritoneal dialysis (PD) (n = 11,664) prior to transplantation demonstrated a 10% lower all-cause mortality (P = 0.014) but similar death-censored graft survival (P = 0.39) as recipients treated with haemodialysis (n = 45,651). This lower all-cause mortality in PD patients was primarily a consequence of a significantly lower rate of cardiovascular death with a functioning graft (P < 0.013) in a subcohort of patients defined as at increased risk.\n## CONCLUSIONS\nPretransplant dialysis modality per se has no significant impact on allograft outcome. Superior all-cause survival of PD patients is primarily due to a lower rate of cardiovascular death in a subcohort of high-risk recipients. This might explain the conflicting results published to date.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Dialysis as a bridge therapy to renal transplantation: comparison of graft outcomes according to mode of dialysis treatment.",
        "key_reference_abstract": "## BACKGROUND\nRenal transplantation is the ideal renal replacement therapy in patients with end-stage renal disease. It was unclear whether a difference in dialysis modality influences outcomes after kidney transplantation. Therefore, we evaluated the influence of dialysis modality.\n## METHODS\nWe compared various clinical and laboratory parameters of 70 peritoneal dialysis (PD) and 180 hemodialysis (HD) patients (n=250), including 91 females and an overall age 36.7\u00b19.7 years who underwent transplantation between 2000 and 2008 to evaluate factors affecting delayed graft function (DGF) and of transplant graft failure.\n## RESULTS\nOverall graft survival was 82% at 3 and 75% at 5 years. Among HD patients, 16% displayed DGF, versus 12% of PD patients. Multivariate analysis showed that factors affecting DGF were: mode of dialysis (relative risk [RR]=1.39, 95% confidence interval (CI): 1.35-1.43; P<.01); parathyroid hormone (RR=0.32, 95% CI: 0.30-0.34, P<.05), C-reative protein (RR=1.03, 95% CI: 0.97-1.09; P<.05), hemoglobin levels (RR=.75, 95% CI: 0.72-0.79; P<.05). At 3 and 5 years follow-up, PD patients' showed fewer graft failures than HD patients (14% vs 20%; P<.05 and 17% vs 28%; P<.05).\n## CONCLUSION\nEarly graft function rates were better for PD than for HD patients. Inflammation and anemia should be carefully investigated and corrected to achieve better graft function.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Association between pre-transplant dialysis modality and patient and graft survival after kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nPrevious studies have found inconsistent associations between pre-transplant dialysis modality and subsequent post-transplant survival. We aimed to examine this relationship using the instrumental variable method and to compare the results with standard Cox regression.\n## METHODS\nWe included 29 088 patients (age >20 years) from 16 European national or regional renal registries who received a first kidney transplant between 1 January 1999 and 31 December 2008 and were on dialysis before transplantation for a period between 90 days and 10 years. Standard multivariable Cox regression examined the association of individually assigned pre-transplant dialysis modality with post-transplant patient and graft survival. To decrease confounding-by-indication through unmeasured factors, we applied the instrumental variable method that used the case-mix adjusted centre percentage of peritoneal dialysis (PD) as predictor variable.\n## RESULTS\nStandard analyses adjusted for age, sex, primary renal disease, donor type, duration of dialysis, year of transplantation and country suggested that PD before transplantation was associated with better patient [hazard ratio, HR (95% CI) = 0.83 (0.76-0.91)] and graft survival (HR (95% CI) 0.90 (0.84-0.96)) when compared with haemodialysis (HD). In contrast, the instrumental variable analysis showed that a 10% increase in the case-mix adjusted centre percentage of patients on PD was neither associated with post-transplant patient survival [HR (95% CI = 1.00 (0.97-1.04)] nor with graft survival [HR (95% CI) = 1.01 (0.98-1.04)].\n## CONCLUSIONS\nThe instrumental variable method failed to confirm the associations found in standard Cox regression between pre-transplant dialysis modality and patient and graft survival after transplantation. The lack of association in instrumental variable analysis may be due to better control of residual confounding.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Dialysis modality and outcomes in kidney transplant recipients.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe influence of pretransplant dialysis modality on post-transplant outcomes is not clear. This study examined associations of pretransplant dialysis modality with post-transplant outcomes in a large national cohort of kidney transplant recipients.\n## DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nLinking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, 12,416 hemodialysis and 2092 peritoneal dialysis patients who underwent first kidney transplantation were identified. Mortality or graft failure and delayed graft function risks were estimated by Cox regression (hazard ratio) and logistic regression (odds ratio), respectively.\n## RESULTS\nRecipients treated with peritoneal dialysis pretransplantation had lower (21.9/1000 patient-years [95% confidence interval: 18.1-26.5]) crude all-cause mortality rate than those recipients treated with hemodialysis (32.8/1000 patient-years [30.8-35.0]). Pretransplant peritoneal dialysis use was associated with 43% lower adjusted all-cause and 66% lower cardiovascular death. Furthermore, pretransplant peritoneal dialysis use was associated with 17% and 36% lower unadjusted death-censored graft failure and delayed graft function risk, respectively. However, after additional adjustment for relevant covariates, pretransplant peritoneal dialysis modality was not a significant predictor of death-censored graft failure delayed graft function, respectively. Similar trends were noted on analyses using a propensity score matched cohort of 2092 pairs of patients.\n## CONCLUSIONS\nCompared with hemodialysis, patients treated with peritoneal dialysis before transplantation had lower mortality but similar graft loss or delayed graft function. Confounding by residual selection bias cannot be ruled out.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes.\n## METHODS\nWe conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012.\n## RESULTS\nIn the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12].\n## CONCLUSION\nPretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome.",
        "key_reference_abstract": "It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 \u00b1 23 vs. 21 \u00b1 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Pre-transplant dialysis modality does not influence short- or long-term outcome in kidney transplant recipients: analysis of paired kidneys from the same deceased donor.",
        "key_reference_abstract": "Previous studies have reported contradictory results regarding the effect of pre-transplant dialysis modality on the outcomes after kidney transplantation (KT). To minimize the confounding effect of donor-related variables, we performed a donor-matched retrospective comparison of 160 patients that received only one modality of pre-transplant dialysis (peritoneal dialysis [PD] and hemodialysis [HD] in 80 patients each) and that subsequently underwent KT at our center between January 1990 and December 2007. Cox regression models were used to evaluate the association between pre-transplant dialysis modality and primary study outcomes (death-censored graft survival and patient survival). To control for imbalances in recipient-related baseline characteristics, we performed additional adjustments for the propensity score (PS) for receiving pre-transplant PD (versus HD). There were no significant differences according to pre-transplant dialysis modality in death-censored graft survival (PS-adjusted hazard ratio [aHR]: 0.65; 95% confidence interval [95% CI]: 0.25-1.68) or patient survival (aHR: 0.58; 95% CI: 0.13-2.68). There were no differences in 10-year graft function or in the incidence of post-transplant complications either, except for a higher risk of lymphocele in patients undergoing PD (odds ratio: 4.31; 95% CI: 1.15-16.21). In conclusion, pre-transplant dialysis modality in KT recipients does not impact short- or long-term graft outcomes or patient survival.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Paired Analysis of Outcomes After Kidney Transplantation in Peritoneal and Hemodialysis Patients.",
        "key_reference_abstract": "## BACKGROUND\nThe impact of dialysis modality before kidney transplantation (hemodialysis or peritoneal dialysis) on outcomes is not clear. In this study we retrospectively analyzed the impact of dialysis modality on posttransplant follow-up.\n## METHODS\nTo minimize donor bias, a paired kidney analysis was applied. One hundred thirty-three pairs of peritoneal dialysis (PD) and hemodialysis (HD) patients were transplanted at our center between 1994 and 2016. Those who received kidneys from the same donor were included in the study. HD patients were significantly older (44 vs 48 years), but the Charlson Comorbidity Index was similar (3.12 vs 3.46) in both groups. The groups did not differ significantly with respect to immunosuppressive protocols and number of mismatches (2.96 vs 2.95).\n## RESULTS\nOne-year patient (98% vs 96%) and graft (90% vs 93%) survival was similar in the PD and HD patient groups. The Kaplan-Meier curves of the patients and graft survival did not differ significantly. Delayed graft function (DGF) and acute rejection (AR) occurred significantly more often in the HD recipients. Graft vessel thrombosis resulting in graft loss occurred in 9 PD (6.7%) and 4 HD (3%) patients (P > .05). Serum creatinine concentration and estimated glomerular filtration rate (using the Modification of Diet in Renal Disease guidelines) showed no difference at 1 month, 1 year, and at final visit. On multivariate analysis, factors significantly associated with graft loss were graft vessel thrombosis, DGF, and graft function 1 month after transplantation. On univariate analysis, age, coronary heart disease, and graft loss were associated with death. Among these factors, only coronary heart disease (model 1) and graft loss were significant predictors of death on multivariate analysis.\n## CONCLUSION\nThe long-term outcome for renal transplantation is similar in patients with PD and HD. These groups differ in some aspects, however, such as susceptibility to vascular thrombosis in PD patients, and to DGF and AR in HD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.",
        "key_reference_abstract": "## OBJECTIVE\nMost patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients.\n## DESIGN\nRetrospective nationwide cohort study.\n## SETTING\nData retrieved from the Taiwan National Health Insurance Research Database.\n## PARTICIPANTS\nThe National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation.\n## OUTCOME MEASURES\nThe pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model.\n## RESULTS\nThere were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival.\n## CONCLUSIONS\nPretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Outcome of patients with hemodialysis or peritoneal dialysis undergoing simultaneous pancreas-kidney transplantation. Comparative study.",
        "key_reference_abstract": "## BACKGROUND\nControversy remains with regard to the higher risk of intra-abdominal infections and lower patient and graft survival when peritoneal dialysis (PD) rather than hemodialysis (HD) is used in simultaneous pancreas-kidney transplantation (SPKT).\n## METHODS\nFrom March 1995 to December 2015, we performed 165 SPKTs. Prior to transplant, patients received hemodialysis (group HD; n\u00a0=\u00a098) or peritoneal dialysis (group PD; n\u00a0=\u00a067). A comparison was made to analyze post-transplant complications and patient, pancreas, and kidney graft survivals.\n## RESULTS\nDonor, pretransplant, and perioperative recipient variables were similar in both groups. Overall rates of infections (69.4% in HD vs 73.1% in PD; P\u00a0=\u00a0.50) and intra-abdominal infections (31.6% in HD vs 35.8 in PD; P\u00a0=\u00a0.57) were similar in both groups. The rates of pancreatitis, hemorrhage or thrombosis of the graft, duodenal graft leak, relaparotomy, transplantectomy, pancreas rejection, and retransplantation were similar in both groups. Patient survival at 1, 3, and 5\u00a0years (95.9%, 93.9%, and 93.9% in HD vs 95.5%, 92.2%, and 90.4% in PD; P\u00a0=\u00a0.54) and pancreas graft survival (83.6%, 78.0%, and 71.8% in HD vs 79.2%, 77.4%, and 71.0% in PD; P\u00a0=\u00a0.8) were similar in both groups. Kidney graft survival was similar in both groups. Pancreas graft thrombosis, rejection, and relaparotomy for intra-abdominal complications were independent predictors of lower pancreas graft survival, but dialysis modality did not influence patient or graft survival.\n## CONCLUSIONS\nPre-SPKT modality of dialysis does not significantly influence overall or intra-abdominal infection and patient, pancreas, or kidney graft survivals.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study.",
        "key_reference_abstract": "Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality \u226560\u00a0days as grouped into \"no RRT\" (n\u00a0=\u00a0136), \"haemodialysis (HD)\" (n\u00a0=\u00a01847), \"peritoneal dialysis (PD)\" (n\u00a0=\u00a0159), and \"HD\u00a0+\u00a0PD\" (n\u00a0=\u00a0135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR\u00a0=\u00a00.707 (0.469-1.064)], and rejection was less frequent [HR\u00a0=\u00a00.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in \"PD\" versus \"HD\" groups. Living donation benefit for allograft function was most pronounced in groups \"no RRT\" and \"PD\". Functional allograft decline (eGFR slope) was lowest for \"PD\". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Impact of pre-transplant dialysis modality on the outcome and health-related quality of life of patients after simultaneous pancreas-kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nSimultaneous pancreas-kidney transplantation (SPKT) profoundly improves the health-related quality of life (HRQoL) of recipients. However, the influence of the pre-transplant dialysis modality on the success of the SPKT and post-transplant HRQoL remains unknown.\n## METHODS\nWe analyzed the surgical outcome, long-term survival, as well as HRQoL of 83 SPKTs that were performed in our hospital between 2000 and 2016. Prior to transplant, 64 patients received hemodialysis (HD) and nineteen patients received peritoneal dialysis (PD). Physical and mental quality of life results from eight basic scales and the physical and mental component summaries (PCS and MCS) were measured using the Short Form 36 (SF-36) survey.\n## RESULTS\nPeri- and postoperative complications, as well as patient and graft survival were similar between the two groups. Both groups showed an improvement of HRQoL in all SF-36 domains after transplantation. Compared with patients who received HD before transplantation, PD patients showed significantly better results in four of the eight SF-36 domains: physical functioning (mean difference HD - PD: -\u200912.4\u2009\u00b1\u20094.9, P\u2009=\u2009<\u20090.01), bodily pain (-\u200914.2\u2009\u00b1\u20096.3, P\u00a0<\u20090.01), general health (-\u20096.3\u2009\u00b1\u20092.8, P\u00a0=\u20090.04), vitality (-\u20096.8\u2009\u00b1\u20092.6, P\u2009=\u20090.04), and PCS (-\u20095.2\u2009\u00b1\u20091.5, P\u00a0<\u20090.01) after SPKT. In the overall study population, graft loss was associated with significant worsening of the HRQoL in all physical components (each P\u2009<\u20090.01).\n## CONCLUSIONS\nThe results of this analysis show that pre-transplant dialysis modality has no influence on the outcome and survival rate after SPKT. Regarding HRQoL, patients receiving PD prior to SPKT seem to have a slight advantage compared with patients with HD before transplantation.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "The Association of Pre-Kidney Transplant Dialysis Modality with de novo Posttransplant Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nHeart failure (HF) after kidney transplantation is a significant but understudied problem. Pretransplant dialysis modality could influence incident HF risk through differing cardiac stressors. However, whether pretransplant dialysis modality is associated with the development of posttransplant HF is unknown.\n## METHODS\nWe used the US Renal Data System to assemble a cohort of 27,701 patients who underwent their first kidney transplant in the USA between the years 2005 and 2012 and who had Medicare fee-for-service coverage for >6 months preceding their transplant date. Patients with any HF diagnosis prior to transplant were excluded. Detailed baseline patient characteristics and comorbidities were abstracted. The outcome of interest was de novo posttransplant HF. Pretransplant dialysis modality was defined as the dialysis modality used at the time of transplant. We conducted time-to-event analyses using Cox regression. Death was treated as a competing risk in the study's primary analysis. Graft failure was included as a time-varying covariate.\n## RESULTS\nAmong eligible patients, 81% were treated with hemodialysis prior to transplant, and hemodialysis patients were more likely to be male, had a shorter dialysis vintage, and had more diabetes and vascular disease diagnoses. When adjusted for all available demographic and clinical data, pretransplant treatment with hemodialysis (vs. peritoneal dialysis) was associated with a 19% increased risk in de novo posttransplant HF, with sub-distribution HR 1.19 (95% CI: 1.09-1.29).\n## CONCLUSIONS\nOur results suggest that choice of pretransplant dialysis modality may impact the development of posttransplant HF.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Factors Influencing Long-Term Patient and Allograft Outcomes in Elderly Kidney Transplant Recipients.",
        "key_reference_abstract": "## INTRODUCTION\nIndividuals aged\u00a0\u226565 years are increasingly prevalent on the waitlist for kidney transplantation, yet evidence on recipient and donor factors that define optimal outcomes in elderly patients after kidney transplantation is scarce.\n## METHODS\nWe used multivariable Cox regression modeling to determine the factors associated with all-cause death, death with a functioning graft, and overall and death-censored graft survival, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry.\n## RESULTS\nA total of 802 kidney transplant recipients aged\u00a0\u226565 years underwent their first transplantation between June 2006 and December 2016. Median age at transplantation was 68 years (interquartile range\u00a0= 66-69 years). The 1-year and 5-year overall patient and graft survivals (95% confidence interval [CI]) were 95.1 (93.5-96.7) and 79.0 (75.1-82.9), and 92.9 (91.1-94.7) and 75.4 (71.3-79.5), respectively. Factors associated with higher risks of all-cause death included prevalent coronary artery disease (adjusted hazard ratio [95% confidence interval]\u00a0= 1.47 [1.03-2.11]), cerebrovascular disease (1.99 [1.26-3.16]), increasing graft ischemic time (1.06 per hour [1.03-1.09]), donor age (1.02 per year [1.01-1.03]), delayed graft function (1.64 [1.13-2.39]), and peritoneal dialysis pretransplantation (1.71 [1.17-2.51]).\n## CONCLUSION\nPrevalent vascular disease and peritoneal dialysis as a pretransplantation dialysis modality are risk factors associated with poorer outcomes in transplant recipients aged\u00a0\u226565 years. Careful selection and evaluation of potential candidates may improve graft and patient outcomes in older patients.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of All-Cause Mortality - All",
        "key_reference_title": "Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.\n## METHODS\nWe analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first.\n## RESULTS\nPatients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.\n## CONCLUSIONS\nIn France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Peritoneal dialysis is not a risk factor for primary vascular graft thrombosis after renal transplantation.",
        "key_reference_abstract": "## OBJECTIVE\nTo find out if patients undergoing peritoneal dialysis (PD) have an increased risk of primary vascular thrombosis of the renal allograft, compared with patients on hemodialysis (HD).\n## DESIGN\nObservational, retrospective cohort study.\n## SETTING\nTertiary care hospital, covering an approximate population of 2,000,000. Extensive use of suboptimal donors for renal transplantation.\n## PATIENTS AND METHODS\nThe study included 827 patients receiving a cadaveric renal transplantation (RTx) in our center between 1988 and 1997 (700 on HD and 127 on PD). We searched for a potential difference in the incidence of graft thrombosis, according to the pretransplant dialysis modality and taking into consideration the main reported risk factors for this complication of RTx.\n## RESULTS\nThe accumulated incidence of primary graft thrombosis was 4.7% in PD patients, and 6.1% in HD patients (NS). Arterial and venous thrombosis were also similar in both groups. Logistic regression analysis demonstrated that extremes of age of the donor, use of the right kidney, protracted cold ischemia, delayed graft function, and transplantation to a hypersensitized recipient independently predicted graft thrombosis. Peritoneal dialysis was not independently associated with the complication under study (adjusted odds ratio HD/PD = 2.5, 95% CI = 0.8-7.7).\n## CONCLUSIONS\nPeritoneal dialysis is not associated with an increased risk of primary vascular thrombosis of the renal allograft.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Dialysis modality and delayed graft function after cadaveric renal transplantation.",
        "key_reference_abstract": "The purpose of this investigation was to compare outcomes in the immediate posttransplant period for hemodialysis (HD) and peritoneal (PD) dialysis patients who received cadaveric renal transplantation. Data were obtained from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation between April 1994 and December 1995. Baseline characteristics were compared between groups, and multivariate logistic regression was performed with outcome measures including urine production in the first 24 h posttransplantation (U24), requirement for dialysis in the first week posttransplant (FWDIAL), and treatment for acute rejection during the initial hospitalization. The odds of oliguria (not producing urine in the first 24 h) were 1.49 (1.28 to 1.74) times higher in HD versus PD patients. After adjustment for other comorbid conditions including age, gender, race, HLA mismatch, time on dialysis, panel-reactive antibodies, and cold and warm ischemia time, the odds of oliguria were 1.60 (1.14 to 2.25) times higher in black HD patients compared with PD patients and 1.29 (1.06 to 1.57) times higher in white HD patients. In a similar manner, after adjustment for significant comorbid conditions, the odds of requiring dialysis in the first week were 1.56 (1.22 to 2.0) times higher in black HD patients versus PD patients and 1.40 (1.21 to 1.60) times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. These results suggest that there is an association between hemodialysis and delayed graft function. Differences in biocompatibility between the two modalities could potentially be responsible.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.",
        "key_reference_abstract": "## BACKGROUND\nRenal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients.\n## METHODS\nRenal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression.\n## RESULTS\nForty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs).\n## CONCLUSIONS\nThe strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis.",
        "key_reference_abstract": "## BACKGROUND\nDelayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF.\n## METHODS\nThe records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed.\n## RESULTS\nDGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01).\n## CONCLUSION\nPD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "A comparison of transplant outcomes in peritoneal and hemodialysis patients.",
        "key_reference_abstract": "## BACKGROUND\nStudies examining the effect of pre-transplant dialysis modality on graft and patient survival after kidney transplantation have produced conflicting results. Therefore, we studied the effects of pre-transplant dialysis modality on outcomes in a large United States cohort.\n## METHODS\nWe compared rates of transplantation between peritoneal dialysis and hemodialysis patients from the years 1995 to 1998 in the United States (N = 252,402) and outcomes after transplantation (N = 22,776), using data from the Centers for Medicare and Medicaid Services.\n## RESULTS\nIn a Cox proportional hazards analysis that was adjusted for multiple patient characteristics, kidney transplantation was 1.39 (95% CI = 1.35 to 1.43) times more likely in peritoneal dialysis vs. hemodialysis patients (P < 0.0001). Over the entire follow-up period, the adjusted risk for death-censored graft failure was 1.15 (1.04 to 1.26) times higher in peritoneal dialysis vs. hemodialysis (P < 0.05), but mortality and overall graft failure rates were not different. Pre-transplant dialysis modality did not affect outcomes for patients who survived with a functioning kidney for at least 3 months. However, in adjusted Cox analyses restricted to the first 3 months, peritoneal dialysis was associated with a 1.23 (1.09 to 1.39) times higher risk for early graft failure (P < 0.001) and a 1.33 (1.16 to 1.53) times higher risk for death-censored graft failure (P < 0.001). Peritoneal dialysis patients, however, were seen to have a lower incidence of delayed graft function. In a smaller sample of patients with data on causes of early graft failure, graft thrombosis was more commonly listed as a cause of graft failure among peritoneal dialysis patients, 41% (64/156), compared to hemodialysis patients, 30% (106/349), P < 0.05.\n## CONCLUSIONS\nKidney transplantation is more frequent in peritoneal dialysis than in hemodialysis patients, and transplantation in peritoneal dialysis patients is more frequently associated with early, but not late, graft failure. Delayed graft function was less common in peritoneal dialysis patients but this potential benefit appears to be offset by other factors which are associated with early graft loss. Additional studies are needed to determine what factors may help understand this early risk of graft failure.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Access to, and outcome of, renal transplantation according to treatment modality of end-stage renal disease in France.",
        "key_reference_abstract": "## BACKGROUND\nAlthough peritoneal dialysis (PD) is recognized as one of the methods of treatment of end-stage renal disease (ESRD), there have been recurrent concerns about the access of patients treated by this modality to kidney transplantation (KTx), as well as reports showing increased complications of KTx in such patients, such as graft thrombosis and infections.\n## METHODS\nThe aim of this study was to provide a comprehensive view of the impact on transplantation of pretransplant modality of treatment of ESRD using a multivariate analysis of the French database. From 1997 to 2000, after exclusion of pediatric patients, multiple transplantations, and living donors, 6420 were patients registered on the waiting list, and 3464 were transplanted.\n## RESULTS\nUsing a Cox proportional hazard analysis, we found a shorter waiting time for PD patients (RR 0.71, P < 0.0001), which became equivalent to hemodialysis (HD) patients when taking into account the transplant center as a variable (RR 1.0, P= 0.95). Concerning graft survival, only preemptive transplantation had a significant impact, being associated to a decreased risk of graft failure (RR 0.46, P= 0.005). Conclusion. Our study supports the concept that the choice of any pretransplant dialysis modality does not influence waiting time for transplant or the results of transplantation.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Impact of pretransplant dialysis on early graft function in pediatric kidney recipients.",
        "key_reference_abstract": "Delayed graft function (DGF) is a frequent complication of kidney transplantation (KT) that may affect both short- and long-term graft outcome. It has been reported that pretransplantation peritoneal dialysis was correlated with a better recovery of graft function than hemodialysis in adult kidney recipients. However, the effect of pretransplantation dialysis mode (PDM) seemed to be unclear on the early outcome of KT in pediatric recipients. In this study, the potential impact of PDM on early graft function was evaluated in 174 pediatric patients who underwent KT by using cadaveric donors. The primary outcome parameter was the time to reach a serum creatinine (SCr) level 50% of the pretransplantation value [T(1/2(SCr))], while DGF was defined as a T(1/2(SCr)) >3 days after KT (n = 40). By stratifying kidney recipients for normal function graft or DGF, this latter group showed a significantly higher body weight (BW) on the day of KT (P = 0.014), body surface area (BSA) (P = 0.005), warm ischemia time (WIT) (P = 0.022), early SCr on the day 1 after KT (P < 0.001), and T(1/2(SCr)) (P < 0.001), whereas lower urine volume (UV) collected in the first 24 h after KT (P < 0.001) and fluid load (P < 0.001) occurred. Univariate exponential correlation that was carried out between T(1/2(SCr)) and all the other variables had shown a better value than the linear correlation for BW (R(2) = 0.28 vs. R(2) = 0.04), BSA (R(2) = 0.29 vs. R(2) = 0.03), and SCr (R(2) = 0.51 vs. R(2) = 0.28). In a multivariate regression analysis performed by entering T(1/2(SCr)) as dependent variable and following a forward stepwise method, cold ischemia time (CIT) (P = 0.027) but not PDM (P = 0.195) reached significance. In a Cox regression analysis carried out with T(1/2(SCr)) as dependent variable, neither CIT nor PDM gained significance. This study suggests that PDM does not affect early graft function in pediatric kidney recipients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival.",
        "key_reference_abstract": "## BACKGROUND\nThe effect of pretransplantation renal replacement therapy (RRT) modality on allograft and recipient survival outcome is not well understood.\n## METHODS\nWe studied allograft and recipient survival by using US Renal Data System records from January 1, 1990, to December 31, 1999, with a follow-up period through December 31, 2000 (n = 92,844; 60% males; 70% white; 23% black). Pretransplantation and predominant RRT modality during the end-stage renal disease (ESRD) period and number and specific combinations of RRT modalities were evaluated.\n## RESULTS\nCompared with hemodialysis (HD), a Cox model showed that peritoneal dialysis (PD) immediately before transplantation predicts a 3% lower risk for graft failure (P < 0.05) and 6% lower risk for recipient death (P < 0.001). When predominant RRT modality was analyzed (modality used for > 50% of the ESRD time), PD (hazard ratio [HR], 0.97; P < 0.05) had a protective effect for graft survival compared with HD. Better recipient survival also was associated with PD (HR, 0.96; P < 0.05). Increased number of RRT modalities during the ESRD course was associated with increased risk for graft failure (HR, 1.04 per additional modality used; P < 0.005) and recipient death (HR, 1.11 per additional modality used; P < 0.001). Any combination or any single modality (except for PD + HD for graft survival and PD + HD and PD + HD + transplantation for recipient survival) had protective effects on graft and recipient survival compared with HD.\n## CONCLUSION\nOur results suggest that compared with PD, HD as an RRT modality immediately before transplantation or as a predominant RRT modality during the ESRD course, used alone or in combination with other RRT modalities, is associated with increased risks for graft failure and recipient death. Increased number of RRT modalities used during the ESRD course is associated with worsening of graft and recipient survival.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Influence of dialysis duration and modality on kidney transplant outcomes.",
        "key_reference_abstract": "## BACKGROUND\nThe influence of pretransplantation dialysis on kidney transplant outcomes has been the subject of longstanding interest. Although increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survivals, analyses of the impact of dialysis modality on kidney allograft outcome have produced conflicting results.\n## OBJECTIVE\nThe objective of this study was to evaluate the influence of dialysis duration and modality on the function and survival of renal allografts.\n## PATIENTS\nWe retrospectively reviewed the clinical data of 421 adults who received first kidney transplantations from cadaveric heart-beating donors performed in our unit from May 1989 to May 2007. Three hundred seventy-four patients (88.8%) were on hemodialysis (HD) prior to kidney transplantation, including 247 patients (58.7%) on treatment for at least 24 months.\n## RESULTS\nPatients with a dialysis duration > or =24 months were significantly older (45.9 vs 42.8 years; P = .013). Renal function at 3, 12, 60, and 96 months was similar between the 2 groups. Longer duration on dialysis was associated with poorer overall graft and patient survivals. No differences were observed in renal function or graft and patient survivals comparing HD or peritoneal dialysis (PD). Multivariate analysis confirmed the lack of correlation between dialysis duration or modality and allograft failure.\n## CONCLUSION\nLonger dialysis duration influenced overall graft and patient survival. However, dialysis modality showed no influence on graft function or survival.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Impact of pre-transplant dialysis modality on post-transplant diabetes mellitus after kidney transplantation.",
        "key_reference_abstract": "Post-transplant diabetes mellitus (PTDM) is a well-known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre-transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti-diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre-transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p\u2003=\u20030.85). In the multivariate analysis, age (p\u2003<\u20030.001), body mass index (BMI) (p\u2003<\u20030.001), use of tacrolimus (p\u2003=\u20030.002), and rejection episodes (p\u2003<\u20030.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p\u2003=\u20030.004), had lower BMI (p\u2003=\u20030.07), and were less likely to have a history of hepatitis C (p\u2003=\u20030.007) and autosomal dominant polycystic kidney disease (p\u2003=\u20030.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre-transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients.",
        "key_reference_abstract": "## BACKGROUND\nPost-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD).\n## METHODS\nThree hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model.\n## RESULTS\nIn the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 \u00b1 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007).\n## CONCLUSIONS\nTreatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "The role of pretransplant dialysis modality on renal allograft outcome.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe pretransplant dialysis modality might influence renal allograft and patient survival after transplantation. Studies published to date yielded conflicting results.\n## METHODS\nDeceased-donor allograft recipients reported to the 'Collaborative Transplant Study' were analysed, using multivariate Cox regression analysis, considering potential confounders which included pretransplant patient cardiovascular risk evaluation as well as immunological and treatment parameters. Primary end points were all-cause graft survival, death-censored graft survival and patient survival.\n## RESULTS\nIn total, 60,008 recipients were analysed. Patients who were on peritoneal dialysis (PD) (n = 11,664) prior to transplantation demonstrated a 10% lower all-cause mortality (P = 0.014) but similar death-censored graft survival (P = 0.39) as recipients treated with haemodialysis (n = 45,651). This lower all-cause mortality in PD patients was primarily a consequence of a significantly lower rate of cardiovascular death with a functioning graft (P < 0.013) in a subcohort of patients defined as at increased risk.\n## CONCLUSIONS\nPretransplant dialysis modality per se has no significant impact on allograft outcome. Superior all-cause survival of PD patients is primarily due to a lower rate of cardiovascular death in a subcohort of high-risk recipients. This might explain the conflicting results published to date.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Dialysis as a bridge therapy to renal transplantation: comparison of graft outcomes according to mode of dialysis treatment.",
        "key_reference_abstract": "## BACKGROUND\nRenal transplantation is the ideal renal replacement therapy in patients with end-stage renal disease. It was unclear whether a difference in dialysis modality influences outcomes after kidney transplantation. Therefore, we evaluated the influence of dialysis modality.\n## METHODS\nWe compared various clinical and laboratory parameters of 70 peritoneal dialysis (PD) and 180 hemodialysis (HD) patients (n=250), including 91 females and an overall age 36.7\u00b19.7 years who underwent transplantation between 2000 and 2008 to evaluate factors affecting delayed graft function (DGF) and of transplant graft failure.\n## RESULTS\nOverall graft survival was 82% at 3 and 75% at 5 years. Among HD patients, 16% displayed DGF, versus 12% of PD patients. Multivariate analysis showed that factors affecting DGF were: mode of dialysis (relative risk [RR]=1.39, 95% confidence interval (CI): 1.35-1.43; P<.01); parathyroid hormone (RR=0.32, 95% CI: 0.30-0.34, P<.05), C-reative protein (RR=1.03, 95% CI: 0.97-1.09; P<.05), hemoglobin levels (RR=.75, 95% CI: 0.72-0.79; P<.05). At 3 and 5 years follow-up, PD patients' showed fewer graft failures than HD patients (14% vs 20%; P<.05 and 17% vs 28%; P<.05).\n## CONCLUSION\nEarly graft function rates were better for PD than for HD patients. Inflammation and anemia should be carefully investigated and corrected to achieve better graft function.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Association between pre-transplant dialysis modality and patient and graft survival after kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nPrevious studies have found inconsistent associations between pre-transplant dialysis modality and subsequent post-transplant survival. We aimed to examine this relationship using the instrumental variable method and to compare the results with standard Cox regression.\n## METHODS\nWe included 29 088 patients (age >20 years) from 16 European national or regional renal registries who received a first kidney transplant between 1 January 1999 and 31 December 2008 and were on dialysis before transplantation for a period between 90 days and 10 years. Standard multivariable Cox regression examined the association of individually assigned pre-transplant dialysis modality with post-transplant patient and graft survival. To decrease confounding-by-indication through unmeasured factors, we applied the instrumental variable method that used the case-mix adjusted centre percentage of peritoneal dialysis (PD) as predictor variable.\n## RESULTS\nStandard analyses adjusted for age, sex, primary renal disease, donor type, duration of dialysis, year of transplantation and country suggested that PD before transplantation was associated with better patient [hazard ratio, HR (95% CI) = 0.83 (0.76-0.91)] and graft survival (HR (95% CI) 0.90 (0.84-0.96)) when compared with haemodialysis (HD). In contrast, the instrumental variable analysis showed that a 10% increase in the case-mix adjusted centre percentage of patients on PD was neither associated with post-transplant patient survival [HR (95% CI = 1.00 (0.97-1.04)] nor with graft survival [HR (95% CI) = 1.01 (0.98-1.04)].\n## CONCLUSIONS\nThe instrumental variable method failed to confirm the associations found in standard Cox regression between pre-transplant dialysis modality and patient and graft survival after transplantation. The lack of association in instrumental variable analysis may be due to better control of residual confounding.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Dialysis modality and outcomes in kidney transplant recipients.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe influence of pretransplant dialysis modality on post-transplant outcomes is not clear. This study examined associations of pretransplant dialysis modality with post-transplant outcomes in a large national cohort of kidney transplant recipients.\n## DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nLinking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, 12,416 hemodialysis and 2092 peritoneal dialysis patients who underwent first kidney transplantation were identified. Mortality or graft failure and delayed graft function risks were estimated by Cox regression (hazard ratio) and logistic regression (odds ratio), respectively.\n## RESULTS\nRecipients treated with peritoneal dialysis pretransplantation had lower (21.9/1000 patient-years [95% confidence interval: 18.1-26.5]) crude all-cause mortality rate than those recipients treated with hemodialysis (32.8/1000 patient-years [30.8-35.0]). Pretransplant peritoneal dialysis use was associated with 43% lower adjusted all-cause and 66% lower cardiovascular death. Furthermore, pretransplant peritoneal dialysis use was associated with 17% and 36% lower unadjusted death-censored graft failure and delayed graft function risk, respectively. However, after additional adjustment for relevant covariates, pretransplant peritoneal dialysis modality was not a significant predictor of death-censored graft failure delayed graft function, respectively. Similar trends were noted on analyses using a propensity score matched cohort of 2092 pairs of patients.\n## CONCLUSIONS\nCompared with hemodialysis, patients treated with peritoneal dialysis before transplantation had lower mortality but similar graft loss or delayed graft function. Confounding by residual selection bias cannot be ruled out.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes.\n## METHODS\nWe conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012.\n## RESULTS\nIn the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12].\n## CONCLUSION\nPretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome.",
        "key_reference_abstract": "It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 \u00b1 23 vs. 21 \u00b1 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Pre-transplant dialysis modality does not influence short- or long-term outcome in kidney transplant recipients: analysis of paired kidneys from the same deceased donor.",
        "key_reference_abstract": "Previous studies have reported contradictory results regarding the effect of pre-transplant dialysis modality on the outcomes after kidney transplantation (KT). To minimize the confounding effect of donor-related variables, we performed a donor-matched retrospective comparison of 160 patients that received only one modality of pre-transplant dialysis (peritoneal dialysis [PD] and hemodialysis [HD] in 80 patients each) and that subsequently underwent KT at our center between January 1990 and December 2007. Cox regression models were used to evaluate the association between pre-transplant dialysis modality and primary study outcomes (death-censored graft survival and patient survival). To control for imbalances in recipient-related baseline characteristics, we performed additional adjustments for the propensity score (PS) for receiving pre-transplant PD (versus HD). There were no significant differences according to pre-transplant dialysis modality in death-censored graft survival (PS-adjusted hazard ratio [aHR]: 0.65; 95% confidence interval [95% CI]: 0.25-1.68) or patient survival (aHR: 0.58; 95% CI: 0.13-2.68). There were no differences in 10-year graft function or in the incidence of post-transplant complications either, except for a higher risk of lymphocele in patients undergoing PD (odds ratio: 4.31; 95% CI: 1.15-16.21). In conclusion, pre-transplant dialysis modality in KT recipients does not impact short- or long-term graft outcomes or patient survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Paired Analysis of Outcomes After Kidney Transplantation in Peritoneal and Hemodialysis Patients.",
        "key_reference_abstract": "## BACKGROUND\nThe impact of dialysis modality before kidney transplantation (hemodialysis or peritoneal dialysis) on outcomes is not clear. In this study we retrospectively analyzed the impact of dialysis modality on posttransplant follow-up.\n## METHODS\nTo minimize donor bias, a paired kidney analysis was applied. One hundred thirty-three pairs of peritoneal dialysis (PD) and hemodialysis (HD) patients were transplanted at our center between 1994 and 2016. Those who received kidneys from the same donor were included in the study. HD patients were significantly older (44 vs 48 years), but the Charlson Comorbidity Index was similar (3.12 vs 3.46) in both groups. The groups did not differ significantly with respect to immunosuppressive protocols and number of mismatches (2.96 vs 2.95).\n## RESULTS\nOne-year patient (98% vs 96%) and graft (90% vs 93%) survival was similar in the PD and HD patient groups. The Kaplan-Meier curves of the patients and graft survival did not differ significantly. Delayed graft function (DGF) and acute rejection (AR) occurred significantly more often in the HD recipients. Graft vessel thrombosis resulting in graft loss occurred in 9 PD (6.7%) and 4 HD (3%) patients (P > .05). Serum creatinine concentration and estimated glomerular filtration rate (using the Modification of Diet in Renal Disease guidelines) showed no difference at 1 month, 1 year, and at final visit. On multivariate analysis, factors significantly associated with graft loss were graft vessel thrombosis, DGF, and graft function 1 month after transplantation. On univariate analysis, age, coronary heart disease, and graft loss were associated with death. Among these factors, only coronary heart disease (model 1) and graft loss were significant predictors of death on multivariate analysis.\n## CONCLUSION\nThe long-term outcome for renal transplantation is similar in patients with PD and HD. These groups differ in some aspects, however, such as susceptibility to vascular thrombosis in PD patients, and to DGF and AR in HD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.",
        "key_reference_abstract": "## OBJECTIVE\nMost patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients.\n## DESIGN\nRetrospective nationwide cohort study.\n## SETTING\nData retrieved from the Taiwan National Health Insurance Research Database.\n## PARTICIPANTS\nThe National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation.\n## OUTCOME MEASURES\nThe pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model.\n## RESULTS\nThere were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival.\n## CONCLUSIONS\nPretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Outcome of patients with hemodialysis or peritoneal dialysis undergoing simultaneous pancreas-kidney transplantation. Comparative study.",
        "key_reference_abstract": "## BACKGROUND\nControversy remains with regard to the higher risk of intra-abdominal infections and lower patient and graft survival when peritoneal dialysis (PD) rather than hemodialysis (HD) is used in simultaneous pancreas-kidney transplantation (SPKT).\n## METHODS\nFrom March 1995 to December 2015, we performed 165 SPKTs. Prior to transplant, patients received hemodialysis (group HD; n\u00a0=\u00a098) or peritoneal dialysis (group PD; n\u00a0=\u00a067). A comparison was made to analyze post-transplant complications and patient, pancreas, and kidney graft survivals.\n## RESULTS\nDonor, pretransplant, and perioperative recipient variables were similar in both groups. Overall rates of infections (69.4% in HD vs 73.1% in PD; P\u00a0=\u00a0.50) and intra-abdominal infections (31.6% in HD vs 35.8 in PD; P\u00a0=\u00a0.57) were similar in both groups. The rates of pancreatitis, hemorrhage or thrombosis of the graft, duodenal graft leak, relaparotomy, transplantectomy, pancreas rejection, and retransplantation were similar in both groups. Patient survival at 1, 3, and 5\u00a0years (95.9%, 93.9%, and 93.9% in HD vs 95.5%, 92.2%, and 90.4% in PD; P\u00a0=\u00a0.54) and pancreas graft survival (83.6%, 78.0%, and 71.8% in HD vs 79.2%, 77.4%, and 71.0% in PD; P\u00a0=\u00a0.8) were similar in both groups. Kidney graft survival was similar in both groups. Pancreas graft thrombosis, rejection, and relaparotomy for intra-abdominal complications were independent predictors of lower pancreas graft survival, but dialysis modality did not influence patient or graft survival.\n## CONCLUSIONS\nPre-SPKT modality of dialysis does not significantly influence overall or intra-abdominal infection and patient, pancreas, or kidney graft survivals.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study.",
        "key_reference_abstract": "Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality \u226560\u00a0days as grouped into \"no RRT\" (n\u00a0=\u00a0136), \"haemodialysis (HD)\" (n\u00a0=\u00a01847), \"peritoneal dialysis (PD)\" (n\u00a0=\u00a0159), and \"HD\u00a0+\u00a0PD\" (n\u00a0=\u00a0135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR\u00a0=\u00a00.707 (0.469-1.064)], and rejection was less frequent [HR\u00a0=\u00a00.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in \"PD\" versus \"HD\" groups. Living donation benefit for allograft function was most pronounced in groups \"no RRT\" and \"PD\". Functional allograft decline (eGFR slope) was lowest for \"PD\". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Impact of pre-transplant dialysis modality on the outcome and health-related quality of life of patients after simultaneous pancreas-kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nSimultaneous pancreas-kidney transplantation (SPKT) profoundly improves the health-related quality of life (HRQoL) of recipients. However, the influence of the pre-transplant dialysis modality on the success of the SPKT and post-transplant HRQoL remains unknown.\n## METHODS\nWe analyzed the surgical outcome, long-term survival, as well as HRQoL of 83 SPKTs that were performed in our hospital between 2000 and 2016. Prior to transplant, 64 patients received hemodialysis (HD) and nineteen patients received peritoneal dialysis (PD). Physical and mental quality of life results from eight basic scales and the physical and mental component summaries (PCS and MCS) were measured using the Short Form 36 (SF-36) survey.\n## RESULTS\nPeri- and postoperative complications, as well as patient and graft survival were similar between the two groups. Both groups showed an improvement of HRQoL in all SF-36 domains after transplantation. Compared with patients who received HD before transplantation, PD patients showed significantly better results in four of the eight SF-36 domains: physical functioning (mean difference HD - PD: -\u200912.4\u2009\u00b1\u20094.9, P\u2009=\u2009<\u20090.01), bodily pain (-\u200914.2\u2009\u00b1\u20096.3, P\u00a0<\u20090.01), general health (-\u20096.3\u2009\u00b1\u20092.8, P\u00a0=\u20090.04), vitality (-\u20096.8\u2009\u00b1\u20092.6, P\u2009=\u20090.04), and PCS (-\u20095.2\u2009\u00b1\u20091.5, P\u00a0<\u20090.01) after SPKT. In the overall study population, graft loss was associated with significant worsening of the HRQoL in all physical components (each P\u2009<\u20090.01).\n## CONCLUSIONS\nThe results of this analysis show that pre-transplant dialysis modality has no influence on the outcome and survival rate after SPKT. Regarding HRQoL, patients receiving PD prior to SPKT seem to have a slight advantage compared with patients with HD before transplantation.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "The Association of Pre-Kidney Transplant Dialysis Modality with de novo Posttransplant Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nHeart failure (HF) after kidney transplantation is a significant but understudied problem. Pretransplant dialysis modality could influence incident HF risk through differing cardiac stressors. However, whether pretransplant dialysis modality is associated with the development of posttransplant HF is unknown.\n## METHODS\nWe used the US Renal Data System to assemble a cohort of 27,701 patients who underwent their first kidney transplant in the USA between the years 2005 and 2012 and who had Medicare fee-for-service coverage for >6 months preceding their transplant date. Patients with any HF diagnosis prior to transplant were excluded. Detailed baseline patient characteristics and comorbidities were abstracted. The outcome of interest was de novo posttransplant HF. Pretransplant dialysis modality was defined as the dialysis modality used at the time of transplant. We conducted time-to-event analyses using Cox regression. Death was treated as a competing risk in the study's primary analysis. Graft failure was included as a time-varying covariate.\n## RESULTS\nAmong eligible patients, 81% were treated with hemodialysis prior to transplant, and hemodialysis patients were more likely to be male, had a shorter dialysis vintage, and had more diabetes and vascular disease diagnoses. When adjusted for all available demographic and clinical data, pretransplant treatment with hemodialysis (vs. peritoneal dialysis) was associated with a 19% increased risk in de novo posttransplant HF, with sub-distribution HR 1.19 (95% CI: 1.09-1.29).\n## CONCLUSIONS\nOur results suggest that choice of pretransplant dialysis modality may impact the development of posttransplant HF.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Factors Influencing Long-Term Patient and Allograft Outcomes in Elderly Kidney Transplant Recipients.",
        "key_reference_abstract": "## INTRODUCTION\nIndividuals aged\u00a0\u226565 years are increasingly prevalent on the waitlist for kidney transplantation, yet evidence on recipient and donor factors that define optimal outcomes in elderly patients after kidney transplantation is scarce.\n## METHODS\nWe used multivariable Cox regression modeling to determine the factors associated with all-cause death, death with a functioning graft, and overall and death-censored graft survival, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry.\n## RESULTS\nA total of 802 kidney transplant recipients aged\u00a0\u226565 years underwent their first transplantation between June 2006 and December 2016. Median age at transplantation was 68 years (interquartile range\u00a0= 66-69 years). The 1-year and 5-year overall patient and graft survivals (95% confidence interval [CI]) were 95.1 (93.5-96.7) and 79.0 (75.1-82.9), and 92.9 (91.1-94.7) and 75.4 (71.3-79.5), respectively. Factors associated with higher risks of all-cause death included prevalent coronary artery disease (adjusted hazard ratio [95% confidence interval]\u00a0= 1.47 [1.03-2.11]), cerebrovascular disease (1.99 [1.26-3.16]), increasing graft ischemic time (1.06 per hour [1.03-1.09]), donor age (1.02 per year [1.01-1.03]), delayed graft function (1.64 [1.13-2.39]), and peritoneal dialysis pretransplantation (1.71 [1.17-2.51]).\n## CONCLUSION\nPrevalent vascular disease and peritoneal dialysis as a pretransplantation dialysis modality are risk factors associated with poorer outcomes in transplant recipients aged\u00a0\u226565 years. Careful selection and evaluation of potential candidates may improve graft and patient outcomes in older patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Overall graft failure",
        "key_reference_title": "Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.\n## METHODS\nWe analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first.\n## RESULTS\nPatients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.\n## CONCLUSIONS\nIn France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Peritoneal dialysis is not a risk factor for primary vascular graft thrombosis after renal transplantation.",
        "key_reference_abstract": "## OBJECTIVE\nTo find out if patients undergoing peritoneal dialysis (PD) have an increased risk of primary vascular thrombosis of the renal allograft, compared with patients on hemodialysis (HD).\n## DESIGN\nObservational, retrospective cohort study.\n## SETTING\nTertiary care hospital, covering an approximate population of 2,000,000. Extensive use of suboptimal donors for renal transplantation.\n## PATIENTS AND METHODS\nThe study included 827 patients receiving a cadaveric renal transplantation (RTx) in our center between 1988 and 1997 (700 on HD and 127 on PD). We searched for a potential difference in the incidence of graft thrombosis, according to the pretransplant dialysis modality and taking into consideration the main reported risk factors for this complication of RTx.\n## RESULTS\nThe accumulated incidence of primary graft thrombosis was 4.7% in PD patients, and 6.1% in HD patients (NS). Arterial and venous thrombosis were also similar in both groups. Logistic regression analysis demonstrated that extremes of age of the donor, use of the right kidney, protracted cold ischemia, delayed graft function, and transplantation to a hypersensitized recipient independently predicted graft thrombosis. Peritoneal dialysis was not independently associated with the complication under study (adjusted odds ratio HD/PD = 2.5, 95% CI = 0.8-7.7).\n## CONCLUSIONS\nPeritoneal dialysis is not associated with an increased risk of primary vascular thrombosis of the renal allograft.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Dialysis modality and delayed graft function after cadaveric renal transplantation.",
        "key_reference_abstract": "The purpose of this investigation was to compare outcomes in the immediate posttransplant period for hemodialysis (HD) and peritoneal (PD) dialysis patients who received cadaveric renal transplantation. Data were obtained from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation between April 1994 and December 1995. Baseline characteristics were compared between groups, and multivariate logistic regression was performed with outcome measures including urine production in the first 24 h posttransplantation (U24), requirement for dialysis in the first week posttransplant (FWDIAL), and treatment for acute rejection during the initial hospitalization. The odds of oliguria (not producing urine in the first 24 h) were 1.49 (1.28 to 1.74) times higher in HD versus PD patients. After adjustment for other comorbid conditions including age, gender, race, HLA mismatch, time on dialysis, panel-reactive antibodies, and cold and warm ischemia time, the odds of oliguria were 1.60 (1.14 to 2.25) times higher in black HD patients compared with PD patients and 1.29 (1.06 to 1.57) times higher in white HD patients. In a similar manner, after adjustment for significant comorbid conditions, the odds of requiring dialysis in the first week were 1.56 (1.22 to 2.0) times higher in black HD patients versus PD patients and 1.40 (1.21 to 1.60) times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. These results suggest that there is an association between hemodialysis and delayed graft function. Differences in biocompatibility between the two modalities could potentially be responsible.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.",
        "key_reference_abstract": "## BACKGROUND\nRenal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients.\n## METHODS\nRenal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression.\n## RESULTS\nForty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs).\n## CONCLUSIONS\nThe strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis.",
        "key_reference_abstract": "## BACKGROUND\nDelayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF.\n## METHODS\nThe records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed.\n## RESULTS\nDGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01).\n## CONCLUSION\nPD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "A comparison of transplant outcomes in peritoneal and hemodialysis patients.",
        "key_reference_abstract": "## BACKGROUND\nStudies examining the effect of pre-transplant dialysis modality on graft and patient survival after kidney transplantation have produced conflicting results. Therefore, we studied the effects of pre-transplant dialysis modality on outcomes in a large United States cohort.\n## METHODS\nWe compared rates of transplantation between peritoneal dialysis and hemodialysis patients from the years 1995 to 1998 in the United States (N = 252,402) and outcomes after transplantation (N = 22,776), using data from the Centers for Medicare and Medicaid Services.\n## RESULTS\nIn a Cox proportional hazards analysis that was adjusted for multiple patient characteristics, kidney transplantation was 1.39 (95% CI = 1.35 to 1.43) times more likely in peritoneal dialysis vs. hemodialysis patients (P < 0.0001). Over the entire follow-up period, the adjusted risk for death-censored graft failure was 1.15 (1.04 to 1.26) times higher in peritoneal dialysis vs. hemodialysis (P < 0.05), but mortality and overall graft failure rates were not different. Pre-transplant dialysis modality did not affect outcomes for patients who survived with a functioning kidney for at least 3 months. However, in adjusted Cox analyses restricted to the first 3 months, peritoneal dialysis was associated with a 1.23 (1.09 to 1.39) times higher risk for early graft failure (P < 0.001) and a 1.33 (1.16 to 1.53) times higher risk for death-censored graft failure (P < 0.001). Peritoneal dialysis patients, however, were seen to have a lower incidence of delayed graft function. In a smaller sample of patients with data on causes of early graft failure, graft thrombosis was more commonly listed as a cause of graft failure among peritoneal dialysis patients, 41% (64/156), compared to hemodialysis patients, 30% (106/349), P < 0.05.\n## CONCLUSIONS\nKidney transplantation is more frequent in peritoneal dialysis than in hemodialysis patients, and transplantation in peritoneal dialysis patients is more frequently associated with early, but not late, graft failure. Delayed graft function was less common in peritoneal dialysis patients but this potential benefit appears to be offset by other factors which are associated with early graft loss. Additional studies are needed to determine what factors may help understand this early risk of graft failure.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Access to, and outcome of, renal transplantation according to treatment modality of end-stage renal disease in France.",
        "key_reference_abstract": "## BACKGROUND\nAlthough peritoneal dialysis (PD) is recognized as one of the methods of treatment of end-stage renal disease (ESRD), there have been recurrent concerns about the access of patients treated by this modality to kidney transplantation (KTx), as well as reports showing increased complications of KTx in such patients, such as graft thrombosis and infections.\n## METHODS\nThe aim of this study was to provide a comprehensive view of the impact on transplantation of pretransplant modality of treatment of ESRD using a multivariate analysis of the French database. From 1997 to 2000, after exclusion of pediatric patients, multiple transplantations, and living donors, 6420 were patients registered on the waiting list, and 3464 were transplanted.\n## RESULTS\nUsing a Cox proportional hazard analysis, we found a shorter waiting time for PD patients (RR 0.71, P < 0.0001), which became equivalent to hemodialysis (HD) patients when taking into account the transplant center as a variable (RR 1.0, P= 0.95). Concerning graft survival, only preemptive transplantation had a significant impact, being associated to a decreased risk of graft failure (RR 0.46, P= 0.005). Conclusion. Our study supports the concept that the choice of any pretransplant dialysis modality does not influence waiting time for transplant or the results of transplantation.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Impact of pretransplant dialysis on early graft function in pediatric kidney recipients.",
        "key_reference_abstract": "Delayed graft function (DGF) is a frequent complication of kidney transplantation (KT) that may affect both short- and long-term graft outcome. It has been reported that pretransplantation peritoneal dialysis was correlated with a better recovery of graft function than hemodialysis in adult kidney recipients. However, the effect of pretransplantation dialysis mode (PDM) seemed to be unclear on the early outcome of KT in pediatric recipients. In this study, the potential impact of PDM on early graft function was evaluated in 174 pediatric patients who underwent KT by using cadaveric donors. The primary outcome parameter was the time to reach a serum creatinine (SCr) level 50% of the pretransplantation value [T(1/2(SCr))], while DGF was defined as a T(1/2(SCr)) >3 days after KT (n = 40). By stratifying kidney recipients for normal function graft or DGF, this latter group showed a significantly higher body weight (BW) on the day of KT (P = 0.014), body surface area (BSA) (P = 0.005), warm ischemia time (WIT) (P = 0.022), early SCr on the day 1 after KT (P < 0.001), and T(1/2(SCr)) (P < 0.001), whereas lower urine volume (UV) collected in the first 24 h after KT (P < 0.001) and fluid load (P < 0.001) occurred. Univariate exponential correlation that was carried out between T(1/2(SCr)) and all the other variables had shown a better value than the linear correlation for BW (R(2) = 0.28 vs. R(2) = 0.04), BSA (R(2) = 0.29 vs. R(2) = 0.03), and SCr (R(2) = 0.51 vs. R(2) = 0.28). In a multivariate regression analysis performed by entering T(1/2(SCr)) as dependent variable and following a forward stepwise method, cold ischemia time (CIT) (P = 0.027) but not PDM (P = 0.195) reached significance. In a Cox regression analysis carried out with T(1/2(SCr)) as dependent variable, neither CIT nor PDM gained significance. This study suggests that PDM does not affect early graft function in pediatric kidney recipients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival.",
        "key_reference_abstract": "## BACKGROUND\nThe effect of pretransplantation renal replacement therapy (RRT) modality on allograft and recipient survival outcome is not well understood.\n## METHODS\nWe studied allograft and recipient survival by using US Renal Data System records from January 1, 1990, to December 31, 1999, with a follow-up period through December 31, 2000 (n = 92,844; 60% males; 70% white; 23% black). Pretransplantation and predominant RRT modality during the end-stage renal disease (ESRD) period and number and specific combinations of RRT modalities were evaluated.\n## RESULTS\nCompared with hemodialysis (HD), a Cox model showed that peritoneal dialysis (PD) immediately before transplantation predicts a 3% lower risk for graft failure (P < 0.05) and 6% lower risk for recipient death (P < 0.001). When predominant RRT modality was analyzed (modality used for > 50% of the ESRD time), PD (hazard ratio [HR], 0.97; P < 0.05) had a protective effect for graft survival compared with HD. Better recipient survival also was associated with PD (HR, 0.96; P < 0.05). Increased number of RRT modalities during the ESRD course was associated with increased risk for graft failure (HR, 1.04 per additional modality used; P < 0.005) and recipient death (HR, 1.11 per additional modality used; P < 0.001). Any combination or any single modality (except for PD + HD for graft survival and PD + HD and PD + HD + transplantation for recipient survival) had protective effects on graft and recipient survival compared with HD.\n## CONCLUSION\nOur results suggest that compared with PD, HD as an RRT modality immediately before transplantation or as a predominant RRT modality during the ESRD course, used alone or in combination with other RRT modalities, is associated with increased risks for graft failure and recipient death. Increased number of RRT modalities used during the ESRD course is associated with worsening of graft and recipient survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Influence of dialysis duration and modality on kidney transplant outcomes.",
        "key_reference_abstract": "## BACKGROUND\nThe influence of pretransplantation dialysis on kidney transplant outcomes has been the subject of longstanding interest. Although increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survivals, analyses of the impact of dialysis modality on kidney allograft outcome have produced conflicting results.\n## OBJECTIVE\nThe objective of this study was to evaluate the influence of dialysis duration and modality on the function and survival of renal allografts.\n## PATIENTS\nWe retrospectively reviewed the clinical data of 421 adults who received first kidney transplantations from cadaveric heart-beating donors performed in our unit from May 1989 to May 2007. Three hundred seventy-four patients (88.8%) were on hemodialysis (HD) prior to kidney transplantation, including 247 patients (58.7%) on treatment for at least 24 months.\n## RESULTS\nPatients with a dialysis duration > or =24 months were significantly older (45.9 vs 42.8 years; P = .013). Renal function at 3, 12, 60, and 96 months was similar between the 2 groups. Longer duration on dialysis was associated with poorer overall graft and patient survivals. No differences were observed in renal function or graft and patient survivals comparing HD or peritoneal dialysis (PD). Multivariate analysis confirmed the lack of correlation between dialysis duration or modality and allograft failure.\n## CONCLUSION\nLonger dialysis duration influenced overall graft and patient survival. However, dialysis modality showed no influence on graft function or survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Impact of pre-transplant dialysis modality on post-transplant diabetes mellitus after kidney transplantation.",
        "key_reference_abstract": "Post-transplant diabetes mellitus (PTDM) is a well-known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre-transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti-diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre-transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p\u2003=\u20030.85). In the multivariate analysis, age (p\u2003<\u20030.001), body mass index (BMI) (p\u2003<\u20030.001), use of tacrolimus (p\u2003=\u20030.002), and rejection episodes (p\u2003<\u20030.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p\u2003=\u20030.004), had lower BMI (p\u2003=\u20030.07), and were less likely to have a history of hepatitis C (p\u2003=\u20030.007) and autosomal dominant polycystic kidney disease (p\u2003=\u20030.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre-transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients.",
        "key_reference_abstract": "## BACKGROUND\nPost-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD).\n## METHODS\nThree hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model.\n## RESULTS\nIn the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 \u00b1 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007).\n## CONCLUSIONS\nTreatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "The role of pretransplant dialysis modality on renal allograft outcome.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe pretransplant dialysis modality might influence renal allograft and patient survival after transplantation. Studies published to date yielded conflicting results.\n## METHODS\nDeceased-donor allograft recipients reported to the 'Collaborative Transplant Study' were analysed, using multivariate Cox regression analysis, considering potential confounders which included pretransplant patient cardiovascular risk evaluation as well as immunological and treatment parameters. Primary end points were all-cause graft survival, death-censored graft survival and patient survival.\n## RESULTS\nIn total, 60,008 recipients were analysed. Patients who were on peritoneal dialysis (PD) (n = 11,664) prior to transplantation demonstrated a 10% lower all-cause mortality (P = 0.014) but similar death-censored graft survival (P = 0.39) as recipients treated with haemodialysis (n = 45,651). This lower all-cause mortality in PD patients was primarily a consequence of a significantly lower rate of cardiovascular death with a functioning graft (P < 0.013) in a subcohort of patients defined as at increased risk.\n## CONCLUSIONS\nPretransplant dialysis modality per se has no significant impact on allograft outcome. Superior all-cause survival of PD patients is primarily due to a lower rate of cardiovascular death in a subcohort of high-risk recipients. This might explain the conflicting results published to date.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Dialysis as a bridge therapy to renal transplantation: comparison of graft outcomes according to mode of dialysis treatment.",
        "key_reference_abstract": "## BACKGROUND\nRenal transplantation is the ideal renal replacement therapy in patients with end-stage renal disease. It was unclear whether a difference in dialysis modality influences outcomes after kidney transplantation. Therefore, we evaluated the influence of dialysis modality.\n## METHODS\nWe compared various clinical and laboratory parameters of 70 peritoneal dialysis (PD) and 180 hemodialysis (HD) patients (n=250), including 91 females and an overall age 36.7\u00b19.7 years who underwent transplantation between 2000 and 2008 to evaluate factors affecting delayed graft function (DGF) and of transplant graft failure.\n## RESULTS\nOverall graft survival was 82% at 3 and 75% at 5 years. Among HD patients, 16% displayed DGF, versus 12% of PD patients. Multivariate analysis showed that factors affecting DGF were: mode of dialysis (relative risk [RR]=1.39, 95% confidence interval (CI): 1.35-1.43; P<.01); parathyroid hormone (RR=0.32, 95% CI: 0.30-0.34, P<.05), C-reative protein (RR=1.03, 95% CI: 0.97-1.09; P<.05), hemoglobin levels (RR=.75, 95% CI: 0.72-0.79; P<.05). At 3 and 5 years follow-up, PD patients' showed fewer graft failures than HD patients (14% vs 20%; P<.05 and 17% vs 28%; P<.05).\n## CONCLUSION\nEarly graft function rates were better for PD than for HD patients. Inflammation and anemia should be carefully investigated and corrected to achieve better graft function.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Association between pre-transplant dialysis modality and patient and graft survival after kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nPrevious studies have found inconsistent associations between pre-transplant dialysis modality and subsequent post-transplant survival. We aimed to examine this relationship using the instrumental variable method and to compare the results with standard Cox regression.\n## METHODS\nWe included 29 088 patients (age >20 years) from 16 European national or regional renal registries who received a first kidney transplant between 1 January 1999 and 31 December 2008 and were on dialysis before transplantation for a period between 90 days and 10 years. Standard multivariable Cox regression examined the association of individually assigned pre-transplant dialysis modality with post-transplant patient and graft survival. To decrease confounding-by-indication through unmeasured factors, we applied the instrumental variable method that used the case-mix adjusted centre percentage of peritoneal dialysis (PD) as predictor variable.\n## RESULTS\nStandard analyses adjusted for age, sex, primary renal disease, donor type, duration of dialysis, year of transplantation and country suggested that PD before transplantation was associated with better patient [hazard ratio, HR (95% CI) = 0.83 (0.76-0.91)] and graft survival (HR (95% CI) 0.90 (0.84-0.96)) when compared with haemodialysis (HD). In contrast, the instrumental variable analysis showed that a 10% increase in the case-mix adjusted centre percentage of patients on PD was neither associated with post-transplant patient survival [HR (95% CI = 1.00 (0.97-1.04)] nor with graft survival [HR (95% CI) = 1.01 (0.98-1.04)].\n## CONCLUSIONS\nThe instrumental variable method failed to confirm the associations found in standard Cox regression between pre-transplant dialysis modality and patient and graft survival after transplantation. The lack of association in instrumental variable analysis may be due to better control of residual confounding.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Dialysis modality and outcomes in kidney transplant recipients.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe influence of pretransplant dialysis modality on post-transplant outcomes is not clear. This study examined associations of pretransplant dialysis modality with post-transplant outcomes in a large national cohort of kidney transplant recipients.\n## DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nLinking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, 12,416 hemodialysis and 2092 peritoneal dialysis patients who underwent first kidney transplantation were identified. Mortality or graft failure and delayed graft function risks were estimated by Cox regression (hazard ratio) and logistic regression (odds ratio), respectively.\n## RESULTS\nRecipients treated with peritoneal dialysis pretransplantation had lower (21.9/1000 patient-years [95% confidence interval: 18.1-26.5]) crude all-cause mortality rate than those recipients treated with hemodialysis (32.8/1000 patient-years [30.8-35.0]). Pretransplant peritoneal dialysis use was associated with 43% lower adjusted all-cause and 66% lower cardiovascular death. Furthermore, pretransplant peritoneal dialysis use was associated with 17% and 36% lower unadjusted death-censored graft failure and delayed graft function risk, respectively. However, after additional adjustment for relevant covariates, pretransplant peritoneal dialysis modality was not a significant predictor of death-censored graft failure delayed graft function, respectively. Similar trends were noted on analyses using a propensity score matched cohort of 2092 pairs of patients.\n## CONCLUSIONS\nCompared with hemodialysis, patients treated with peritoneal dialysis before transplantation had lower mortality but similar graft loss or delayed graft function. Confounding by residual selection bias cannot be ruled out.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes.\n## METHODS\nWe conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012.\n## RESULTS\nIn the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12].\n## CONCLUSION\nPretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome.",
        "key_reference_abstract": "It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 \u00b1 23 vs. 21 \u00b1 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Pre-transplant dialysis modality does not influence short- or long-term outcome in kidney transplant recipients: analysis of paired kidneys from the same deceased donor.",
        "key_reference_abstract": "Previous studies have reported contradictory results regarding the effect of pre-transplant dialysis modality on the outcomes after kidney transplantation (KT). To minimize the confounding effect of donor-related variables, we performed a donor-matched retrospective comparison of 160 patients that received only one modality of pre-transplant dialysis (peritoneal dialysis [PD] and hemodialysis [HD] in 80 patients each) and that subsequently underwent KT at our center between January 1990 and December 2007. Cox regression models were used to evaluate the association between pre-transplant dialysis modality and primary study outcomes (death-censored graft survival and patient survival). To control for imbalances in recipient-related baseline characteristics, we performed additional adjustments for the propensity score (PS) for receiving pre-transplant PD (versus HD). There were no significant differences according to pre-transplant dialysis modality in death-censored graft survival (PS-adjusted hazard ratio [aHR]: 0.65; 95% confidence interval [95% CI]: 0.25-1.68) or patient survival (aHR: 0.58; 95% CI: 0.13-2.68). There were no differences in 10-year graft function or in the incidence of post-transplant complications either, except for a higher risk of lymphocele in patients undergoing PD (odds ratio: 4.31; 95% CI: 1.15-16.21). In conclusion, pre-transplant dialysis modality in KT recipients does not impact short- or long-term graft outcomes or patient survival.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Paired Analysis of Outcomes After Kidney Transplantation in Peritoneal and Hemodialysis Patients.",
        "key_reference_abstract": "## BACKGROUND\nThe impact of dialysis modality before kidney transplantation (hemodialysis or peritoneal dialysis) on outcomes is not clear. In this study we retrospectively analyzed the impact of dialysis modality on posttransplant follow-up.\n## METHODS\nTo minimize donor bias, a paired kidney analysis was applied. One hundred thirty-three pairs of peritoneal dialysis (PD) and hemodialysis (HD) patients were transplanted at our center between 1994 and 2016. Those who received kidneys from the same donor were included in the study. HD patients were significantly older (44 vs 48 years), but the Charlson Comorbidity Index was similar (3.12 vs 3.46) in both groups. The groups did not differ significantly with respect to immunosuppressive protocols and number of mismatches (2.96 vs 2.95).\n## RESULTS\nOne-year patient (98% vs 96%) and graft (90% vs 93%) survival was similar in the PD and HD patient groups. The Kaplan-Meier curves of the patients and graft survival did not differ significantly. Delayed graft function (DGF) and acute rejection (AR) occurred significantly more often in the HD recipients. Graft vessel thrombosis resulting in graft loss occurred in 9 PD (6.7%) and 4 HD (3%) patients (P > .05). Serum creatinine concentration and estimated glomerular filtration rate (using the Modification of Diet in Renal Disease guidelines) showed no difference at 1 month, 1 year, and at final visit. On multivariate analysis, factors significantly associated with graft loss were graft vessel thrombosis, DGF, and graft function 1 month after transplantation. On univariate analysis, age, coronary heart disease, and graft loss were associated with death. Among these factors, only coronary heart disease (model 1) and graft loss were significant predictors of death on multivariate analysis.\n## CONCLUSION\nThe long-term outcome for renal transplantation is similar in patients with PD and HD. These groups differ in some aspects, however, such as susceptibility to vascular thrombosis in PD patients, and to DGF and AR in HD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.",
        "key_reference_abstract": "## OBJECTIVE\nMost patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients.\n## DESIGN\nRetrospective nationwide cohort study.\n## SETTING\nData retrieved from the Taiwan National Health Insurance Research Database.\n## PARTICIPANTS\nThe National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation.\n## OUTCOME MEASURES\nThe pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model.\n## RESULTS\nThere were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival.\n## CONCLUSIONS\nPretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Outcome of patients with hemodialysis or peritoneal dialysis undergoing simultaneous pancreas-kidney transplantation. Comparative study.",
        "key_reference_abstract": "## BACKGROUND\nControversy remains with regard to the higher risk of intra-abdominal infections and lower patient and graft survival when peritoneal dialysis (PD) rather than hemodialysis (HD) is used in simultaneous pancreas-kidney transplantation (SPKT).\n## METHODS\nFrom March 1995 to December 2015, we performed 165 SPKTs. Prior to transplant, patients received hemodialysis (group HD; n\u00a0=\u00a098) or peritoneal dialysis (group PD; n\u00a0=\u00a067). A comparison was made to analyze post-transplant complications and patient, pancreas, and kidney graft survivals.\n## RESULTS\nDonor, pretransplant, and perioperative recipient variables were similar in both groups. Overall rates of infections (69.4% in HD vs 73.1% in PD; P\u00a0=\u00a0.50) and intra-abdominal infections (31.6% in HD vs 35.8 in PD; P\u00a0=\u00a0.57) were similar in both groups. The rates of pancreatitis, hemorrhage or thrombosis of the graft, duodenal graft leak, relaparotomy, transplantectomy, pancreas rejection, and retransplantation were similar in both groups. Patient survival at 1, 3, and 5\u00a0years (95.9%, 93.9%, and 93.9% in HD vs 95.5%, 92.2%, and 90.4% in PD; P\u00a0=\u00a0.54) and pancreas graft survival (83.6%, 78.0%, and 71.8% in HD vs 79.2%, 77.4%, and 71.0% in PD; P\u00a0=\u00a0.8) were similar in both groups. Kidney graft survival was similar in both groups. Pancreas graft thrombosis, rejection, and relaparotomy for intra-abdominal complications were independent predictors of lower pancreas graft survival, but dialysis modality did not influence patient or graft survival.\n## CONCLUSIONS\nPre-SPKT modality of dialysis does not significantly influence overall or intra-abdominal infection and patient, pancreas, or kidney graft survivals.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study.",
        "key_reference_abstract": "Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality \u226560\u00a0days as grouped into \"no RRT\" (n\u00a0=\u00a0136), \"haemodialysis (HD)\" (n\u00a0=\u00a01847), \"peritoneal dialysis (PD)\" (n\u00a0=\u00a0159), and \"HD\u00a0+\u00a0PD\" (n\u00a0=\u00a0135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR\u00a0=\u00a00.707 (0.469-1.064)], and rejection was less frequent [HR\u00a0=\u00a00.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in \"PD\" versus \"HD\" groups. Living donation benefit for allograft function was most pronounced in groups \"no RRT\" and \"PD\". Functional allograft decline (eGFR slope) was lowest for \"PD\". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Impact of pre-transplant dialysis modality on the outcome and health-related quality of life of patients after simultaneous pancreas-kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nSimultaneous pancreas-kidney transplantation (SPKT) profoundly improves the health-related quality of life (HRQoL) of recipients. However, the influence of the pre-transplant dialysis modality on the success of the SPKT and post-transplant HRQoL remains unknown.\n## METHODS\nWe analyzed the surgical outcome, long-term survival, as well as HRQoL of 83 SPKTs that were performed in our hospital between 2000 and 2016. Prior to transplant, 64 patients received hemodialysis (HD) and nineteen patients received peritoneal dialysis (PD). Physical and mental quality of life results from eight basic scales and the physical and mental component summaries (PCS and MCS) were measured using the Short Form 36 (SF-36) survey.\n## RESULTS\nPeri- and postoperative complications, as well as patient and graft survival were similar between the two groups. Both groups showed an improvement of HRQoL in all SF-36 domains after transplantation. Compared with patients who received HD before transplantation, PD patients showed significantly better results in four of the eight SF-36 domains: physical functioning (mean difference HD - PD: -\u200912.4\u2009\u00b1\u20094.9, P\u2009=\u2009<\u20090.01), bodily pain (-\u200914.2\u2009\u00b1\u20096.3, P\u00a0<\u20090.01), general health (-\u20096.3\u2009\u00b1\u20092.8, P\u00a0=\u20090.04), vitality (-\u20096.8\u2009\u00b1\u20092.6, P\u2009=\u20090.04), and PCS (-\u20095.2\u2009\u00b1\u20091.5, P\u00a0<\u20090.01) after SPKT. In the overall study population, graft loss was associated with significant worsening of the HRQoL in all physical components (each P\u2009<\u20090.01).\n## CONCLUSIONS\nThe results of this analysis show that pre-transplant dialysis modality has no influence on the outcome and survival rate after SPKT. Regarding HRQoL, patients receiving PD prior to SPKT seem to have a slight advantage compared with patients with HD before transplantation.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "The Association of Pre-Kidney Transplant Dialysis Modality with de novo Posttransplant Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nHeart failure (HF) after kidney transplantation is a significant but understudied problem. Pretransplant dialysis modality could influence incident HF risk through differing cardiac stressors. However, whether pretransplant dialysis modality is associated with the development of posttransplant HF is unknown.\n## METHODS\nWe used the US Renal Data System to assemble a cohort of 27,701 patients who underwent their first kidney transplant in the USA between the years 2005 and 2012 and who had Medicare fee-for-service coverage for >6 months preceding their transplant date. Patients with any HF diagnosis prior to transplant were excluded. Detailed baseline patient characteristics and comorbidities were abstracted. The outcome of interest was de novo posttransplant HF. Pretransplant dialysis modality was defined as the dialysis modality used at the time of transplant. We conducted time-to-event analyses using Cox regression. Death was treated as a competing risk in the study's primary analysis. Graft failure was included as a time-varying covariate.\n## RESULTS\nAmong eligible patients, 81% were treated with hemodialysis prior to transplant, and hemodialysis patients were more likely to be male, had a shorter dialysis vintage, and had more diabetes and vascular disease diagnoses. When adjusted for all available demographic and clinical data, pretransplant treatment with hemodialysis (vs. peritoneal dialysis) was associated with a 19% increased risk in de novo posttransplant HF, with sub-distribution HR 1.19 (95% CI: 1.09-1.29).\n## CONCLUSIONS\nOur results suggest that choice of pretransplant dialysis modality may impact the development of posttransplant HF.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Factors Influencing Long-Term Patient and Allograft Outcomes in Elderly Kidney Transplant Recipients.",
        "key_reference_abstract": "## INTRODUCTION\nIndividuals aged\u00a0\u226565 years are increasingly prevalent on the waitlist for kidney transplantation, yet evidence on recipient and donor factors that define optimal outcomes in elderly patients after kidney transplantation is scarce.\n## METHODS\nWe used multivariable Cox regression modeling to determine the factors associated with all-cause death, death with a functioning graft, and overall and death-censored graft survival, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry.\n## RESULTS\nA total of 802 kidney transplant recipients aged\u00a0\u226565 years underwent their first transplantation between June 2006 and December 2016. Median age at transplantation was 68 years (interquartile range\u00a0= 66-69 years). The 1-year and 5-year overall patient and graft survivals (95% confidence interval [CI]) were 95.1 (93.5-96.7) and 79.0 (75.1-82.9), and 92.9 (91.1-94.7) and 75.4 (71.3-79.5), respectively. Factors associated with higher risks of all-cause death included prevalent coronary artery disease (adjusted hazard ratio [95% confidence interval]\u00a0= 1.47 [1.03-2.11]), cerebrovascular disease (1.99 [1.26-3.16]), increasing graft ischemic time (1.06 per hour [1.03-1.09]), donor age (1.02 per year [1.01-1.03]), delayed graft function (1.64 [1.13-2.39]), and peritoneal dialysis pretransplantation (1.71 [1.17-2.51]).\n## CONCLUSION\nPrevalent vascular disease and peritoneal dialysis as a pretransplantation dialysis modality are risk factors associated with poorer outcomes in transplant recipients aged\u00a0\u226565 years. Careful selection and evaluation of potential candidates may improve graft and patient outcomes in older patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Overall Graft Failure and Death-Censored Graft Failure - Death-censored graft failure",
        "key_reference_title": "Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.\n## METHODS\nWe analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first.\n## RESULTS\nPatients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.\n## CONCLUSIONS\nIn France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Peritoneal dialysis is not a risk factor for primary vascular graft thrombosis after renal transplantation.",
        "key_reference_abstract": "## OBJECTIVE\nTo find out if patients undergoing peritoneal dialysis (PD) have an increased risk of primary vascular thrombosis of the renal allograft, compared with patients on hemodialysis (HD).\n## DESIGN\nObservational, retrospective cohort study.\n## SETTING\nTertiary care hospital, covering an approximate population of 2,000,000. Extensive use of suboptimal donors for renal transplantation.\n## PATIENTS AND METHODS\nThe study included 827 patients receiving a cadaveric renal transplantation (RTx) in our center between 1988 and 1997 (700 on HD and 127 on PD). We searched for a potential difference in the incidence of graft thrombosis, according to the pretransplant dialysis modality and taking into consideration the main reported risk factors for this complication of RTx.\n## RESULTS\nThe accumulated incidence of primary graft thrombosis was 4.7% in PD patients, and 6.1% in HD patients (NS). Arterial and venous thrombosis were also similar in both groups. Logistic regression analysis demonstrated that extremes of age of the donor, use of the right kidney, protracted cold ischemia, delayed graft function, and transplantation to a hypersensitized recipient independently predicted graft thrombosis. Peritoneal dialysis was not independently associated with the complication under study (adjusted odds ratio HD/PD = 2.5, 95% CI = 0.8-7.7).\n## CONCLUSIONS\nPeritoneal dialysis is not associated with an increased risk of primary vascular thrombosis of the renal allograft.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Dialysis modality and delayed graft function after cadaveric renal transplantation.",
        "key_reference_abstract": "The purpose of this investigation was to compare outcomes in the immediate posttransplant period for hemodialysis (HD) and peritoneal (PD) dialysis patients who received cadaveric renal transplantation. Data were obtained from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation between April 1994 and December 1995. Baseline characteristics were compared between groups, and multivariate logistic regression was performed with outcome measures including urine production in the first 24 h posttransplantation (U24), requirement for dialysis in the first week posttransplant (FWDIAL), and treatment for acute rejection during the initial hospitalization. The odds of oliguria (not producing urine in the first 24 h) were 1.49 (1.28 to 1.74) times higher in HD versus PD patients. After adjustment for other comorbid conditions including age, gender, race, HLA mismatch, time on dialysis, panel-reactive antibodies, and cold and warm ischemia time, the odds of oliguria were 1.60 (1.14 to 2.25) times higher in black HD patients compared with PD patients and 1.29 (1.06 to 1.57) times higher in white HD patients. In a similar manner, after adjustment for significant comorbid conditions, the odds of requiring dialysis in the first week were 1.56 (1.22 to 2.0) times higher in black HD patients versus PD patients and 1.40 (1.21 to 1.60) times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. These results suggest that there is an association between hemodialysis and delayed graft function. Differences in biocompatibility between the two modalities could potentially be responsible.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.",
        "key_reference_abstract": "## BACKGROUND\nRenal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients.\n## METHODS\nRenal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression.\n## RESULTS\nForty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs).\n## CONCLUSIONS\nThe strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis.",
        "key_reference_abstract": "## BACKGROUND\nDelayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF.\n## METHODS\nThe records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed.\n## RESULTS\nDGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01).\n## CONCLUSION\nPD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "A comparison of transplant outcomes in peritoneal and hemodialysis patients.",
        "key_reference_abstract": "## BACKGROUND\nStudies examining the effect of pre-transplant dialysis modality on graft and patient survival after kidney transplantation have produced conflicting results. Therefore, we studied the effects of pre-transplant dialysis modality on outcomes in a large United States cohort.\n## METHODS\nWe compared rates of transplantation between peritoneal dialysis and hemodialysis patients from the years 1995 to 1998 in the United States (N = 252,402) and outcomes after transplantation (N = 22,776), using data from the Centers for Medicare and Medicaid Services.\n## RESULTS\nIn a Cox proportional hazards analysis that was adjusted for multiple patient characteristics, kidney transplantation was 1.39 (95% CI = 1.35 to 1.43) times more likely in peritoneal dialysis vs. hemodialysis patients (P < 0.0001). Over the entire follow-up period, the adjusted risk for death-censored graft failure was 1.15 (1.04 to 1.26) times higher in peritoneal dialysis vs. hemodialysis (P < 0.05), but mortality and overall graft failure rates were not different. Pre-transplant dialysis modality did not affect outcomes for patients who survived with a functioning kidney for at least 3 months. However, in adjusted Cox analyses restricted to the first 3 months, peritoneal dialysis was associated with a 1.23 (1.09 to 1.39) times higher risk for early graft failure (P < 0.001) and a 1.33 (1.16 to 1.53) times higher risk for death-censored graft failure (P < 0.001). Peritoneal dialysis patients, however, were seen to have a lower incidence of delayed graft function. In a smaller sample of patients with data on causes of early graft failure, graft thrombosis was more commonly listed as a cause of graft failure among peritoneal dialysis patients, 41% (64/156), compared to hemodialysis patients, 30% (106/349), P < 0.05.\n## CONCLUSIONS\nKidney transplantation is more frequent in peritoneal dialysis than in hemodialysis patients, and transplantation in peritoneal dialysis patients is more frequently associated with early, but not late, graft failure. Delayed graft function was less common in peritoneal dialysis patients but this potential benefit appears to be offset by other factors which are associated with early graft loss. Additional studies are needed to determine what factors may help understand this early risk of graft failure.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Access to, and outcome of, renal transplantation according to treatment modality of end-stage renal disease in France.",
        "key_reference_abstract": "## BACKGROUND\nAlthough peritoneal dialysis (PD) is recognized as one of the methods of treatment of end-stage renal disease (ESRD), there have been recurrent concerns about the access of patients treated by this modality to kidney transplantation (KTx), as well as reports showing increased complications of KTx in such patients, such as graft thrombosis and infections.\n## METHODS\nThe aim of this study was to provide a comprehensive view of the impact on transplantation of pretransplant modality of treatment of ESRD using a multivariate analysis of the French database. From 1997 to 2000, after exclusion of pediatric patients, multiple transplantations, and living donors, 6420 were patients registered on the waiting list, and 3464 were transplanted.\n## RESULTS\nUsing a Cox proportional hazard analysis, we found a shorter waiting time for PD patients (RR 0.71, P < 0.0001), which became equivalent to hemodialysis (HD) patients when taking into account the transplant center as a variable (RR 1.0, P= 0.95). Concerning graft survival, only preemptive transplantation had a significant impact, being associated to a decreased risk of graft failure (RR 0.46, P= 0.005). Conclusion. Our study supports the concept that the choice of any pretransplant dialysis modality does not influence waiting time for transplant or the results of transplantation.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Impact of pretransplant dialysis on early graft function in pediatric kidney recipients.",
        "key_reference_abstract": "Delayed graft function (DGF) is a frequent complication of kidney transplantation (KT) that may affect both short- and long-term graft outcome. It has been reported that pretransplantation peritoneal dialysis was correlated with a better recovery of graft function than hemodialysis in adult kidney recipients. However, the effect of pretransplantation dialysis mode (PDM) seemed to be unclear on the early outcome of KT in pediatric recipients. In this study, the potential impact of PDM on early graft function was evaluated in 174 pediatric patients who underwent KT by using cadaveric donors. The primary outcome parameter was the time to reach a serum creatinine (SCr) level 50% of the pretransplantation value [T(1/2(SCr))], while DGF was defined as a T(1/2(SCr)) >3 days after KT (n = 40). By stratifying kidney recipients for normal function graft or DGF, this latter group showed a significantly higher body weight (BW) on the day of KT (P = 0.014), body surface area (BSA) (P = 0.005), warm ischemia time (WIT) (P = 0.022), early SCr on the day 1 after KT (P < 0.001), and T(1/2(SCr)) (P < 0.001), whereas lower urine volume (UV) collected in the first 24 h after KT (P < 0.001) and fluid load (P < 0.001) occurred. Univariate exponential correlation that was carried out between T(1/2(SCr)) and all the other variables had shown a better value than the linear correlation for BW (R(2) = 0.28 vs. R(2) = 0.04), BSA (R(2) = 0.29 vs. R(2) = 0.03), and SCr (R(2) = 0.51 vs. R(2) = 0.28). In a multivariate regression analysis performed by entering T(1/2(SCr)) as dependent variable and following a forward stepwise method, cold ischemia time (CIT) (P = 0.027) but not PDM (P = 0.195) reached significance. In a Cox regression analysis carried out with T(1/2(SCr)) as dependent variable, neither CIT nor PDM gained significance. This study suggests that PDM does not affect early graft function in pediatric kidney recipients.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival.",
        "key_reference_abstract": "## BACKGROUND\nThe effect of pretransplantation renal replacement therapy (RRT) modality on allograft and recipient survival outcome is not well understood.\n## METHODS\nWe studied allograft and recipient survival by using US Renal Data System records from January 1, 1990, to December 31, 1999, with a follow-up period through December 31, 2000 (n = 92,844; 60% males; 70% white; 23% black). Pretransplantation and predominant RRT modality during the end-stage renal disease (ESRD) period and number and specific combinations of RRT modalities were evaluated.\n## RESULTS\nCompared with hemodialysis (HD), a Cox model showed that peritoneal dialysis (PD) immediately before transplantation predicts a 3% lower risk for graft failure (P < 0.05) and 6% lower risk for recipient death (P < 0.001). When predominant RRT modality was analyzed (modality used for > 50% of the ESRD time), PD (hazard ratio [HR], 0.97; P < 0.05) had a protective effect for graft survival compared with HD. Better recipient survival also was associated with PD (HR, 0.96; P < 0.05). Increased number of RRT modalities during the ESRD course was associated with increased risk for graft failure (HR, 1.04 per additional modality used; P < 0.005) and recipient death (HR, 1.11 per additional modality used; P < 0.001). Any combination or any single modality (except for PD + HD for graft survival and PD + HD and PD + HD + transplantation for recipient survival) had protective effects on graft and recipient survival compared with HD.\n## CONCLUSION\nOur results suggest that compared with PD, HD as an RRT modality immediately before transplantation or as a predominant RRT modality during the ESRD course, used alone or in combination with other RRT modalities, is associated with increased risks for graft failure and recipient death. Increased number of RRT modalities used during the ESRD course is associated with worsening of graft and recipient survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Influence of dialysis duration and modality on kidney transplant outcomes.",
        "key_reference_abstract": "## BACKGROUND\nThe influence of pretransplantation dialysis on kidney transplant outcomes has been the subject of longstanding interest. Although increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survivals, analyses of the impact of dialysis modality on kidney allograft outcome have produced conflicting results.\n## OBJECTIVE\nThe objective of this study was to evaluate the influence of dialysis duration and modality on the function and survival of renal allografts.\n## PATIENTS\nWe retrospectively reviewed the clinical data of 421 adults who received first kidney transplantations from cadaveric heart-beating donors performed in our unit from May 1989 to May 2007. Three hundred seventy-four patients (88.8%) were on hemodialysis (HD) prior to kidney transplantation, including 247 patients (58.7%) on treatment for at least 24 months.\n## RESULTS\nPatients with a dialysis duration > or =24 months were significantly older (45.9 vs 42.8 years; P = .013). Renal function at 3, 12, 60, and 96 months was similar between the 2 groups. Longer duration on dialysis was associated with poorer overall graft and patient survivals. No differences were observed in renal function or graft and patient survivals comparing HD or peritoneal dialysis (PD). Multivariate analysis confirmed the lack of correlation between dialysis duration or modality and allograft failure.\n## CONCLUSION\nLonger dialysis duration influenced overall graft and patient survival. However, dialysis modality showed no influence on graft function or survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Impact of pre-transplant dialysis modality on post-transplant diabetes mellitus after kidney transplantation.",
        "key_reference_abstract": "Post-transplant diabetes mellitus (PTDM) is a well-known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre-transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti-diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre-transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p\u2003=\u20030.85). In the multivariate analysis, age (p\u2003<\u20030.001), body mass index (BMI) (p\u2003<\u20030.001), use of tacrolimus (p\u2003=\u20030.002), and rejection episodes (p\u2003<\u20030.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p\u2003=\u20030.004), had lower BMI (p\u2003=\u20030.07), and were less likely to have a history of hepatitis C (p\u2003=\u20030.007) and autosomal dominant polycystic kidney disease (p\u2003=\u20030.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre-transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients.",
        "key_reference_abstract": "## BACKGROUND\nPost-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD).\n## METHODS\nThree hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model.\n## RESULTS\nIn the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 \u00b1 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007).\n## CONCLUSIONS\nTreatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "The role of pretransplant dialysis modality on renal allograft outcome.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe pretransplant dialysis modality might influence renal allograft and patient survival after transplantation. Studies published to date yielded conflicting results.\n## METHODS\nDeceased-donor allograft recipients reported to the 'Collaborative Transplant Study' were analysed, using multivariate Cox regression analysis, considering potential confounders which included pretransplant patient cardiovascular risk evaluation as well as immunological and treatment parameters. Primary end points were all-cause graft survival, death-censored graft survival and patient survival.\n## RESULTS\nIn total, 60,008 recipients were analysed. Patients who were on peritoneal dialysis (PD) (n = 11,664) prior to transplantation demonstrated a 10% lower all-cause mortality (P = 0.014) but similar death-censored graft survival (P = 0.39) as recipients treated with haemodialysis (n = 45,651). This lower all-cause mortality in PD patients was primarily a consequence of a significantly lower rate of cardiovascular death with a functioning graft (P < 0.013) in a subcohort of patients defined as at increased risk.\n## CONCLUSIONS\nPretransplant dialysis modality per se has no significant impact on allograft outcome. Superior all-cause survival of PD patients is primarily due to a lower rate of cardiovascular death in a subcohort of high-risk recipients. This might explain the conflicting results published to date.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Dialysis as a bridge therapy to renal transplantation: comparison of graft outcomes according to mode of dialysis treatment.",
        "key_reference_abstract": "## BACKGROUND\nRenal transplantation is the ideal renal replacement therapy in patients with end-stage renal disease. It was unclear whether a difference in dialysis modality influences outcomes after kidney transplantation. Therefore, we evaluated the influence of dialysis modality.\n## METHODS\nWe compared various clinical and laboratory parameters of 70 peritoneal dialysis (PD) and 180 hemodialysis (HD) patients (n=250), including 91 females and an overall age 36.7\u00b19.7 years who underwent transplantation between 2000 and 2008 to evaluate factors affecting delayed graft function (DGF) and of transplant graft failure.\n## RESULTS\nOverall graft survival was 82% at 3 and 75% at 5 years. Among HD patients, 16% displayed DGF, versus 12% of PD patients. Multivariate analysis showed that factors affecting DGF were: mode of dialysis (relative risk [RR]=1.39, 95% confidence interval (CI): 1.35-1.43; P<.01); parathyroid hormone (RR=0.32, 95% CI: 0.30-0.34, P<.05), C-reative protein (RR=1.03, 95% CI: 0.97-1.09; P<.05), hemoglobin levels (RR=.75, 95% CI: 0.72-0.79; P<.05). At 3 and 5 years follow-up, PD patients' showed fewer graft failures than HD patients (14% vs 20%; P<.05 and 17% vs 28%; P<.05).\n## CONCLUSION\nEarly graft function rates were better for PD than for HD patients. Inflammation and anemia should be carefully investigated and corrected to achieve better graft function.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Association between pre-transplant dialysis modality and patient and graft survival after kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nPrevious studies have found inconsistent associations between pre-transplant dialysis modality and subsequent post-transplant survival. We aimed to examine this relationship using the instrumental variable method and to compare the results with standard Cox regression.\n## METHODS\nWe included 29 088 patients (age >20 years) from 16 European national or regional renal registries who received a first kidney transplant between 1 January 1999 and 31 December 2008 and were on dialysis before transplantation for a period between 90 days and 10 years. Standard multivariable Cox regression examined the association of individually assigned pre-transplant dialysis modality with post-transplant patient and graft survival. To decrease confounding-by-indication through unmeasured factors, we applied the instrumental variable method that used the case-mix adjusted centre percentage of peritoneal dialysis (PD) as predictor variable.\n## RESULTS\nStandard analyses adjusted for age, sex, primary renal disease, donor type, duration of dialysis, year of transplantation and country suggested that PD before transplantation was associated with better patient [hazard ratio, HR (95% CI) = 0.83 (0.76-0.91)] and graft survival (HR (95% CI) 0.90 (0.84-0.96)) when compared with haemodialysis (HD). In contrast, the instrumental variable analysis showed that a 10% increase in the case-mix adjusted centre percentage of patients on PD was neither associated with post-transplant patient survival [HR (95% CI = 1.00 (0.97-1.04)] nor with graft survival [HR (95% CI) = 1.01 (0.98-1.04)].\n## CONCLUSIONS\nThe instrumental variable method failed to confirm the associations found in standard Cox regression between pre-transplant dialysis modality and patient and graft survival after transplantation. The lack of association in instrumental variable analysis may be due to better control of residual confounding.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Dialysis modality and outcomes in kidney transplant recipients.",
        "key_reference_abstract": "## BACKGROUND AND OBJECTIVES\nThe influence of pretransplant dialysis modality on post-transplant outcomes is not clear. This study examined associations of pretransplant dialysis modality with post-transplant outcomes in a large national cohort of kidney transplant recipients.\n## DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nLinking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, 12,416 hemodialysis and 2092 peritoneal dialysis patients who underwent first kidney transplantation were identified. Mortality or graft failure and delayed graft function risks were estimated by Cox regression (hazard ratio) and logistic regression (odds ratio), respectively.\n## RESULTS\nRecipients treated with peritoneal dialysis pretransplantation had lower (21.9/1000 patient-years [95% confidence interval: 18.1-26.5]) crude all-cause mortality rate than those recipients treated with hemodialysis (32.8/1000 patient-years [30.8-35.0]). Pretransplant peritoneal dialysis use was associated with 43% lower adjusted all-cause and 66% lower cardiovascular death. Furthermore, pretransplant peritoneal dialysis use was associated with 17% and 36% lower unadjusted death-censored graft failure and delayed graft function risk, respectively. However, after additional adjustment for relevant covariates, pretransplant peritoneal dialysis modality was not a significant predictor of death-censored graft failure delayed graft function, respectively. Similar trends were noted on analyses using a propensity score matched cohort of 2092 pairs of patients.\n## CONCLUSIONS\nCompared with hemodialysis, patients treated with peritoneal dialysis before transplantation had lower mortality but similar graft loss or delayed graft function. Confounding by residual selection bias cannot be ruled out.",
        "truth": "True"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes.\n## METHODS\nWe conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012.\n## RESULTS\nIn the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12].\n## CONCLUSION\nPretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome.",
        "key_reference_abstract": "It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 \u00b1 23 vs. 21 \u00b1 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Pre-transplant dialysis modality does not influence short- or long-term outcome in kidney transplant recipients: analysis of paired kidneys from the same deceased donor.",
        "key_reference_abstract": "Previous studies have reported contradictory results regarding the effect of pre-transplant dialysis modality on the outcomes after kidney transplantation (KT). To minimize the confounding effect of donor-related variables, we performed a donor-matched retrospective comparison of 160 patients that received only one modality of pre-transplant dialysis (peritoneal dialysis [PD] and hemodialysis [HD] in 80 patients each) and that subsequently underwent KT at our center between January 1990 and December 2007. Cox regression models were used to evaluate the association between pre-transplant dialysis modality and primary study outcomes (death-censored graft survival and patient survival). To control for imbalances in recipient-related baseline characteristics, we performed additional adjustments for the propensity score (PS) for receiving pre-transplant PD (versus HD). There were no significant differences according to pre-transplant dialysis modality in death-censored graft survival (PS-adjusted hazard ratio [aHR]: 0.65; 95% confidence interval [95% CI]: 0.25-1.68) or patient survival (aHR: 0.58; 95% CI: 0.13-2.68). There were no differences in 10-year graft function or in the incidence of post-transplant complications either, except for a higher risk of lymphocele in patients undergoing PD (odds ratio: 4.31; 95% CI: 1.15-16.21). In conclusion, pre-transplant dialysis modality in KT recipients does not impact short- or long-term graft outcomes or patient survival.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Paired Analysis of Outcomes After Kidney Transplantation in Peritoneal and Hemodialysis Patients.",
        "key_reference_abstract": "## BACKGROUND\nThe impact of dialysis modality before kidney transplantation (hemodialysis or peritoneal dialysis) on outcomes is not clear. In this study we retrospectively analyzed the impact of dialysis modality on posttransplant follow-up.\n## METHODS\nTo minimize donor bias, a paired kidney analysis was applied. One hundred thirty-three pairs of peritoneal dialysis (PD) and hemodialysis (HD) patients were transplanted at our center between 1994 and 2016. Those who received kidneys from the same donor were included in the study. HD patients were significantly older (44 vs 48 years), but the Charlson Comorbidity Index was similar (3.12 vs 3.46) in both groups. The groups did not differ significantly with respect to immunosuppressive protocols and number of mismatches (2.96 vs 2.95).\n## RESULTS\nOne-year patient (98% vs 96%) and graft (90% vs 93%) survival was similar in the PD and HD patient groups. The Kaplan-Meier curves of the patients and graft survival did not differ significantly. Delayed graft function (DGF) and acute rejection (AR) occurred significantly more often in the HD recipients. Graft vessel thrombosis resulting in graft loss occurred in 9 PD (6.7%) and 4 HD (3%) patients (P > .05). Serum creatinine concentration and estimated glomerular filtration rate (using the Modification of Diet in Renal Disease guidelines) showed no difference at 1 month, 1 year, and at final visit. On multivariate analysis, factors significantly associated with graft loss were graft vessel thrombosis, DGF, and graft function 1 month after transplantation. On univariate analysis, age, coronary heart disease, and graft loss were associated with death. Among these factors, only coronary heart disease (model 1) and graft loss were significant predictors of death on multivariate analysis.\n## CONCLUSION\nThe long-term outcome for renal transplantation is similar in patients with PD and HD. These groups differ in some aspects, however, such as susceptibility to vascular thrombosis in PD patients, and to DGF and AR in HD patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.",
        "key_reference_abstract": "## OBJECTIVE\nMost patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients.\n## DESIGN\nRetrospective nationwide cohort study.\n## SETTING\nData retrieved from the Taiwan National Health Insurance Research Database.\n## PARTICIPANTS\nThe National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation.\n## OUTCOME MEASURES\nThe pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model.\n## RESULTS\nThere were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival.\n## CONCLUSIONS\nPretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Outcome of patients with hemodialysis or peritoneal dialysis undergoing simultaneous pancreas-kidney transplantation. Comparative study.",
        "key_reference_abstract": "## BACKGROUND\nControversy remains with regard to the higher risk of intra-abdominal infections and lower patient and graft survival when peritoneal dialysis (PD) rather than hemodialysis (HD) is used in simultaneous pancreas-kidney transplantation (SPKT).\n## METHODS\nFrom March 1995 to December 2015, we performed 165 SPKTs. Prior to transplant, patients received hemodialysis (group HD; n\u00a0=\u00a098) or peritoneal dialysis (group PD; n\u00a0=\u00a067). A comparison was made to analyze post-transplant complications and patient, pancreas, and kidney graft survivals.\n## RESULTS\nDonor, pretransplant, and perioperative recipient variables were similar in both groups. Overall rates of infections (69.4% in HD vs 73.1% in PD; P\u00a0=\u00a0.50) and intra-abdominal infections (31.6% in HD vs 35.8 in PD; P\u00a0=\u00a0.57) were similar in both groups. The rates of pancreatitis, hemorrhage or thrombosis of the graft, duodenal graft leak, relaparotomy, transplantectomy, pancreas rejection, and retransplantation were similar in both groups. Patient survival at 1, 3, and 5\u00a0years (95.9%, 93.9%, and 93.9% in HD vs 95.5%, 92.2%, and 90.4% in PD; P\u00a0=\u00a0.54) and pancreas graft survival (83.6%, 78.0%, and 71.8% in HD vs 79.2%, 77.4%, and 71.0% in PD; P\u00a0=\u00a0.8) were similar in both groups. Kidney graft survival was similar in both groups. Pancreas graft thrombosis, rejection, and relaparotomy for intra-abdominal complications were independent predictors of lower pancreas graft survival, but dialysis modality did not influence patient or graft survival.\n## CONCLUSIONS\nPre-SPKT modality of dialysis does not significantly influence overall or intra-abdominal infection and patient, pancreas, or kidney graft survivals.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study.",
        "key_reference_abstract": "Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality \u226560\u00a0days as grouped into \"no RRT\" (n\u00a0=\u00a0136), \"haemodialysis (HD)\" (n\u00a0=\u00a01847), \"peritoneal dialysis (PD)\" (n\u00a0=\u00a0159), and \"HD\u00a0+\u00a0PD\" (n\u00a0=\u00a0135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR\u00a0=\u00a00.707 (0.469-1.064)], and rejection was less frequent [HR\u00a0=\u00a00.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in \"PD\" versus \"HD\" groups. Living donation benefit for allograft function was most pronounced in groups \"no RRT\" and \"PD\". Functional allograft decline (eGFR slope) was lowest for \"PD\". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Impact of pre-transplant dialysis modality on the outcome and health-related quality of life of patients after simultaneous pancreas-kidney transplantation.",
        "key_reference_abstract": "## BACKGROUND\nSimultaneous pancreas-kidney transplantation (SPKT) profoundly improves the health-related quality of life (HRQoL) of recipients. However, the influence of the pre-transplant dialysis modality on the success of the SPKT and post-transplant HRQoL remains unknown.\n## METHODS\nWe analyzed the surgical outcome, long-term survival, as well as HRQoL of 83 SPKTs that were performed in our hospital between 2000 and 2016. Prior to transplant, 64 patients received hemodialysis (HD) and nineteen patients received peritoneal dialysis (PD). Physical and mental quality of life results from eight basic scales and the physical and mental component summaries (PCS and MCS) were measured using the Short Form 36 (SF-36) survey.\n## RESULTS\nPeri- and postoperative complications, as well as patient and graft survival were similar between the two groups. Both groups showed an improvement of HRQoL in all SF-36 domains after transplantation. Compared with patients who received HD before transplantation, PD patients showed significantly better results in four of the eight SF-36 domains: physical functioning (mean difference HD - PD: -\u200912.4\u2009\u00b1\u20094.9, P\u2009=\u2009<\u20090.01), bodily pain (-\u200914.2\u2009\u00b1\u20096.3, P\u00a0<\u20090.01), general health (-\u20096.3\u2009\u00b1\u20092.8, P\u00a0=\u20090.04), vitality (-\u20096.8\u2009\u00b1\u20092.6, P\u2009=\u20090.04), and PCS (-\u20095.2\u2009\u00b1\u20091.5, P\u00a0<\u20090.01) after SPKT. In the overall study population, graft loss was associated with significant worsening of the HRQoL in all physical components (each P\u2009<\u20090.01).\n## CONCLUSIONS\nThe results of this analysis show that pre-transplant dialysis modality has no influence on the outcome and survival rate after SPKT. Regarding HRQoL, patients receiving PD prior to SPKT seem to have a slight advantage compared with patients with HD before transplantation.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "The Association of Pre-Kidney Transplant Dialysis Modality with de novo Posttransplant Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nHeart failure (HF) after kidney transplantation is a significant but understudied problem. Pretransplant dialysis modality could influence incident HF risk through differing cardiac stressors. However, whether pretransplant dialysis modality is associated with the development of posttransplant HF is unknown.\n## METHODS\nWe used the US Renal Data System to assemble a cohort of 27,701 patients who underwent their first kidney transplant in the USA between the years 2005 and 2012 and who had Medicare fee-for-service coverage for >6 months preceding their transplant date. Patients with any HF diagnosis prior to transplant were excluded. Detailed baseline patient characteristics and comorbidities were abstracted. The outcome of interest was de novo posttransplant HF. Pretransplant dialysis modality was defined as the dialysis modality used at the time of transplant. We conducted time-to-event analyses using Cox regression. Death was treated as a competing risk in the study's primary analysis. Graft failure was included as a time-varying covariate.\n## RESULTS\nAmong eligible patients, 81% were treated with hemodialysis prior to transplant, and hemodialysis patients were more likely to be male, had a shorter dialysis vintage, and had more diabetes and vascular disease diagnoses. When adjusted for all available demographic and clinical data, pretransplant treatment with hemodialysis (vs. peritoneal dialysis) was associated with a 19% increased risk in de novo posttransplant HF, with sub-distribution HR 1.19 (95% CI: 1.09-1.29).\n## CONCLUSIONS\nOur results suggest that choice of pretransplant dialysis modality may impact the development of posttransplant HF.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Factors Influencing Long-Term Patient and Allograft Outcomes in Elderly Kidney Transplant Recipients.",
        "key_reference_abstract": "## INTRODUCTION\nIndividuals aged\u00a0\u226565 years are increasingly prevalent on the waitlist for kidney transplantation, yet evidence on recipient and donor factors that define optimal outcomes in elderly patients after kidney transplantation is scarce.\n## METHODS\nWe used multivariable Cox regression modeling to determine the factors associated with all-cause death, death with a functioning graft, and overall and death-censored graft survival, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry.\n## RESULTS\nA total of 802 kidney transplant recipients aged\u00a0\u226565 years underwent their first transplantation between June 2006 and December 2016. Median age at transplantation was 68 years (interquartile range\u00a0= 66-69 years). The 1-year and 5-year overall patient and graft survivals (95% confidence interval [CI]) were 95.1 (93.5-96.7) and 79.0 (75.1-82.9), and 92.9 (91.1-94.7) and 75.4 (71.3-79.5), respectively. Factors associated with higher risks of all-cause death included prevalent coronary artery disease (adjusted hazard ratio [95% confidence interval]\u00a0= 1.47 [1.03-2.11]), cerebrovascular disease (1.99 [1.26-3.16]), increasing graft ischemic time (1.06 per hour [1.03-1.09]), donor age (1.02 per year [1.01-1.03]), delayed graft function (1.64 [1.13-2.39]), and peritoneal dialysis pretransplantation (1.71 [1.17-2.51]).\n## CONCLUSION\nPrevalent vascular disease and peritoneal dialysis as a pretransplantation dialysis modality are risk factors associated with poorer outcomes in transplant recipients aged\u00a0\u226565 years. Careful selection and evaluation of potential candidates may improve graft and patient outcomes in older patients.",
        "truth": "False"
    },
    {
        "pmid": "36264575",
        "meta_analysis_title": "Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What benefits and disadvantages are associated with pretransplant dialysis modalities for posttransplant outcomes in patients with end-stage kidney disease?",
        "criteria": "Electronic databases, including MEDLINE, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, were searched from inception to March 18, 2022, without language restrictions (eTable 1 in the Supplement). To identify all relevant articles, we supplemented the search with gray literature from Google Scholar, key scientific nephrology and transplant meetings, and preprint reports. Moreover, the manual search of relevant publications as well as key nephrology and transplant journals was extended to April 1, 2022.",
        "subgroup": "Meta-analysis of Pretransplant Dialysis Modality and the Risk of Delayed Graft Function - All",
        "key_reference_title": "Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.",
        "key_reference_abstract": "## BACKGROUND\nKidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.\n## METHODS\nWe analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first.\n## RESULTS\nPatients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.\n## CONCLUSIONS\nIn France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.",
        "truth": "False"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Validity of the patient health questionnaire-2 (PHQ-2) for the detection of depression in primary care in Colombia.",
        "key_reference_abstract": "## BACKGROUND\nThe PHQ-2 is a screening test for major depressive disorder (MDD) derived from PHQ-9, which has shown to be useful in the detection of cases of clinical significance in previous studies. The psychometric properties of PHQ-2 in the Colombian population are unknown.\n## METHODS\nPHQ-2 were assessed in 243 patients in general medical consultations using the Mini-International Neuropsychiatric Interview (MINI) as the gold standard. Internal consistency, convergent validity and criterion validity were calculated by analyzing the Receptor Operating Characteristics (ROC) and the area under the curve (AUC).\n## RESULTS\nCronbach's alpha and McDonald's omega coefficients were 0.71. Spearman's rho coefficients for correlations with PHQ-9 and HADS-D scores were 0.63 and 0.59 (p<0.01). AUC was 0.89. The optimal cut point was \u22652 with the following indicators: sensitivity 0.87 specificity 0.74; Youden index 0.60; PPV 0.47; NPV 0.95; (LR+) 3.24; (LR-) 0.18 (95% CI 0.09-0.37). Kappa coefficient between PHQ-2 and MINI for depression was .458 and 0.46 for HADS-D.\n## LIMITATIONS\nSince this study was done with people attending hospital, which could has implications for the prevalence of depression, affecting the validity indicators of the instrument.\n## CONCLUSIONS\nPHQ-2 show an acceptable test performance in the context of the study. However, the test could yield a considerable amount of false positives that would require specialized evaluation to establish a reliable diagnosis.",
        "truth": "False"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Psychometric Properties of the Patient Health Questionnaire-9 in Elderly Chilean Primary Care Users.",
        "key_reference_abstract": "Background: This study aimed to assess the measurement properties (reliability, factor structure, and criterion validity) of the Patient Health Questionnaire (PHQ-9) as an instrument for screening major depressive disorder (MDD) in elderly primary care users in Chile. Method: About 582 participants aged between 65 and 80 years were enrolled from primary care centers. They completed the Composite International Diagnostic Interview (CIDI), a survey with sociodemographic characteristics and the PHQ-9. Results: The PHQ-9 revealed an acceptable internal consistency (\u03c9 = 0.79 [95% CI: 0.75-0.80] and \u03b1 = 0.78 [95% CI: 0.75-0.81]); confirmatory factor analysis demonstrated a good fit for both 1- and 2-factor solutions. The chi-square difference test (\u03c72 = 0.61, gl = 1, p = 0.43) and correlation between the somatic and the cognitive-effective latent factors were very high (r = 0.97, p < 0.001), indicating that the 1 factor model was more parsimonious. Utilizing the CIDI as the gold standard, the area under the curve (AUC) was 0.88 (SE = 0.04, 95% CI: 0.84-0.90). The optimal cut-off score of \u2265 6 yielded good sensitivity and specificity for detecting MDD (0.95 and 0.76, respectively). However, considering the clinical utility index, the cut-off score of \u22659 proved to be a more effective marker for discarding cases of MDD. Conclusion: The PHQ-9 has adequate psychometric properties for elderly primary care users. In clinical settings, it showed its greatest utility in ruling out the presence of an MDD, however, its clinical value for identifying possible cases of MDD is limited. In cases above the cut-off point, it is recommended to perform a more thorough evaluation.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Validity of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adult primary care users in Bucaramanga, Colombia.",
        "key_reference_abstract": "The patient health questionnaire-9 (PHQ-9) is one of the most widely used self-report instruments in primary care. There is no criterion validity of the PHQ-9 in Colombia. The objective was to validate the PHQ-9 as a screening tool in primary care. A cross-sectional, scale criterion validity study was performed using as reference criterion the mini neuropsychiatric interview (MINI) in male and female adult users of primary care centres. We calculated the internal consistency and convergent and criterion validity of the PHQ-9 by analysing the receiver operating characteristics (ROC) and the area under the curve (AUC). We analysed 243 participants; 184 (75.7%) were female. The average age was 34.05 (median of 31 and SD = 12.47). Cronbach's \u03b1 was 0.80 and McDonald's \u03c9 was 0.81. Spearman's Rho was 0.64 for HADS-D (P <0.010) and 0.70 for PHQ-2 (P\u00a0<0.010). The AUC was 0.92 (95% CI 0.880-0.963). The optimal cut-off point of PHQ-9 was \u22657: sensitivity of 90.38 (95% CI: 81.41-99.36); specificity of 81.68 (95%\u00a0CI: 75.93-87.42); PPV 57.32 (95% CI: 46.00-68.63); NPV 96.89 (95% CI: 93.90-99.88); Youden index 0.72 (95% CI: 0.62-0.82); LR+ 4.93 (95% CI: 3.61-6.74); LR- 0.12 (95% CI: 0.005-0.270). In sum, the Colombian version of PHQ-9 is a valid and reliable instrument for depression screening in primary care in Bucaramanga, with a cut-off point \u22657.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Psychometric properties of the Patient Health Questionnaire nine-item version (PHQ-9) for use among hospitalized non-psychiatric medical patients.",
        "key_reference_abstract": "Depression is a highly prevalent and disabling condition among the general population, and its prevalence is even higher among patients hospitalized due to medical illnesses. It has been estimated that one out of four patients hospitalized for medical illness has a comorbid major depressive episode (MDE) The presence of depression in a patient hospitalized due to a medical illness worsens the medical prognosis, increases symptom burden, complicates self-care and treatment-adherence, extends the hospitalization stay, and inflates the costs of care and mortality. Taking into account that patients with depression can be effectively treated with medication and psychotherapy, early diagnosis and treatment can significantly reduce this burden . Despite this, almost 50% of patients who suffer comorbid depression when hospitalized for medical conditions do not have the condition detected by clinicians. This is explained, at least in part, by the lack of quick and sensitive diagnostic tools, especially for use in specific languages and cultures. Structured clinical interviews such as the composite international diagnostic interview (CIDI)  or the mini international neuropsychiatric interview (MINI) are the gold standard for diagnosing depression. However, the use of these instruments require administration by trained mental health professionals, are time-consuming and difficult to systematically apply in routine clinical practice. This highlights the need for reliable, valid, and easily applicable self-assessment screening tools to detect depression in patients hospitalized due to a non-psychiatric medical illness. Several self-screening tools are available for screening, tracking and documenting depressive symptoms with minimal clinician time, such as the Patient Health Questionnaire 9 (PHQ-9), the Beck Depression Inventory-II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS). To our knowledge, no studies have compared, at the same time and with the same sample, the psychometric properties of these three self-rated questionaries' with a semi-structured clinical interview in patients hospitalized for non-psychiatric medical illness. To cover this gap, we designed the present study. Our aims are to: (1) compare the operating characteristics of PHQ-9, BDI-II and HADS according to an independent criterion standard for MDE in patients hospitalized due to non-psychiatric medical illness; (2) determine the optimum cut-off scores of these self-rating scales for discriminating between patients with and without MDE in this specific group of patients. The results of this study will provide general practitioners with highly valuable information to choose an assessment tool for depression in this subgroup of patients.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Utility of the PHQ-9 to identify major depressive disorder in adult patients in Spanish primary care centres.",
        "key_reference_abstract": "## BACKGROUND\nThe prevalence of major depressive disorder (MDD) in Spanish primary care (PC) centres is high. However, MDD is frequently underdiagnosed and consequently only some patients receive the appropriate treatment. The present study aims to determine the utility of the Patient Health Questionnaire-9 (PHQ-9) to identify MDD in a subset of PC patients participating in the large PsicAP study.\n## METHODS\nA total of 178 patients completed the full PHQ test, including the depression module (PHQ-9). Also, a Spanish version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was implemented by clinical psychologists that were blinded to the PHQ-9 results. We evaluated the psychometric properties of the PHQ-9 as a screening tool as compared to the SCID-I as a reference standard.\n## RESULTS\nThe psychometric properties of the PHQ-9 for a cut-off value of 10 points were as follows: sensitivity, 0.95; specificity, 0.67. Using a cut-off of 12 points, the values were: sensitivity, 0.84; specificity, 0.78. Finally, using the diagnostic algorithm for depression (DSM-IV criteria), the sensitivity was 0.88 and the specificity 0.80.\n## CONCLUSIONS\nAs a screening instrument, the PHQ-9 performed better with a cut-off value of 12 versus the standard cut-off of 10. However, the best psychometric properties were obtained with the DSM-IV diagnostic algorithm for depression. These findings indicate that the PHQ-9 is a highly satisfactory tool that can be used for screening MDD in the PC setting.\n## TRIAL REGISTRATION\nCurrent Controlled Trials ISRCTN58437086 . Registered 20 May 2013.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "[Psychometric characteristics of the Patient Health Questionnaire (PHQ-9)].",
        "key_reference_abstract": "## BACKGROUND\nSimple and brief questionnaires with adequate psychometric properties are useful for the early detection of depressive disorders.\n## AIM\nTo analyze the psychometric behavior of the Patient Health Questionnaire (PHQ-9) in Chile.\n## MATERIAL AND METHODS\nData were collected from 1,738 adult patients, consulting in primary health care centers. The values obtained in the PHQ-9 were compared with those of the Composite International Diagnostic Interview (CIDI).\n## RESULTS\nThe mean score of PHQ-9 was 4.85 \u00b1 5.57. Internal consistency indices were high. McDonald's \u03c9 coefficient of was 0.90 and Cronbach alpha 0.89. A confirmatory factor analysis showed a good fit of the one-dimensional model. Using a cutoff score of seven determined with the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the instrument were 0.8 and 0.7, when compared with CIDI diagnoses.\n## CONCLUSIONS\nPHQ-9 is a useful instrument for the screening of depressive disorders in primary health care centers in Chile.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Validation and calibration of the patient health questionnaire (PHQ-9) in Argentina.",
        "key_reference_abstract": "## BACKGROUND\nThe Patient Health Questionnaire-9 (PHQ-9) is a brief tool to assess the presence and severity of depressive symptoms. This study aimed to validate and calibrate the PHQ-9 to determine appropriate cut-off points for different degrees of severity of depression in Argentina.\n## METHODS\nWe conducted a cross-sectional study on an intentional sample of adult ambulatory care patients with different degrees of severity of depression. All patients who completed the PHQ-9 were further interviewed by a trained clinician with the Mini International Neuropsychiatric Interview (MINI) and the Beck Depression Inventory-II (BDI-II). Reliability and validity tests, including receiver operating curve analysis, were performed.\n## RESULTS\nOne hundred sixty-nine patients were recruited with a mean age of 47.4\u2009years (SD\u2009=\u200914.8), of whom 102 were females (60.4%). The local PHQ-9 had high internal consistency (Cronbach's alpha\u2009=\u20090.87) and satisfactory convergent validity with the BDI-II scale [Pearson's correlation\u2009=\u20090.88 (p\u00a0<\u20090.01)]. For the diagnosis of Major Depressive Episode (MDE) according to the MINI, a PHQ-9\u2009\u2265\u20098 was the optimal cut-off point found (sensitivity 88.2%, specificity 86.6%, PPV 90.91%). The local version of PHQ-9 showed good ability to discriminate among depression severity categories according to the BDI-II scale. The best cut off points were 6-8 for mild cases, 9-14 for moderate and 15 or more for severe depressive symptoms respectively.\n## CONCLUSIONS\nThe Argentine version of the PHQ-9 questionnaire has shown acceptable validity and reliability for both screening and severity assessment of depressive symptoms.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "The Validity and Reliability of the PHQ-9 and PHQ-2 on Screening for Major Depression in Spanish Speaking Immigrants in Chile: A Cross-Sectional Study.",
        "key_reference_abstract": "## BACKGROUND\nThe study aimed to explore the psychometric properties of two versions of the Patient Health Questionnaires (PHQ-9 and PHQ-2) on screening for Major Depressive Disorder (MDD) among Spanish-speaking Latin American adult immigrants in Santiago, and to explore factors associated with a higher risk of occurrence of MDD among them.\n## METHODS\nA representative sample of 897 Spanish-speaking immigrants completed the PHQ-9. The Composite International Diagnostic Interview (CIDI) was employed to evaluate MDD. Internal consistency and structural validity were evaluated using Cronbach's \u03b1 coefficient and confirmatory factor analysis (CFA). Convergent validity with the 7-item General Anxiety Disorder Scale (GAD-7) was assessed using Spearman's correlations. Sensitivity, specificity, positive predictive values, and area under the receiver operating characteristic (ROC) curve were calculated for different cut-off points. Logistic regression analysis was used to identify factors associated with the risk of MDD.\n## RESULTS\nCronbach's \u03b1 coefficient of the PHQ-9 was 0.90; item-total correlation coefficients ranged from 0.61 to 0.76 and correlation with the GAD-7 was moderate (\n## CONCLUSIONS\nThe PHQ-2 and the PHQ-9 are reliable and valid instruments for use as screeners for MDD among Spanish-speaking populations of Latin America.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Utility of PHQ-2, PHQ-8 and PHQ-9 for detecting major depression in primary health care: a validation study in Spain.",
        "key_reference_abstract": "## BACKGROUND\nPrimary health care (PHC) professionals may play a crucial role in improving early diagnosis of depressive disorders. However, only 50% of cases are detected in PHC. The most widely used screening instrument for major depression is the Patient Health Questionnaire (PHQ), including the two-, eight- and nine-item versions. Surprisingly, there is neither enough evidence about the validity of PHQ in PHC patients in Spain nor indications about how to interpret the total scores. This study aimed to gather validity evidence to support the use of the three PHQ versions to screen for major depression in PHC in Spain. Additionally, the present study provided information for helping professionals to choose the best PHQ version according to the context.\n## METHODS\nThe sample was composed of 2579 participants from 22 Spanish PHC centers participating in the EIRA-3 study. The reliability and validity of the three PHQ versions for Spanish PHC patients were assessed based on responses to the questionnaire.\n## RESULTS\nThe PHQ-8 and PHQ-9 showed high internal consistency. The results obtained confirm the theoretically expected relationship between PHQ results and anxiety, social support and health-related QoL. A single-factor solution was confirmed. Regarding to the level of agreement with the CIDI interview (used as the criterion), our results indicate that the PHQ has a good discrimination power. The optimal cut-off values were: \u2a7e2 for PHQ-2, \u2a7e7 for PHQ-8 and \u2a7e8 for PHQ-9.\n## CONCLUSIONS\nPHQ is a good and valuable tool for detecting major depression in PHC patients in Spain.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Sensitivity",
        "key_reference_title": "Improving detection of depression symptoms in Latino farmworkers: Latino Farmworker Affective Scale.",
        "key_reference_abstract": "Latino farmworkers (LFWs) experience depression at a significant higher rate than non-Latino Whites; yet, research regarding depression-screening instruments in Spanish is scarce. The first author created a depression screener using terms used by LFWs to describe symptoms of depression. This study evaluated the effectiveness of the Latino Farmworker Affective Scale (LFAS-15) in accurately detecting symptoms of depression in this population as compared with the Patient Health Questionnaire (PHQ-9), the Brief Symptom Inventory (BSI-18), and the Center for Epidemiologic Studies Depression Scale (CESD-10) using the DSM structured clinical interview (SCID) as the reference standard. Study results indicated that the LFAS-15, as well as the PHQ-9, and the BSI-18 performed. The data also indicated that the LFAS-15 has good internal consistency, measures primarily one construct (depression), demonstrated convergent validity with the SCID, and has good combined sensitivity and specificity. Recommendations for clinical practice, policy, and research are offered.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Validity of the patient health questionnaire-2 (PHQ-2) for the detection of depression in primary care in Colombia.",
        "key_reference_abstract": "## BACKGROUND\nThe PHQ-2 is a screening test for major depressive disorder (MDD) derived from PHQ-9, which has shown to be useful in the detection of cases of clinical significance in previous studies. The psychometric properties of PHQ-2 in the Colombian population are unknown.\n## METHODS\nPHQ-2 were assessed in 243 patients in general medical consultations using the Mini-International Neuropsychiatric Interview (MINI) as the gold standard. Internal consistency, convergent validity and criterion validity were calculated by analyzing the Receptor Operating Characteristics (ROC) and the area under the curve (AUC).\n## RESULTS\nCronbach's alpha and McDonald's omega coefficients were 0.71. Spearman's rho coefficients for correlations with PHQ-9 and HADS-D scores were 0.63 and 0.59 (p<0.01). AUC was 0.89. The optimal cut point was \u22652 with the following indicators: sensitivity 0.87 specificity 0.74; Youden index 0.60; PPV 0.47; NPV 0.95; (LR+) 3.24; (LR-) 0.18 (95% CI 0.09-0.37). Kappa coefficient between PHQ-2 and MINI for depression was .458 and 0.46 for HADS-D.\n## LIMITATIONS\nSince this study was done with people attending hospital, which could has implications for the prevalence of depression, affecting the validity indicators of the instrument.\n## CONCLUSIONS\nPHQ-2 show an acceptable test performance in the context of the study. However, the test could yield a considerable amount of false positives that would require specialized evaluation to establish a reliable diagnosis.",
        "truth": "False"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Psychometric Properties of the Patient Health Questionnaire-9 in Elderly Chilean Primary Care Users.",
        "key_reference_abstract": "Background: This study aimed to assess the measurement properties (reliability, factor structure, and criterion validity) of the Patient Health Questionnaire (PHQ-9) as an instrument for screening major depressive disorder (MDD) in elderly primary care users in Chile. Method: About 582 participants aged between 65 and 80 years were enrolled from primary care centers. They completed the Composite International Diagnostic Interview (CIDI), a survey with sociodemographic characteristics and the PHQ-9. Results: The PHQ-9 revealed an acceptable internal consistency (\u03c9 = 0.79 [95% CI: 0.75-0.80] and \u03b1 = 0.78 [95% CI: 0.75-0.81]); confirmatory factor analysis demonstrated a good fit for both 1- and 2-factor solutions. The chi-square difference test (\u03c72 = 0.61, gl = 1, p = 0.43) and correlation between the somatic and the cognitive-effective latent factors were very high (r = 0.97, p < 0.001), indicating that the 1 factor model was more parsimonious. Utilizing the CIDI as the gold standard, the area under the curve (AUC) was 0.88 (SE = 0.04, 95% CI: 0.84-0.90). The optimal cut-off score of \u2265 6 yielded good sensitivity and specificity for detecting MDD (0.95 and 0.76, respectively). However, considering the clinical utility index, the cut-off score of \u22659 proved to be a more effective marker for discarding cases of MDD. Conclusion: The PHQ-9 has adequate psychometric properties for elderly primary care users. In clinical settings, it showed its greatest utility in ruling out the presence of an MDD, however, its clinical value for identifying possible cases of MDD is limited. In cases above the cut-off point, it is recommended to perform a more thorough evaluation.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Validity of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adult primary care users in Bucaramanga, Colombia.",
        "key_reference_abstract": "The patient health questionnaire-9 (PHQ-9) is one of the most widely used self-report instruments in primary care. There is no criterion validity of the PHQ-9 in Colombia. The objective was to validate the PHQ-9 as a screening tool in primary care. A cross-sectional, scale criterion validity study was performed using as reference criterion the mini neuropsychiatric interview (MINI) in male and female adult users of primary care centres. We calculated the internal consistency and convergent and criterion validity of the PHQ-9 by analysing the receiver operating characteristics (ROC) and the area under the curve (AUC). We analysed 243 participants; 184 (75.7%) were female. The average age was 34.05 (median of 31 and SD = 12.47). Cronbach's \u03b1 was 0.80 and McDonald's \u03c9 was 0.81. Spearman's Rho was 0.64 for HADS-D (P <0.010) and 0.70 for PHQ-2 (P\u00a0<0.010). The AUC was 0.92 (95% CI 0.880-0.963). The optimal cut-off point of PHQ-9 was \u22657: sensitivity of 90.38 (95% CI: 81.41-99.36); specificity of 81.68 (95%\u00a0CI: 75.93-87.42); PPV 57.32 (95% CI: 46.00-68.63); NPV 96.89 (95% CI: 93.90-99.88); Youden index 0.72 (95% CI: 0.62-0.82); LR+ 4.93 (95% CI: 3.61-6.74); LR- 0.12 (95% CI: 0.005-0.270). In sum, the Colombian version of PHQ-9 is a valid and reliable instrument for depression screening in primary care in Bucaramanga, with a cut-off point \u22657.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Psychometric properties of the Patient Health Questionnaire nine-item version (PHQ-9) for use among hospitalized non-psychiatric medical patients.",
        "key_reference_abstract": "Depression is a highly prevalent and disabling condition among the general population, and its prevalence is even higher among patients hospitalized due to medical illnesses. It has been estimated that one out of four patients hospitalized for medical illness has a comorbid major depressive episode (MDE) The presence of depression in a patient hospitalized due to a medical illness worsens the medical prognosis, increases symptom burden, complicates self-care and treatment-adherence, extends the hospitalization stay, and inflates the costs of care and mortality. Taking into account that patients with depression can be effectively treated with medication and psychotherapy, early diagnosis and treatment can significantly reduce this burden . Despite this, almost 50% of patients who suffer comorbid depression when hospitalized for medical conditions do not have the condition detected by clinicians. This is explained, at least in part, by the lack of quick and sensitive diagnostic tools, especially for use in specific languages and cultures. Structured clinical interviews such as the composite international diagnostic interview (CIDI)  or the mini international neuropsychiatric interview (MINI) are the gold standard for diagnosing depression. However, the use of these instruments require administration by trained mental health professionals, are time-consuming and difficult to systematically apply in routine clinical practice. This highlights the need for reliable, valid, and easily applicable self-assessment screening tools to detect depression in patients hospitalized due to a non-psychiatric medical illness. Several self-screening tools are available for screening, tracking and documenting depressive symptoms with minimal clinician time, such as the Patient Health Questionnaire 9 (PHQ-9), the Beck Depression Inventory-II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS). To our knowledge, no studies have compared, at the same time and with the same sample, the psychometric properties of these three self-rated questionaries' with a semi-structured clinical interview in patients hospitalized for non-psychiatric medical illness. To cover this gap, we designed the present study. Our aims are to: (1) compare the operating characteristics of PHQ-9, BDI-II and HADS according to an independent criterion standard for MDE in patients hospitalized due to non-psychiatric medical illness; (2) determine the optimum cut-off scores of these self-rating scales for discriminating between patients with and without MDE in this specific group of patients. The results of this study will provide general practitioners with highly valuable information to choose an assessment tool for depression in this subgroup of patients.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Utility of the PHQ-9 to identify major depressive disorder in adult patients in Spanish primary care centres.",
        "key_reference_abstract": "## BACKGROUND\nThe prevalence of major depressive disorder (MDD) in Spanish primary care (PC) centres is high. However, MDD is frequently underdiagnosed and consequently only some patients receive the appropriate treatment. The present study aims to determine the utility of the Patient Health Questionnaire-9 (PHQ-9) to identify MDD in a subset of PC patients participating in the large PsicAP study.\n## METHODS\nA total of 178 patients completed the full PHQ test, including the depression module (PHQ-9). Also, a Spanish version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was implemented by clinical psychologists that were blinded to the PHQ-9 results. We evaluated the psychometric properties of the PHQ-9 as a screening tool as compared to the SCID-I as a reference standard.\n## RESULTS\nThe psychometric properties of the PHQ-9 for a cut-off value of 10 points were as follows: sensitivity, 0.95; specificity, 0.67. Using a cut-off of 12 points, the values were: sensitivity, 0.84; specificity, 0.78. Finally, using the diagnostic algorithm for depression (DSM-IV criteria), the sensitivity was 0.88 and the specificity 0.80.\n## CONCLUSIONS\nAs a screening instrument, the PHQ-9 performed better with a cut-off value of 12 versus the standard cut-off of 10. However, the best psychometric properties were obtained with the DSM-IV diagnostic algorithm for depression. These findings indicate that the PHQ-9 is a highly satisfactory tool that can be used for screening MDD in the PC setting.\n## TRIAL REGISTRATION\nCurrent Controlled Trials ISRCTN58437086 . Registered 20 May 2013.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "[Psychometric characteristics of the Patient Health Questionnaire (PHQ-9)].",
        "key_reference_abstract": "## BACKGROUND\nSimple and brief questionnaires with adequate psychometric properties are useful for the early detection of depressive disorders.\n## AIM\nTo analyze the psychometric behavior of the Patient Health Questionnaire (PHQ-9) in Chile.\n## MATERIAL AND METHODS\nData were collected from 1,738 adult patients, consulting in primary health care centers. The values obtained in the PHQ-9 were compared with those of the Composite International Diagnostic Interview (CIDI).\n## RESULTS\nThe mean score of PHQ-9 was 4.85 \u00b1 5.57. Internal consistency indices were high. McDonald's \u03c9 coefficient of was 0.90 and Cronbach alpha 0.89. A confirmatory factor analysis showed a good fit of the one-dimensional model. Using a cutoff score of seven determined with the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the instrument were 0.8 and 0.7, when compared with CIDI diagnoses.\n## CONCLUSIONS\nPHQ-9 is a useful instrument for the screening of depressive disorders in primary health care centers in Chile.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Validation and calibration of the patient health questionnaire (PHQ-9) in Argentina.",
        "key_reference_abstract": "## BACKGROUND\nThe Patient Health Questionnaire-9 (PHQ-9) is a brief tool to assess the presence and severity of depressive symptoms. This study aimed to validate and calibrate the PHQ-9 to determine appropriate cut-off points for different degrees of severity of depression in Argentina.\n## METHODS\nWe conducted a cross-sectional study on an intentional sample of adult ambulatory care patients with different degrees of severity of depression. All patients who completed the PHQ-9 were further interviewed by a trained clinician with the Mini International Neuropsychiatric Interview (MINI) and the Beck Depression Inventory-II (BDI-II). Reliability and validity tests, including receiver operating curve analysis, were performed.\n## RESULTS\nOne hundred sixty-nine patients were recruited with a mean age of 47.4\u2009years (SD\u2009=\u200914.8), of whom 102 were females (60.4%). The local PHQ-9 had high internal consistency (Cronbach's alpha\u2009=\u20090.87) and satisfactory convergent validity with the BDI-II scale [Pearson's correlation\u2009=\u20090.88 (p\u00a0<\u20090.01)]. For the diagnosis of Major Depressive Episode (MDE) according to the MINI, a PHQ-9\u2009\u2265\u20098 was the optimal cut-off point found (sensitivity 88.2%, specificity 86.6%, PPV 90.91%). The local version of PHQ-9 showed good ability to discriminate among depression severity categories according to the BDI-II scale. The best cut off points were 6-8 for mild cases, 9-14 for moderate and 15 or more for severe depressive symptoms respectively.\n## CONCLUSIONS\nThe Argentine version of the PHQ-9 questionnaire has shown acceptable validity and reliability for both screening and severity assessment of depressive symptoms.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "The Validity and Reliability of the PHQ-9 and PHQ-2 on Screening for Major Depression in Spanish Speaking Immigrants in Chile: A Cross-Sectional Study.",
        "key_reference_abstract": "## BACKGROUND\nThe study aimed to explore the psychometric properties of two versions of the Patient Health Questionnaires (PHQ-9 and PHQ-2) on screening for Major Depressive Disorder (MDD) among Spanish-speaking Latin American adult immigrants in Santiago, and to explore factors associated with a higher risk of occurrence of MDD among them.\n## METHODS\nA representative sample of 897 Spanish-speaking immigrants completed the PHQ-9. The Composite International Diagnostic Interview (CIDI) was employed to evaluate MDD. Internal consistency and structural validity were evaluated using Cronbach's \u03b1 coefficient and confirmatory factor analysis (CFA). Convergent validity with the 7-item General Anxiety Disorder Scale (GAD-7) was assessed using Spearman's correlations. Sensitivity, specificity, positive predictive values, and area under the receiver operating characteristic (ROC) curve were calculated for different cut-off points. Logistic regression analysis was used to identify factors associated with the risk of MDD.\n## RESULTS\nCronbach's \u03b1 coefficient of the PHQ-9 was 0.90; item-total correlation coefficients ranged from 0.61 to 0.76 and correlation with the GAD-7 was moderate (\n## CONCLUSIONS\nThe PHQ-2 and the PHQ-9 are reliable and valid instruments for use as screeners for MDD among Spanish-speaking populations of Latin America.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Utility of PHQ-2, PHQ-8 and PHQ-9 for detecting major depression in primary health care: a validation study in Spain.",
        "key_reference_abstract": "## BACKGROUND\nPrimary health care (PHC) professionals may play a crucial role in improving early diagnosis of depressive disorders. However, only 50% of cases are detected in PHC. The most widely used screening instrument for major depression is the Patient Health Questionnaire (PHQ), including the two-, eight- and nine-item versions. Surprisingly, there is neither enough evidence about the validity of PHQ in PHC patients in Spain nor indications about how to interpret the total scores. This study aimed to gather validity evidence to support the use of the three PHQ versions to screen for major depression in PHC in Spain. Additionally, the present study provided information for helping professionals to choose the best PHQ version according to the context.\n## METHODS\nThe sample was composed of 2579 participants from 22 Spanish PHC centers participating in the EIRA-3 study. The reliability and validity of the three PHQ versions for Spanish PHC patients were assessed based on responses to the questionnaire.\n## RESULTS\nThe PHQ-8 and PHQ-9 showed high internal consistency. The results obtained confirm the theoretically expected relationship between PHQ results and anxiety, social support and health-related QoL. A single-factor solution was confirmed. Regarding to the level of agreement with the CIDI interview (used as the criterion), our results indicate that the PHQ has a good discrimination power. The optimal cut-off values were: \u2a7e2 for PHQ-2, \u2a7e7 for PHQ-8 and \u2a7e8 for PHQ-9.\n## CONCLUSIONS\nPHQ is a good and valuable tool for detecting major depression in PHC patients in Spain.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analyses of the Sensitivity and Specificity of the Patient Health Questionnaire 9 by Cutoff Score - Specificity",
        "key_reference_title": "Improving detection of depression symptoms in Latino farmworkers: Latino Farmworker Affective Scale.",
        "key_reference_abstract": "Latino farmworkers (LFWs) experience depression at a significant higher rate than non-Latino Whites; yet, research regarding depression-screening instruments in Spanish is scarce. The first author created a depression screener using terms used by LFWs to describe symptoms of depression. This study evaluated the effectiveness of the Latino Farmworker Affective Scale (LFAS-15) in accurately detecting symptoms of depression in this population as compared with the Patient Health Questionnaire (PHQ-9), the Brief Symptom Inventory (BSI-18), and the Center for Epidemiologic Studies Depression Scale (CESD-10) using the DSM structured clinical interview (SCID) as the reference standard. Study results indicated that the LFAS-15, as well as the PHQ-9, and the BSI-18 performed. The data also indicated that the LFAS-15 has good internal consistency, measures primarily one construct (depression), demonstrated convergent validity with the SCID, and has good combined sensitivity and specificity. Recommendations for clinical practice, policy, and research are offered.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Validity of the patient health questionnaire-2 (PHQ-2) for the detection of depression in primary care in Colombia.",
        "key_reference_abstract": "## BACKGROUND\nThe PHQ-2 is a screening test for major depressive disorder (MDD) derived from PHQ-9, which has shown to be useful in the detection of cases of clinical significance in previous studies. The psychometric properties of PHQ-2 in the Colombian population are unknown.\n## METHODS\nPHQ-2 were assessed in 243 patients in general medical consultations using the Mini-International Neuropsychiatric Interview (MINI) as the gold standard. Internal consistency, convergent validity and criterion validity were calculated by analyzing the Receptor Operating Characteristics (ROC) and the area under the curve (AUC).\n## RESULTS\nCronbach's alpha and McDonald's omega coefficients were 0.71. Spearman's rho coefficients for correlations with PHQ-9 and HADS-D scores were 0.63 and 0.59 (p<0.01). AUC was 0.89. The optimal cut point was \u22652 with the following indicators: sensitivity 0.87 specificity 0.74; Youden index 0.60; PPV 0.47; NPV 0.95; (LR+) 3.24; (LR-) 0.18 (95% CI 0.09-0.37). Kappa coefficient between PHQ-2 and MINI for depression was .458 and 0.46 for HADS-D.\n## LIMITATIONS\nSince this study was done with people attending hospital, which could has implications for the prevalence of depression, affecting the validity indicators of the instrument.\n## CONCLUSIONS\nPHQ-2 show an acceptable test performance in the context of the study. However, the test could yield a considerable amount of false positives that would require specialized evaluation to establish a reliable diagnosis.",
        "truth": "False"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Psychometric Properties of the Patient Health Questionnaire-9 in Elderly Chilean Primary Care Users.",
        "key_reference_abstract": "Background: This study aimed to assess the measurement properties (reliability, factor structure, and criterion validity) of the Patient Health Questionnaire (PHQ-9) as an instrument for screening major depressive disorder (MDD) in elderly primary care users in Chile. Method: About 582 participants aged between 65 and 80 years were enrolled from primary care centers. They completed the Composite International Diagnostic Interview (CIDI), a survey with sociodemographic characteristics and the PHQ-9. Results: The PHQ-9 revealed an acceptable internal consistency (\u03c9 = 0.79 [95% CI: 0.75-0.80] and \u03b1 = 0.78 [95% CI: 0.75-0.81]); confirmatory factor analysis demonstrated a good fit for both 1- and 2-factor solutions. The chi-square difference test (\u03c72 = 0.61, gl = 1, p = 0.43) and correlation between the somatic and the cognitive-effective latent factors were very high (r = 0.97, p < 0.001), indicating that the 1 factor model was more parsimonious. Utilizing the CIDI as the gold standard, the area under the curve (AUC) was 0.88 (SE = 0.04, 95% CI: 0.84-0.90). The optimal cut-off score of \u2265 6 yielded good sensitivity and specificity for detecting MDD (0.95 and 0.76, respectively). However, considering the clinical utility index, the cut-off score of \u22659 proved to be a more effective marker for discarding cases of MDD. Conclusion: The PHQ-9 has adequate psychometric properties for elderly primary care users. In clinical settings, it showed its greatest utility in ruling out the presence of an MDD, however, its clinical value for identifying possible cases of MDD is limited. In cases above the cut-off point, it is recommended to perform a more thorough evaluation.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Validity of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adult primary care users in Bucaramanga, Colombia.",
        "key_reference_abstract": "The patient health questionnaire-9 (PHQ-9) is one of the most widely used self-report instruments in primary care. There is no criterion validity of the PHQ-9 in Colombia. The objective was to validate the PHQ-9 as a screening tool in primary care. A cross-sectional, scale criterion validity study was performed using as reference criterion the mini neuropsychiatric interview (MINI) in male and female adult users of primary care centres. We calculated the internal consistency and convergent and criterion validity of the PHQ-9 by analysing the receiver operating characteristics (ROC) and the area under the curve (AUC). We analysed 243 participants; 184 (75.7%) were female. The average age was 34.05 (median of 31 and SD = 12.47). Cronbach's \u03b1 was 0.80 and McDonald's \u03c9 was 0.81. Spearman's Rho was 0.64 for HADS-D (P <0.010) and 0.70 for PHQ-2 (P\u00a0<0.010). The AUC was 0.92 (95% CI 0.880-0.963). The optimal cut-off point of PHQ-9 was \u22657: sensitivity of 90.38 (95% CI: 81.41-99.36); specificity of 81.68 (95%\u00a0CI: 75.93-87.42); PPV 57.32 (95% CI: 46.00-68.63); NPV 96.89 (95% CI: 93.90-99.88); Youden index 0.72 (95% CI: 0.62-0.82); LR+ 4.93 (95% CI: 3.61-6.74); LR- 0.12 (95% CI: 0.005-0.270). In sum, the Colombian version of PHQ-9 is a valid and reliable instrument for depression screening in primary care in Bucaramanga, with a cut-off point \u22657.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Psychometric properties of the Patient Health Questionnaire nine-item version (PHQ-9) for use among hospitalized non-psychiatric medical patients.",
        "key_reference_abstract": "Depression is a highly prevalent and disabling condition among the general population, and its prevalence is even higher among patients hospitalized due to medical illnesses. It has been estimated that one out of four patients hospitalized for medical illness has a comorbid major depressive episode (MDE) The presence of depression in a patient hospitalized due to a medical illness worsens the medical prognosis, increases symptom burden, complicates self-care and treatment-adherence, extends the hospitalization stay, and inflates the costs of care and mortality. Taking into account that patients with depression can be effectively treated with medication and psychotherapy, early diagnosis and treatment can significantly reduce this burden . Despite this, almost 50% of patients who suffer comorbid depression when hospitalized for medical conditions do not have the condition detected by clinicians. This is explained, at least in part, by the lack of quick and sensitive diagnostic tools, especially for use in specific languages and cultures. Structured clinical interviews such as the composite international diagnostic interview (CIDI)  or the mini international neuropsychiatric interview (MINI) are the gold standard for diagnosing depression. However, the use of these instruments require administration by trained mental health professionals, are time-consuming and difficult to systematically apply in routine clinical practice. This highlights the need for reliable, valid, and easily applicable self-assessment screening tools to detect depression in patients hospitalized due to a non-psychiatric medical illness. Several self-screening tools are available for screening, tracking and documenting depressive symptoms with minimal clinician time, such as the Patient Health Questionnaire 9 (PHQ-9), the Beck Depression Inventory-II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS). To our knowledge, no studies have compared, at the same time and with the same sample, the psychometric properties of these three self-rated questionaries' with a semi-structured clinical interview in patients hospitalized for non-psychiatric medical illness. To cover this gap, we designed the present study. Our aims are to: (1) compare the operating characteristics of PHQ-9, BDI-II and HADS according to an independent criterion standard for MDE in patients hospitalized due to non-psychiatric medical illness; (2) determine the optimum cut-off scores of these self-rating scales for discriminating between patients with and without MDE in this specific group of patients. The results of this study will provide general practitioners with highly valuable information to choose an assessment tool for depression in this subgroup of patients.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Utility of the PHQ-9 to identify major depressive disorder in adult patients in Spanish primary care centres.",
        "key_reference_abstract": "## BACKGROUND\nThe prevalence of major depressive disorder (MDD) in Spanish primary care (PC) centres is high. However, MDD is frequently underdiagnosed and consequently only some patients receive the appropriate treatment. The present study aims to determine the utility of the Patient Health Questionnaire-9 (PHQ-9) to identify MDD in a subset of PC patients participating in the large PsicAP study.\n## METHODS\nA total of 178 patients completed the full PHQ test, including the depression module (PHQ-9). Also, a Spanish version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was implemented by clinical psychologists that were blinded to the PHQ-9 results. We evaluated the psychometric properties of the PHQ-9 as a screening tool as compared to the SCID-I as a reference standard.\n## RESULTS\nThe psychometric properties of the PHQ-9 for a cut-off value of 10 points were as follows: sensitivity, 0.95; specificity, 0.67. Using a cut-off of 12 points, the values were: sensitivity, 0.84; specificity, 0.78. Finally, using the diagnostic algorithm for depression (DSM-IV criteria), the sensitivity was 0.88 and the specificity 0.80.\n## CONCLUSIONS\nAs a screening instrument, the PHQ-9 performed better with a cut-off value of 12 versus the standard cut-off of 10. However, the best psychometric properties were obtained with the DSM-IV diagnostic algorithm for depression. These findings indicate that the PHQ-9 is a highly satisfactory tool that can be used for screening MDD in the PC setting.\n## TRIAL REGISTRATION\nCurrent Controlled Trials ISRCTN58437086 . Registered 20 May 2013.",
        "truth": "False"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "[Psychometric characteristics of the Patient Health Questionnaire (PHQ-9)].",
        "key_reference_abstract": "## BACKGROUND\nSimple and brief questionnaires with adequate psychometric properties are useful for the early detection of depressive disorders.\n## AIM\nTo analyze the psychometric behavior of the Patient Health Questionnaire (PHQ-9) in Chile.\n## MATERIAL AND METHODS\nData were collected from 1,738 adult patients, consulting in primary health care centers. The values obtained in the PHQ-9 were compared with those of the Composite International Diagnostic Interview (CIDI).\n## RESULTS\nThe mean score of PHQ-9 was 4.85 \u00b1 5.57. Internal consistency indices were high. McDonald's \u03c9 coefficient of was 0.90 and Cronbach alpha 0.89. A confirmatory factor analysis showed a good fit of the one-dimensional model. Using a cutoff score of seven determined with the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the instrument were 0.8 and 0.7, when compared with CIDI diagnoses.\n## CONCLUSIONS\nPHQ-9 is a useful instrument for the screening of depressive disorders in primary health care centers in Chile.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Validation and calibration of the patient health questionnaire (PHQ-9) in Argentina.",
        "key_reference_abstract": "## BACKGROUND\nThe Patient Health Questionnaire-9 (PHQ-9) is a brief tool to assess the presence and severity of depressive symptoms. This study aimed to validate and calibrate the PHQ-9 to determine appropriate cut-off points for different degrees of severity of depression in Argentina.\n## METHODS\nWe conducted a cross-sectional study on an intentional sample of adult ambulatory care patients with different degrees of severity of depression. All patients who completed the PHQ-9 were further interviewed by a trained clinician with the Mini International Neuropsychiatric Interview (MINI) and the Beck Depression Inventory-II (BDI-II). Reliability and validity tests, including receiver operating curve analysis, were performed.\n## RESULTS\nOne hundred sixty-nine patients were recruited with a mean age of 47.4\u2009years (SD\u2009=\u200914.8), of whom 102 were females (60.4%). The local PHQ-9 had high internal consistency (Cronbach's alpha\u2009=\u20090.87) and satisfactory convergent validity with the BDI-II scale [Pearson's correlation\u2009=\u20090.88 (p\u00a0<\u20090.01)]. For the diagnosis of Major Depressive Episode (MDE) according to the MINI, a PHQ-9\u2009\u2265\u20098 was the optimal cut-off point found (sensitivity 88.2%, specificity 86.6%, PPV 90.91%). The local version of PHQ-9 showed good ability to discriminate among depression severity categories according to the BDI-II scale. The best cut off points were 6-8 for mild cases, 9-14 for moderate and 15 or more for severe depressive symptoms respectively.\n## CONCLUSIONS\nThe Argentine version of the PHQ-9 questionnaire has shown acceptable validity and reliability for both screening and severity assessment of depressive symptoms.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "The Validity and Reliability of the PHQ-9 and PHQ-2 on Screening for Major Depression in Spanish Speaking Immigrants in Chile: A Cross-Sectional Study.",
        "key_reference_abstract": "## BACKGROUND\nThe study aimed to explore the psychometric properties of two versions of the Patient Health Questionnaires (PHQ-9 and PHQ-2) on screening for Major Depressive Disorder (MDD) among Spanish-speaking Latin American adult immigrants in Santiago, and to explore factors associated with a higher risk of occurrence of MDD among them.\n## METHODS\nA representative sample of 897 Spanish-speaking immigrants completed the PHQ-9. The Composite International Diagnostic Interview (CIDI) was employed to evaluate MDD. Internal consistency and structural validity were evaluated using Cronbach's \u03b1 coefficient and confirmatory factor analysis (CFA). Convergent validity with the 7-item General Anxiety Disorder Scale (GAD-7) was assessed using Spearman's correlations. Sensitivity, specificity, positive predictive values, and area under the receiver operating characteristic (ROC) curve were calculated for different cut-off points. Logistic regression analysis was used to identify factors associated with the risk of MDD.\n## RESULTS\nCronbach's \u03b1 coefficient of the PHQ-9 was 0.90; item-total correlation coefficients ranged from 0.61 to 0.76 and correlation with the GAD-7 was moderate (\n## CONCLUSIONS\nThe PHQ-2 and the PHQ-9 are reliable and valid instruments for use as screeners for MDD among Spanish-speaking populations of Latin America.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Utility of PHQ-2, PHQ-8 and PHQ-9 for detecting major depression in primary health care: a validation study in Spain.",
        "key_reference_abstract": "## BACKGROUND\nPrimary health care (PHC) professionals may play a crucial role in improving early diagnosis of depressive disorders. However, only 50% of cases are detected in PHC. The most widely used screening instrument for major depression is the Patient Health Questionnaire (PHQ), including the two-, eight- and nine-item versions. Surprisingly, there is neither enough evidence about the validity of PHQ in PHC patients in Spain nor indications about how to interpret the total scores. This study aimed to gather validity evidence to support the use of the three PHQ versions to screen for major depression in PHC in Spain. Additionally, the present study provided information for helping professionals to choose the best PHQ version according to the context.\n## METHODS\nThe sample was composed of 2579 participants from 22 Spanish PHC centers participating in the EIRA-3 study. The reliability and validity of the three PHQ versions for Spanish PHC patients were assessed based on responses to the questionnaire.\n## RESULTS\nThe PHQ-8 and PHQ-9 showed high internal consistency. The results obtained confirm the theoretically expected relationship between PHQ results and anxiety, social support and health-related QoL. A single-factor solution was confirmed. Regarding to the level of agreement with the CIDI interview (used as the criterion), our results indicate that the PHQ has a good discrimination power. The optimal cut-off values were: \u2a7e2 for PHQ-2, \u2a7e7 for PHQ-8 and \u2a7e8 for PHQ-9.\n## CONCLUSIONS\nPHQ is a good and valuable tool for detecting major depression in PHC patients in Spain.",
        "truth": "True"
    },
    {
        "pmid": "37847505",
        "meta_analysis_title": "Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.",
        "meta_analysis_question": "Are the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) valid, accurate, and reliable depression screening instruments?",
        "criteria": "Studies were included if (1) they included Spanish-speaking participants who were 18 years or older, (2) they evaluated the validity of the PHQ-2 or PHQ-9 in screening for MDD in Spanish, (3) the screening questionnaires were compared with standardized clinical interviews (considered the gold standard), (4) the publications reported peer-reviewed original research, and (5) they were conducted anywhere in the world but specified use of Spanish-language instruments. Gold standard clinical interviews included the Composite International Diagnostic Interview,35 the Mini International Neuropsychiatric Interview,36 the Schedules for Clinical Assessment in Neuropsychiatry,37,38 the Structured Clinical Interview for DSM-III-R,39 and the Primary Care Evaluation of Mental Disorders,40 which have all been validated for diagnosing depression.",
        "subgroup": "Meta-Analysis of the AUC of the Patient Health Questionnaire 9 - Overall",
        "key_reference_title": "Improving detection of depression symptoms in Latino farmworkers: Latino Farmworker Affective Scale.",
        "key_reference_abstract": "Latino farmworkers (LFWs) experience depression at a significant higher rate than non-Latino Whites; yet, research regarding depression-screening instruments in Spanish is scarce. The first author created a depression screener using terms used by LFWs to describe symptoms of depression. This study evaluated the effectiveness of the Latino Farmworker Affective Scale (LFAS-15) in accurately detecting symptoms of depression in this population as compared with the Patient Health Questionnaire (PHQ-9), the Brief Symptom Inventory (BSI-18), and the Center for Epidemiologic Studies Depression Scale (CESD-10) using the DSM structured clinical interview (SCID) as the reference standard. Study results indicated that the LFAS-15, as well as the PHQ-9, and the BSI-18 performed. The data also indicated that the LFAS-15 has good internal consistency, measures primarily one construct (depression), demonstrated convergent validity with the SCID, and has good combined sensitivity and specificity. Recommendations for clinical practice, policy, and research are offered.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Xbox 360 Kinect Cognitive Games Improve Slowness, Complexity of EEG, and Cognitive Functions in Subjects with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity and cognitive training are effective to enhance cognition in older patients with mild cognitive impairment (MCI). Xbox 360 Kinect cognitive games are a combination of physical activity and cognitive training. The objective of this study was to determine the short- and long-term effects of Xbox 360 Kinect cognitive games on slowness and complexity of electroencephalography (EEG) and cognitive functions in older subjects with MCI.\n## MATERIALS AND METHODS\nA clinical trial was conducted on 44 MCI subjects. Both males and females were randomized into experimental group (participated in Xbox 360 Kinect cognitive games) and control group (range of motion exercises only and no Xbox 360 Kinect cognitive games). Subjects were assessed before and after one session of game intervention for short-term effects and after 6 weeks for long-term effects. The outcome measures were the mini-mental state examination (MMSE), Montreal cognitive assessment scale (MoCA), trail making test (TMT) A and B, and slowness and complexity of EEG.\n## RESULTS\nAfter one session of game intervention, delta (0.704\u2009\u00b1\u20090.025; P\u2009=\u20090.013), theta (0.128\u2009\u00b1\u20090.009; P\u2009=\u20090.00127) waves, and complexity of EEG (0.642\u2009\u00b1\u20090.042; P\u2009=\u20090.008) significantly improved, in eyes closed state. Whereas after 6 weeks intervention of games, delta (0.673\u2009\u00b1\u20090.029; P\u2009=\u20090.013), theta (0.129\u2009\u00b1\u20090.013; P\u2009=\u20090.002), beta2 waves (0.044\u2009\u00b1\u20090.009; P\u2009=\u20090.046), complexity of EEG (0.051\u2009\u00b1\u20090.042; P\u2009=\u20090.016), MMSE (26.25\u2009\u00b1\u20090.347 vs. 23.722\u2009\u00b1\u20090.731; P\u2009=\u20090.003), MoCA (25.65\u2009\u00b1\u20090.310 vs. 22.00\u2009\u00b1\u20090.504; P\u2009=\u20090.0001), TMT-A (1.429\u2009\u00b1\u20090.234 vs. 2.225\u2009\u00b1\u20090.259; P\u2009=\u20090.028), and TMT-B (2.393\u2009\u00b1\u20090.201 vs. 3.780\u2009\u00b1\u20090.195; P\u2009=\u20090.0001) improved significantly. These changes were not observed in the control group.\n## CONCLUSION\nXbox 360 Kinect games showed beneficial effects after short- and long-term intervention on MCI subjects. These games can serve as potential therapeutic candidates for MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Exergaming and older adult cognition: a cluster randomized clinical trial.",
        "key_reference_abstract": "## BACKGROUND\nDementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or \"exergames\" may elicit greater participation.\n## PURPOSE\nTo test the following hypotheses: (1) stationary cycling with virtual reality tours (\"cybercycle\") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain improvement; and (3) brain-derived neurotrophic growth factor (BDNF) will increase.\n## DESIGN\nMulti-site cluster randomized clinical trial (RCT) of the impact of 3 months of cybercycling versus traditional exercise, on cognitive function in older adults. Data were collected in 2008-2010; analyses were conducted in 2010-2011.\n## SETTING/PARTICIPANTS\n102 older adults from eight retirement communities enrolled; 79 were randomized and 63 completed.\n## INTERVENTIONS\nA recumbent stationary ergometer was utilized; virtual reality tours and competitors were enabled on the cybercycle.\n## MAIN OUTCOME MEASURES\nExecutive function (Color Trails Difference, Stroop C, Digits Backward); clinical status (mild cognitive impairment; MCI); exercise effort/fitness; and plasma BDNF.\n## RESULTS\nIntent-to-treat analyses, controlling for age, education, and cluster randomization, revealed a significant group X time interaction for composite executive function (p=0.002). Cybercycling yielded a medium effect over traditional exercise (d=0.50). Cybercyclists had a 23% relative risk reduction in clinical progression to MCI. Exercise effort and fitness were comparable, suggesting another underlying mechanism. A significant group X time interaction for BDNF (p=0.05) indicated enhanced neuroplasticity among cybercyclists.\n## CONCLUSIONS\nCybercycling older adults achieved better cognitive function than traditional exercisers, for the same effort, suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline.\n## TRIAL REGISTRATION\nThis study is registered at Clinicaltrials.gov NCT01167400.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The Effects of Virtual Kayak Paddling Exercise on Postural Balance, Muscle Performance, and Cognitive Function in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial.",
        "key_reference_abstract": "Deterioration of physical and psychological health is an important issue in older adults aged 65 years or more. This study aimed to determine whether a virtual kayak paddling (VKP) exercise could improve postural balance, muscle performance, and cognitive function in older adults with mild cognitive impairment. Sixty participants were randomly assigned to the VKP (",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The effect of cognitive-motor dual task training with the biorescue force platform on cognition, balance and dual task performance in institutionalized older adults: a randomized controlled trial.",
        "key_reference_abstract": "[Purpose] This study investigates whether cognition, balance and dual task performance in institutionalized older adults improves by a virtual reality dual task training. [Subjects and Methods] Randomized controlled trial; Twenty institutionalized older adults with mild cognitive impairment (13 female, 7 male; average age, 87.2 \u00b1 5.96\u2005years) were randomized to the intervention (i.e. Virtual reality dual-task training using the BioRescue) or control group (no additional training). The intervention group took part in a 6-week training program while the elderly in the control group maintained their daily activities. Balance was measured with the Instrumented Timed Up-and-Go Test with and without a cognitive task. The Observed Emotion Rating Scale and Intrinsic Motivation Inventory were administered to evaluate the emotions and motivation regarding the exergaming program. [Results] The intervention group improved significantly on the total Timed Up-and-Go duration and the turn-to-sit duration during single-task walking in comparison to the control group who received no additional training. Participants found the virtual reality dual task training pleasant and useful for their concentration, memory and balance. Pleasure and alertness were the two emotions which were mostly seen during the intervention. [Conclusion] The BioRescue is a pleasant and interesting treatment method, well suited for institutionalized older adults in need of lifelong physical therapy.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Interactive video gaming compared with health education in older adults with mild cognitive impairment: a feasibility study.",
        "key_reference_abstract": "## OBJECTIVE\nWe evaluated the feasibility of a trial of Wii interactive video gaming, and its potential efficacy at improving cognitive functioning compared with health education, in a community sample of older adults with neuropsychologically defined mild cognitive impairment.\n## METHODS\nTwenty older adults were equally randomized to either group-based interactive video gaming or health education for 90\u2009min each week for 24\u2009weeks. Although the primary outcomes were related to study feasibility, we also explored the effect of the intervention on neuropsychological performance and other secondary outcomes.\n## RESULTS\nAll 20 participants completed the intervention, and 18 attended at least 80% of the sessions. The majority (80%) of participants were \"very much\" satisfied with the intervention. Bowling was enjoyed by the most participants and was also rated the highest among the games for mental, social, and physical stimulation. We observed medium effect sizes for cognitive and physical functioning in favor of the interactive video gaming condition, but these effects were not statistically significant in this small sample.\n## CONCLUSION\nInteractive video gaming is feasible for older adults with mild cognitive impairment, and medium effect sizes in favor of the Wii group warrant a larger efficacy trial.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The quest for synergy between physical exercise and cognitive stimulation via exergaming in people with dementia: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nExercise is often proposed as a non-pharmacological intervention to delay cognitive decline in people\u00a0with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in older adults with dementia.\n## METHODS\nA three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized and individually trained three times a week during 12\u2009weeks. Cognitive functioning was measured at baseline, after the 12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of covariance.\n## RESULTS\nData from 115 people with dementia (mean (SD) age\u2009=\u200979.2 (6.9) years; mean (SD) MMSE score\u2009=\u200922.9 (3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103-0.637), p\u2009=\u20090.007; exergame versus control 0.326 (0.081-0.571), p\u2009=\u20090.009). The effect size was moderate (partial \u03b7\n## CONCLUSIONS\nTo our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training on cognitive functioning in people with dementia. We found that both exergame training and aerobic training improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as psychomotor speed is an important predictor for functional decline. No effects were found on executive function, episodic memory and working memory.\n## TRIAL REGISTRATION\nNetherlands Trial Register, NTR5581 . Registered on 7 October 2015.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Effects of Virtual Reality-Based Physical and Cognitive Training on Executive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "Background: Walking while performing cognitive and motor tasks simultaneously interferes with gait performance and may lead to falls in older adults with mild cognitive impairment (MCI). Executive function, which seems to play a key role in dual-task gait performance, can be improved by combined physical and cognitive training. Virtual reality (VR) has the potential to assist rehabilitation, and its effect on physical and cognitive function requires further investigation. The purpose of this study was to assess the effects of VR-based physical and cognitive training on executive function and dual-task gait performance in older adults with MCI, as well as to compare VR-based physical and cognitive training with traditional combined physical and cognitive training. Method: Thirty-four community-dwelling older adults with MCI were randomly assigned into either a VR-based physical and cognitive training (VR) group or a combined traditional physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Outcome measures included executive function [Stroop Color and Word Test (SCWT) and trail making test (TMT) A and B], gait performance (gait speed, stride length, and cadence) and dual-task costs (DTCs). Walking tasks were performed during single-task walking, walking while performing serial subtraction (cognitive dual task), and walking while carrying a tray (motor dual task). The GAIT Up system was used to evaluate gait parameters including speed, stride length, cadence and DTCs. DTC were defined as 100 * (single-task gait parameters - dual-task gait parameters)/single-task gait parameters. Results: Both groups showed significant improvements in the SCWT and single-task and motor dual-task gait performance measures. However, only the VR group showed improvements in cognitive dual-task gait performance and the DTC of cadence. Moreover, the VR group showed more improvements than the CPC group in the TMT-B and DTC of cadence with borderline significances. Conclusion: A 12-week VR-based physical and cognitive training program led to significant improvements in dual-task gait performance in older adults with MCI, which may be attributed to improvements in executive function.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Using virtual reality-based training to improve cognitive function, instrumental activities of daily living and neural efficiency in older adults with mild cognitive impairment.",
        "key_reference_abstract": "## BACKGROUND\nA combination of physical and cognitive training appears to be the effective intervention to improve cognitive function in older adults with mild cognitive impairment (MCI). Computing technology such as virtual reality (VR) may have the potential to assist rehabilitation in shaping brain health. However, little is known about the potential of VR-based physical and cognitive training designed as an intervention for cognition and brain activation in elderly patients with MCI. Moreover, whether a VR program designed around functional tasks can improve their instrumental activities of daily living (IADL) requires further investigation.\n## AIM\nThis study investigated the effects of 12 weeks of VR-based physical and cognitive training on cognitive function, brain activation and IADL and compared the VR intervention with combined physical and cognitive training.\n## DESIGN\nA single-blinded randomized controlled trial.\n## SETTING\nCommunities and day care centers in Taipei, Taiwan.\n## POPULATION\nOlder adults with mild cognitive impairment.\n## METHODS\nThirty-four community-dwelling older adults with MCI were randomized into either a VR-based physical and cognitive training (VR) group or a combined physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Participants were assessed for their cognitive function (global cognition, executive function and verbal memory) and IADL at pre- and postintervention. Changes in prefrontal cortex activation during the global cognition test were also captured by functional near-infrared spectroscopy (NIRS) to identify the potential mediating pathway of the intervention.\n## RESULTS\nBoth groups showed improved executive function and verbal memory (immediate recall). However, only the VR group showed significant improvements in global cognition (P<0.001), verbal memory (delayed recall, P=0.002), and IADL (P<0.001) after the intervention. The group \u00d7 time interaction effects further demonstrated that IADL were more significantly improved with VR training than with CPC training (P=0.006). The hemodynamic data revealed decreased activation in prefrontal areas after training (P=0.0015), indicative of increased neural efficiency, in the VR-trained subjects.\n## CONCLUSIONS\nVR-based physical and cognitive training improves cognitive function, IADL and neural efficiency in older adults with MCI.\n## CLINICAL REHABILITATION IMPACT\nVR training could be implemented for older adults with MCI.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Effects of Exergaming-Based Tai Chi on Cognitive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## BACKGROUND\nDeclined cognitive function interferes with dual-task walking ability and may result in falls in older adults with mild cognitive impairment (MCI). The mind-body exercise, Tai Chi (TC), improves cognition and dual-task ability. Exergaming is low-cost, safe, highly scalable, and feasible. Whether the effects of exergaming-based TC is beneficial than traditional TC has not been investigated yet.\n## OBJECTIVES\nThe objective of this study was to investigate effects of exergaming-based TC on cognitive function and dual-task walking among older adults with MCI.\n## METHODS\nFifty patients with MCI were randomly assigned to an exergaming-based TC (EXER-TC) group, a traditional TC (TC) group, or a control group. The EXER-TC and TC groups received 36 training sessions (three, 50-min sessions per week) during a 12-week period. The control group received no intervention and were instructed to maintain their usual daily physical activities. The outcome variables measured included those related to cognitive function, dual-task cost (DTC), and gait performance.\n## RESULTS\nThe EXER-TC and TC groups performed better than the control group on the Chinese version of the Stroop Color and Word Test, the Trail Making Test Parts A and B, the one-back test, gait speed, and DTC of gait speed in cognitive dual-task conditions after training. However, there were no significant differences between the EXER-TC and TC groups. Compared with the control group, only the EXER-TC group experienced beneficial effects for the Montreal Cognitive Assessment.\n## CONCLUSION\nEXER-TC was comparable to traditional TC for enhancement of dual-task gait performance and executive function. These results suggested that the EXER-TC approach has potential therapeutic use in older adults with MCI.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Effects of Combined Physical and Cognitive Virtual Reality-Based Training on Cognitive Impairment and Oxidative Stress in MCI Patients: A Pilot Study.",
        "key_reference_abstract": "The growing elderly population and the increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) call for the improvement of the quality and the efficacy of the healthcare and social support services. Exercise and cognitive stimulation have been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) has been recognized as a factor that contributes to the advancement of neurodegenerative diseases. Taking these aspects into account, the impact of a novel virtual reality (VR)-based program combining aerobic exercise and cognitive training has been evaluated in the pilot study proposed here. Ten patients (aged 73.3 \u00b1 5.7 years) with MCI (Mini-Mental State Examination, MMSE: 23.0 \u00b1 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. The assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while CTR worsened. EXP group showed a greater improvement than CTR in the executive test, memory functions and verbal fluency. No statistical significance was obtained when comparing within and between both the groups, probably due to small number of subjects examined, which amplifies the effect of the slight heterogeneity in scores recorded. Despite a greater worsening of Daily Living Activities tests, all participants reported a better performance in real life, thanks to the elicited self-perceived improvement. After training intervention OxS (i.e., reactive oxygen species (ROS) production, oxidative damage of lipids and DNA) decreased resulting in significantly (range",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Wii-fit for improving gait and balance in an assisted living facility: a pilot study.",
        "key_reference_abstract": "Objectives. To determine the effects on balance and gait of a Wii-Fit program compared to a walking program in subjects with mild Alzheimer's dementia (AD). Methods. A prospective randomized (1\u2009:\u20091) pilot study with two intervention arms was conducted in an assisted living facility with twenty-two mild AD subjects. In both groups the intervention occurred under supervision for 30 minutes daily, five times a week for eight weeks. Repeated measures ANOVA and paired t-tests were used to analyze changes. Results. Both groups showed improvement in Berg Balance Scale (BBS), Tinetti Test (TT) and Timed Up and Go (TUG) over 8 weeks. However, there was no statistically significant difference between the groups over time. Intragroup analysis in the Wii-Fit group showed significant improvement on BBS (P = 0.003), and TT (P = 0.013). The walking group showed a trend towards improvement on BBS (P = 0.06) and TUG (P = 0.07) and significant improvement in TT (P = 0.06). Conclusion. This pilot study demonstrates the safety and efficacy of Wii-Fit in an assisted living facility in subjects with mild AD. Use of Wii-Fit resulted in significant improvements in balance and gait comparable to those in the robust monitored walking program. These results need to be confirmed in a larger, methodologically sound study.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study.",
        "key_reference_abstract": "## BACKGROUND/OBJECTIVE\nBalance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD.\n## METHODS\nA prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73\u00b16.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention).\n## RESULTS\nAt 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p\u200a<\u200a0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p\u200a<\u200a0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p\u200a<\u200a0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p\u200a=\u200a0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p\u200a=\u200a0.445).\n## CONCLUSION\nHome-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Does cognition-specific computer training have better clinical outcomes than non-specific computer training? A single-blind, randomized controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nThe purpose of this study was to investigate differences between non-specific computer training (NCT) and cognition-specific computer training (CCT).\n## DESIGN\nRandomized controlled experimental study.\n## SETTING\nLocal community welfare center.\n## SUBJECTS\nA total of 78 subjects with mild cognitive impairment (MCI) were randomly assigned to the NCT ( n\u2009=\u200939) or CCT group ( n\u2009=\u200939).\n## INTERVENTION\nThe NCT group underwent NCT using Nintendo Wii for improving functional performance, while the CCT group underwent CCT using CoTras for improving function of the cognitive domain specifically. Subjects in both groups received 30-minute intervention three times a week for 10\u2009weeks.\n## MAIN MEASURES\nTo identify effects on cognitive function, the Wechsler Adult Intelligence Scale (WAIS) digit span subtests, Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test-Part B (TMT-B), Rey-Osterrieth Complex Figure Test, and Modified Taylor Complex Figure (MTCF) were used. Health-related quality of life (HRQoL) was assessed using the Short-Form 36-item questionnaire.\n## RESULTS\nAfter 10\u2009weeks, the WAIS subtests (digit span forward: 0.48\u2009\u00b1\u20090.08 vs. 0.12\u2009\u00b1\u20090.04; digit span backward: 0.46\u2009\u00b1\u20090.09 vs. 0.11\u2009\u00b1\u20090.04) and HRQoL (vitality: 9.05\u2009\u00b1\u20091.17 vs. 2.69\u2009\u00b1\u20091.67; role-emotional: 8.31\u2009\u00b1\u20091.20 vs. 4.15\u2009\u00b1\u20090.71; mental health: 11.62\u2009\u00b1\u20091.63 vs. 6.95\u2009\u00b1\u20091.75; bodily pain: 4.21\u2009\u00b1\u20092.17 vs. 0.10\u2009\u00b1\u20090.38) were significantly higher in the NCT group ( P\u2009<\u20090.05).\n## CONCLUSION\nNCT was superior to CCT for improving cognitive function and HRQoL of elderly adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Sensor-based balance training with motion feedback in people with mild cognitive impairment.",
        "key_reference_abstract": "Some individuals with mild cognitive impairment (MCI) experience not only cognitive deficits but also a decline in motor function, including postural balance. This pilot study sought to estimate the feasibility, user experience, and effects of a novel sensor-based balance training program. Patients with amnestic MCI (mean age 78.2 yr) were randomized to an intervention group (IG, n = 12) or control group (CG, n = 10). The IG underwent balance training (4 wk, twice a week) that included weight shifting and virtual obstacle crossing. Real-time visual/audio lower-limb motion feedback was provided from wearable sensors. The CG received no training. User experience was measured by a questionnaire. Postintervention effects on balance (center of mass sway during standing with eyes open [EO] and eyes closed), gait (speed, variability), cognition, and fear of falling were measured. Eleven participants (92%) completed the training and expressed fun, safety, and helpfulness of sensor feedback. Sway (EO, p = 0.04) and fear of falling (p = 0.02) were reduced in the IG compared to the CG. Changes in other measures were nonsignificant. Results suggest that the sensor-based training paradigm is well accepted in the target population and beneficial for improving postural control. Future studies should evaluate the added value of the sensor-based training compared to traditional training.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The Effect of a Virtual Reality-Based Intervention Program on Cognition in Older Adults with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "This study aimed to investigate the association between a virtual reality (VR) intervention program and cognitive, brain and physical functions in high-risk older adults. In a randomized controlled trial, we enrolled 68 individuals with mild cognitive impairment (MCI). The MCI diagnosis was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the Mini-Mental State Examination (MMSE) and frontal cognitive function: trail making test (TMT) A & B, and symbol digit substitute test (SDST). Resting state electroencephalogram (EEG) was measured in eyes open and eyes closed conditions for 5 minutes each, with a 19-channel wireless EEG device. The VR intervention program (3 times/week, 100 min each session) comprised four types of VR game-based content to improve the attention, memory and processing speed. Analysis of the subjects for group-time interactions revealed that the intervention group exhibited a significantly improved executive function and brain function at the resting state. Additionally, gait speed and mobility were also significantly improved between and after the follow-up. The VR-based training program improved cognitive and physical function in patients with MCI relative to controls. Encouraging patients to perform VR and game-based training may be beneficial to prevent cognitive decline.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The Effectiveness of a Virtual Reality-Based Intervention on Cognitive Functions in Older Adults with Mild Cognitive Impairment: A Single-Blind, Randomized Controlled Trial.",
        "key_reference_abstract": "Objective: Mild cognitive impairment (MCI) is a broad term for people at a stage between normal age-related cognitive decline and dementia, where cognitive problems are present but do not impair activities of daily living. This study aimed at evaluating the effectiveness of a virtual reality (VR)-based rehabilitation program on cognitive functions in MCI. Materials and Methods: Sixty-one older adults (25 men, 36 women) with MCI were randomized to the intervention group (n = 30; 70.12 \u00b1 2.57 years) or control (n = 31; 70.30 \u00b1 2.73 years) group. The intervention group received a VR (computer-generated interactive environments) intervention in addition to a conventional cognitive rehabilitation (CR) intervention, whereas the control group received only the CR intervention. Cognitive functions were assessed in both groups before and after the 12-week interventions by using the Loewenstein Occupational Therapy Cognitive Assessment-Geriatric. Results: Between-group comparisons revealed significantly greater improvements in orientation, visual-spatial perception, visuomotor organization, thinking operation, and attention/concentration functions in the VR group than in the control group (P < 0.001 for all). Conclusion: Our results showed that 12 weeks of VR-based rehabilitation enhanced cognitive functions in older adults with MCI. Using VR applications in CR is recommended to improve cognitive functions of older adults with MCI.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Effects of Exergaming on Cognitive and Social Functioning of People with Dementia: A Randomized Controlled Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity in people with dementia (PwD) may enhance physical and mental functioning. Exergaming, which combines physical exercise with cognitive stimulation in a gaming environment, was developed to overcome barriers in performing physical activities. We evaluated the effects of exergaming in day care centers (DCCs) for PwD and informal caregivers (ICs).\n## DESIGN\nA randomized controlled trial among 23 DCCs across the Netherlands randomized to exergaming (interactive cycling during 6\u00a0months) or a care-as-usual control group.\n## SETTING AND PARTICIPANTS\nA total of 112 (73 exergaming, 39 control) community-dwelling dyads (PwD, IC), with the PwD visiting a DCC at least twice per week.\n## METHODS\nAll outcomes were assessed using structured questionnaires during interviews with PwD and ICs at baseline (T0), 3\u00a0months (T1), and 6 months (T2). Primary outcomes: physical activity and mobility of the PwD.\n## SECONDARY OUTCOMES\nphysical, cognitive, emotional and social functioning, and quality of life for PwD. For ICs: experienced burden, quality of life, and positive care experiences.\n## RESULTS\nMixed-model analyses showed no statistically significant effects on primary outcomes. There were statistically significant positive effects on PwD's secondary outcomes at T2 on cognition [Mini-Mental State Examination (MMSE): r\u00a0=\u00a02.30, 95% confidence interval (CI): 0.65, 3.96, P\u00a0=\u00a0.007; and Trail Making Test part A (TMT-A): r\u00a0=\u00a0-28.98, 95% CI:\u00a0-54.89,\u00a0-3.08, P\u00a0=\u00a0.029], social functioning (Behavior Observation Scale for Intramural Psychogeriatrics subscale 1 (GIP): r\u00a0=\u00a0-1.86, 95% CI:\u00a0-3.56,\u00a0-0.17, P\u00a0=\u00a0.031), and positive post-test effects in ICs on distress caused by the PwD's neuropsychiatric symptoms (NPI-Q total distress: r\u00a0=\u00a0-3.30, 95% CI:\u00a0-6.57,\u00a0-0.03, P\u00a0=\u00a0.048) and on sense of competence (SSCQ: r\u00a0=\u00a02.78, 95% CI: 0.85, 4.71, P\u00a0=\u00a0.005).\n## CONCLUSIONS AND IMPLICATIONS\nExergaming appeared not effective on the primary outcomes. Despite the study being underpowered, we found positive effects on secondary outcomes for PwD and ICs, and no negative effects. We therefore recommend further study, dissemination, and implementation.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "The Effects of Exergaming on Executive and Physical Functions in Older Adults With Dementia: Randomized Controlled Trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite increasing interest in the effects of exergaming on cognitive function, little is known about its effects on older adults with dementia.\n## OBJECTIVE\nThe purpose of this is to investigate the effects of exergaming on executive and physical functions in older adults with dementia compared to regular aerobic exercise.\n## METHODS\nIn total, 24 older adults with moderate dementia participated in the study. Participants were randomized into either the exergame group (EXG, n=13, 54%) or the aerobic exercise group (AEG, n=11, 46%). For 12 weeks, EXG engaged in a running-based exergame and AEG performed a cycling exercise. At baseline and postintervention, participants underwent the Ericksen flanker test (accuracy % and response time [RT]) while recording event-related potentials (ERPs) that included the N2 and P3b potentials. Participants also underwent the senior fitness test (SFT) and the body composition test pre- and postintervention. Repeated-measures ANOVA was performed to assess the effects of time (pre- vs postintervention), group (EXG vs AEG), and group\u00d7time interactions.\n## RESULTS\nCompared to AEG, EXG demonstrated greater improvements in the SFT (F\n## CONCLUSIONS\nOur results suggest that exergaming may be associated with greater improvements in brain neuronal activity and enhanced executive function task performance than regular aerobic exercise. Exergaming characterized by both aerobic exercise and cognitive stimulation can be used as an effective intervention to improve cognitive and physical functions in older adults with dementia.\n## TRIAL REGISTRATION\nClinical Research Information Service KCT0008238; https://cris.nih.go.kr/cris/search/detailSearch.do/24170.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "An Evaluation of the Effects of Active Game Play on Cognition, Quality of Life and Depression for Older People with Dementia.",
        "key_reference_abstract": "## OBJECTIVES\nThis pilot study was intended to evaluate the effects of active game play on cognition, quality of life, and depression for older people with dementia.\n## METHODS\nThirty-eight older people with dementia were recruited. Eighteen people received eight-week active game play using Xbox 360 Kinect. Twenty people received their usual care. The Mini Mental State Examination, Quality of Life-Alzheimer's Disease and Cornell Scale for Depression in Dementia were used to measure the outcomes.\n## RESULTS\nThe results showed that there was no significant improvement on the mean scores of Mini Mental State Examination (\n## CONCLUSIONS\nThe study demonstrated that the active game play was effective in improving quality of life and alleviating depression in older people with dementia.\n## CLINICAL IMPLICATIONS\nFindings highlight the potential for gaming as a non-pharmacological interventions for older people with dementia.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - VR-based Exergaming",
        "key_reference_title": "Assessing Virtual Reality Environments as Cognitive Stimulation Method for Patients with MCI",
        "key_reference_abstract": "Advances in technology in the last decade have created a diverse field of applications for the care of persons with cognitive impairment. This chapter is an attempt to introduce a virtual reality computer-based intervention, which can used for cognitive stimulating and disease progression evaluation of a wide range of cognitive disorders ranging from mild cognitive impairment (MCI) to Alzheimer\u2019s disease and various dementias. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. Nevertheless a holistic approach has been attempted, in order to view the research themes and applications that currently exist around the \u2018\u2018intelligent systems\u2019\u2019 healthcare given to the cognitively impaired persons, and thus looking at research directions, systems, technological frameworks and perhaps trends.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Xbox 360 Kinect Cognitive Games Improve Slowness, Complexity of EEG, and Cognitive Functions in Subjects with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity and cognitive training are effective to enhance cognition in older patients with mild cognitive impairment (MCI). Xbox 360 Kinect cognitive games are a combination of physical activity and cognitive training. The objective of this study was to determine the short- and long-term effects of Xbox 360 Kinect cognitive games on slowness and complexity of electroencephalography (EEG) and cognitive functions in older subjects with MCI.\n## MATERIALS AND METHODS\nA clinical trial was conducted on 44 MCI subjects. Both males and females were randomized into experimental group (participated in Xbox 360 Kinect cognitive games) and control group (range of motion exercises only and no Xbox 360 Kinect cognitive games). Subjects were assessed before and after one session of game intervention for short-term effects and after 6 weeks for long-term effects. The outcome measures were the mini-mental state examination (MMSE), Montreal cognitive assessment scale (MoCA), trail making test (TMT) A and B, and slowness and complexity of EEG.\n## RESULTS\nAfter one session of game intervention, delta (0.704\u2009\u00b1\u20090.025; P\u2009=\u20090.013), theta (0.128\u2009\u00b1\u20090.009; P\u2009=\u20090.00127) waves, and complexity of EEG (0.642\u2009\u00b1\u20090.042; P\u2009=\u20090.008) significantly improved, in eyes closed state. Whereas after 6 weeks intervention of games, delta (0.673\u2009\u00b1\u20090.029; P\u2009=\u20090.013), theta (0.129\u2009\u00b1\u20090.013; P\u2009=\u20090.002), beta2 waves (0.044\u2009\u00b1\u20090.009; P\u2009=\u20090.046), complexity of EEG (0.051\u2009\u00b1\u20090.042; P\u2009=\u20090.016), MMSE (26.25\u2009\u00b1\u20090.347 vs. 23.722\u2009\u00b1\u20090.731; P\u2009=\u20090.003), MoCA (25.65\u2009\u00b1\u20090.310 vs. 22.00\u2009\u00b1\u20090.504; P\u2009=\u20090.0001), TMT-A (1.429\u2009\u00b1\u20090.234 vs. 2.225\u2009\u00b1\u20090.259; P\u2009=\u20090.028), and TMT-B (2.393\u2009\u00b1\u20090.201 vs. 3.780\u2009\u00b1\u20090.195; P\u2009=\u20090.0001) improved significantly. These changes were not observed in the control group.\n## CONCLUSION\nXbox 360 Kinect games showed beneficial effects after short- and long-term intervention on MCI subjects. These games can serve as potential therapeutic candidates for MCI.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Exergaming and older adult cognition: a cluster randomized clinical trial.",
        "key_reference_abstract": "## BACKGROUND\nDementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or \"exergames\" may elicit greater participation.\n## PURPOSE\nTo test the following hypotheses: (1) stationary cycling with virtual reality tours (\"cybercycle\") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain improvement; and (3) brain-derived neurotrophic growth factor (BDNF) will increase.\n## DESIGN\nMulti-site cluster randomized clinical trial (RCT) of the impact of 3 months of cybercycling versus traditional exercise, on cognitive function in older adults. Data were collected in 2008-2010; analyses were conducted in 2010-2011.\n## SETTING/PARTICIPANTS\n102 older adults from eight retirement communities enrolled; 79 were randomized and 63 completed.\n## INTERVENTIONS\nA recumbent stationary ergometer was utilized; virtual reality tours and competitors were enabled on the cybercycle.\n## MAIN OUTCOME MEASURES\nExecutive function (Color Trails Difference, Stroop C, Digits Backward); clinical status (mild cognitive impairment; MCI); exercise effort/fitness; and plasma BDNF.\n## RESULTS\nIntent-to-treat analyses, controlling for age, education, and cluster randomization, revealed a significant group X time interaction for composite executive function (p=0.002). Cybercycling yielded a medium effect over traditional exercise (d=0.50). Cybercyclists had a 23% relative risk reduction in clinical progression to MCI. Exercise effort and fitness were comparable, suggesting another underlying mechanism. A significant group X time interaction for BDNF (p=0.05) indicated enhanced neuroplasticity among cybercyclists.\n## CONCLUSIONS\nCybercycling older adults achieved better cognitive function than traditional exercisers, for the same effort, suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline.\n## TRIAL REGISTRATION\nThis study is registered at Clinicaltrials.gov NCT01167400.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The Effects of Virtual Kayak Paddling Exercise on Postural Balance, Muscle Performance, and Cognitive Function in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial.",
        "key_reference_abstract": "Deterioration of physical and psychological health is an important issue in older adults aged 65 years or more. This study aimed to determine whether a virtual kayak paddling (VKP) exercise could improve postural balance, muscle performance, and cognitive function in older adults with mild cognitive impairment. Sixty participants were randomly assigned to the VKP (",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The effect of cognitive-motor dual task training with the biorescue force platform on cognition, balance and dual task performance in institutionalized older adults: a randomized controlled trial.",
        "key_reference_abstract": "[Purpose] This study investigates whether cognition, balance and dual task performance in institutionalized older adults improves by a virtual reality dual task training. [Subjects and Methods] Randomized controlled trial; Twenty institutionalized older adults with mild cognitive impairment (13 female, 7 male; average age, 87.2 \u00b1 5.96\u2005years) were randomized to the intervention (i.e. Virtual reality dual-task training using the BioRescue) or control group (no additional training). The intervention group took part in a 6-week training program while the elderly in the control group maintained their daily activities. Balance was measured with the Instrumented Timed Up-and-Go Test with and without a cognitive task. The Observed Emotion Rating Scale and Intrinsic Motivation Inventory were administered to evaluate the emotions and motivation regarding the exergaming program. [Results] The intervention group improved significantly on the total Timed Up-and-Go duration and the turn-to-sit duration during single-task walking in comparison to the control group who received no additional training. Participants found the virtual reality dual task training pleasant and useful for their concentration, memory and balance. Pleasure and alertness were the two emotions which were mostly seen during the intervention. [Conclusion] The BioRescue is a pleasant and interesting treatment method, well suited for institutionalized older adults in need of lifelong physical therapy.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Interactive video gaming compared with health education in older adults with mild cognitive impairment: a feasibility study.",
        "key_reference_abstract": "## OBJECTIVE\nWe evaluated the feasibility of a trial of Wii interactive video gaming, and its potential efficacy at improving cognitive functioning compared with health education, in a community sample of older adults with neuropsychologically defined mild cognitive impairment.\n## METHODS\nTwenty older adults were equally randomized to either group-based interactive video gaming or health education for 90\u2009min each week for 24\u2009weeks. Although the primary outcomes were related to study feasibility, we also explored the effect of the intervention on neuropsychological performance and other secondary outcomes.\n## RESULTS\nAll 20 participants completed the intervention, and 18 attended at least 80% of the sessions. The majority (80%) of participants were \"very much\" satisfied with the intervention. Bowling was enjoyed by the most participants and was also rated the highest among the games for mental, social, and physical stimulation. We observed medium effect sizes for cognitive and physical functioning in favor of the interactive video gaming condition, but these effects were not statistically significant in this small sample.\n## CONCLUSION\nInteractive video gaming is feasible for older adults with mild cognitive impairment, and medium effect sizes in favor of the Wii group warrant a larger efficacy trial.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The quest for synergy between physical exercise and cognitive stimulation via exergaming in people with dementia: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nExercise is often proposed as a non-pharmacological intervention to delay cognitive decline in people\u00a0with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in older adults with dementia.\n## METHODS\nA three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized and individually trained three times a week during 12\u2009weeks. Cognitive functioning was measured at baseline, after the 12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of covariance.\n## RESULTS\nData from 115 people with dementia (mean (SD) age\u2009=\u200979.2 (6.9) years; mean (SD) MMSE score\u2009=\u200922.9 (3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103-0.637), p\u2009=\u20090.007; exergame versus control 0.326 (0.081-0.571), p\u2009=\u20090.009). The effect size was moderate (partial \u03b7\n## CONCLUSIONS\nTo our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training on cognitive functioning in people with dementia. We found that both exergame training and aerobic training improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as psychomotor speed is an important predictor for functional decline. No effects were found on executive function, episodic memory and working memory.\n## TRIAL REGISTRATION\nNetherlands Trial Register, NTR5581 . Registered on 7 October 2015.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Effects of Virtual Reality-Based Physical and Cognitive Training on Executive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "Background: Walking while performing cognitive and motor tasks simultaneously interferes with gait performance and may lead to falls in older adults with mild cognitive impairment (MCI). Executive function, which seems to play a key role in dual-task gait performance, can be improved by combined physical and cognitive training. Virtual reality (VR) has the potential to assist rehabilitation, and its effect on physical and cognitive function requires further investigation. The purpose of this study was to assess the effects of VR-based physical and cognitive training on executive function and dual-task gait performance in older adults with MCI, as well as to compare VR-based physical and cognitive training with traditional combined physical and cognitive training. Method: Thirty-four community-dwelling older adults with MCI were randomly assigned into either a VR-based physical and cognitive training (VR) group or a combined traditional physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Outcome measures included executive function [Stroop Color and Word Test (SCWT) and trail making test (TMT) A and B], gait performance (gait speed, stride length, and cadence) and dual-task costs (DTCs). Walking tasks were performed during single-task walking, walking while performing serial subtraction (cognitive dual task), and walking while carrying a tray (motor dual task). The GAIT Up system was used to evaluate gait parameters including speed, stride length, cadence and DTCs. DTC were defined as 100 * (single-task gait parameters - dual-task gait parameters)/single-task gait parameters. Results: Both groups showed significant improvements in the SCWT and single-task and motor dual-task gait performance measures. However, only the VR group showed improvements in cognitive dual-task gait performance and the DTC of cadence. Moreover, the VR group showed more improvements than the CPC group in the TMT-B and DTC of cadence with borderline significances. Conclusion: A 12-week VR-based physical and cognitive training program led to significant improvements in dual-task gait performance in older adults with MCI, which may be attributed to improvements in executive function.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Using virtual reality-based training to improve cognitive function, instrumental activities of daily living and neural efficiency in older adults with mild cognitive impairment.",
        "key_reference_abstract": "## BACKGROUND\nA combination of physical and cognitive training appears to be the effective intervention to improve cognitive function in older adults with mild cognitive impairment (MCI). Computing technology such as virtual reality (VR) may have the potential to assist rehabilitation in shaping brain health. However, little is known about the potential of VR-based physical and cognitive training designed as an intervention for cognition and brain activation in elderly patients with MCI. Moreover, whether a VR program designed around functional tasks can improve their instrumental activities of daily living (IADL) requires further investigation.\n## AIM\nThis study investigated the effects of 12 weeks of VR-based physical and cognitive training on cognitive function, brain activation and IADL and compared the VR intervention with combined physical and cognitive training.\n## DESIGN\nA single-blinded randomized controlled trial.\n## SETTING\nCommunities and day care centers in Taipei, Taiwan.\n## POPULATION\nOlder adults with mild cognitive impairment.\n## METHODS\nThirty-four community-dwelling older adults with MCI were randomized into either a VR-based physical and cognitive training (VR) group or a combined physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Participants were assessed for their cognitive function (global cognition, executive function and verbal memory) and IADL at pre- and postintervention. Changes in prefrontal cortex activation during the global cognition test were also captured by functional near-infrared spectroscopy (NIRS) to identify the potential mediating pathway of the intervention.\n## RESULTS\nBoth groups showed improved executive function and verbal memory (immediate recall). However, only the VR group showed significant improvements in global cognition (P<0.001), verbal memory (delayed recall, P=0.002), and IADL (P<0.001) after the intervention. The group \u00d7 time interaction effects further demonstrated that IADL were more significantly improved with VR training than with CPC training (P=0.006). The hemodynamic data revealed decreased activation in prefrontal areas after training (P=0.0015), indicative of increased neural efficiency, in the VR-trained subjects.\n## CONCLUSIONS\nVR-based physical and cognitive training improves cognitive function, IADL and neural efficiency in older adults with MCI.\n## CLINICAL REHABILITATION IMPACT\nVR training could be implemented for older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Effects of Exergaming-Based Tai Chi on Cognitive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## BACKGROUND\nDeclined cognitive function interferes with dual-task walking ability and may result in falls in older adults with mild cognitive impairment (MCI). The mind-body exercise, Tai Chi (TC), improves cognition and dual-task ability. Exergaming is low-cost, safe, highly scalable, and feasible. Whether the effects of exergaming-based TC is beneficial than traditional TC has not been investigated yet.\n## OBJECTIVES\nThe objective of this study was to investigate effects of exergaming-based TC on cognitive function and dual-task walking among older adults with MCI.\n## METHODS\nFifty patients with MCI were randomly assigned to an exergaming-based TC (EXER-TC) group, a traditional TC (TC) group, or a control group. The EXER-TC and TC groups received 36 training sessions (three, 50-min sessions per week) during a 12-week period. The control group received no intervention and were instructed to maintain their usual daily physical activities. The outcome variables measured included those related to cognitive function, dual-task cost (DTC), and gait performance.\n## RESULTS\nThe EXER-TC and TC groups performed better than the control group on the Chinese version of the Stroop Color and Word Test, the Trail Making Test Parts A and B, the one-back test, gait speed, and DTC of gait speed in cognitive dual-task conditions after training. However, there were no significant differences between the EXER-TC and TC groups. Compared with the control group, only the EXER-TC group experienced beneficial effects for the Montreal Cognitive Assessment.\n## CONCLUSION\nEXER-TC was comparable to traditional TC for enhancement of dual-task gait performance and executive function. These results suggested that the EXER-TC approach has potential therapeutic use in older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Effects of Combined Physical and Cognitive Virtual Reality-Based Training on Cognitive Impairment and Oxidative Stress in MCI Patients: A Pilot Study.",
        "key_reference_abstract": "The growing elderly population and the increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) call for the improvement of the quality and the efficacy of the healthcare and social support services. Exercise and cognitive stimulation have been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) has been recognized as a factor that contributes to the advancement of neurodegenerative diseases. Taking these aspects into account, the impact of a novel virtual reality (VR)-based program combining aerobic exercise and cognitive training has been evaluated in the pilot study proposed here. Ten patients (aged 73.3 \u00b1 5.7 years) with MCI (Mini-Mental State Examination, MMSE: 23.0 \u00b1 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. The assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while CTR worsened. EXP group showed a greater improvement than CTR in the executive test, memory functions and verbal fluency. No statistical significance was obtained when comparing within and between both the groups, probably due to small number of subjects examined, which amplifies the effect of the slight heterogeneity in scores recorded. Despite a greater worsening of Daily Living Activities tests, all participants reported a better performance in real life, thanks to the elicited self-perceived improvement. After training intervention OxS (i.e., reactive oxygen species (ROS) production, oxidative damage of lipids and DNA) decreased resulting in significantly (range",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Wii-fit for improving gait and balance in an assisted living facility: a pilot study.",
        "key_reference_abstract": "Objectives. To determine the effects on balance and gait of a Wii-Fit program compared to a walking program in subjects with mild Alzheimer's dementia (AD). Methods. A prospective randomized (1\u2009:\u20091) pilot study with two intervention arms was conducted in an assisted living facility with twenty-two mild AD subjects. In both groups the intervention occurred under supervision for 30 minutes daily, five times a week for eight weeks. Repeated measures ANOVA and paired t-tests were used to analyze changes. Results. Both groups showed improvement in Berg Balance Scale (BBS), Tinetti Test (TT) and Timed Up and Go (TUG) over 8 weeks. However, there was no statistically significant difference between the groups over time. Intragroup analysis in the Wii-Fit group showed significant improvement on BBS (P = 0.003), and TT (P = 0.013). The walking group showed a trend towards improvement on BBS (P = 0.06) and TUG (P = 0.07) and significant improvement in TT (P = 0.06). Conclusion. This pilot study demonstrates the safety and efficacy of Wii-Fit in an assisted living facility in subjects with mild AD. Use of Wii-Fit resulted in significant improvements in balance and gait comparable to those in the robust monitored walking program. These results need to be confirmed in a larger, methodologically sound study.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study.",
        "key_reference_abstract": "## BACKGROUND/OBJECTIVE\nBalance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD.\n## METHODS\nA prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73\u00b16.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention).\n## RESULTS\nAt 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p\u200a<\u200a0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p\u200a<\u200a0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p\u200a<\u200a0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p\u200a=\u200a0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p\u200a=\u200a0.445).\n## CONCLUSION\nHome-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Does cognition-specific computer training have better clinical outcomes than non-specific computer training? A single-blind, randomized controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nThe purpose of this study was to investigate differences between non-specific computer training (NCT) and cognition-specific computer training (CCT).\n## DESIGN\nRandomized controlled experimental study.\n## SETTING\nLocal community welfare center.\n## SUBJECTS\nA total of 78 subjects with mild cognitive impairment (MCI) were randomly assigned to the NCT ( n\u2009=\u200939) or CCT group ( n\u2009=\u200939).\n## INTERVENTION\nThe NCT group underwent NCT using Nintendo Wii for improving functional performance, while the CCT group underwent CCT using CoTras for improving function of the cognitive domain specifically. Subjects in both groups received 30-minute intervention three times a week for 10\u2009weeks.\n## MAIN MEASURES\nTo identify effects on cognitive function, the Wechsler Adult Intelligence Scale (WAIS) digit span subtests, Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test-Part B (TMT-B), Rey-Osterrieth Complex Figure Test, and Modified Taylor Complex Figure (MTCF) were used. Health-related quality of life (HRQoL) was assessed using the Short-Form 36-item questionnaire.\n## RESULTS\nAfter 10\u2009weeks, the WAIS subtests (digit span forward: 0.48\u2009\u00b1\u20090.08 vs. 0.12\u2009\u00b1\u20090.04; digit span backward: 0.46\u2009\u00b1\u20090.09 vs. 0.11\u2009\u00b1\u20090.04) and HRQoL (vitality: 9.05\u2009\u00b1\u20091.17 vs. 2.69\u2009\u00b1\u20091.67; role-emotional: 8.31\u2009\u00b1\u20091.20 vs. 4.15\u2009\u00b1\u20090.71; mental health: 11.62\u2009\u00b1\u20091.63 vs. 6.95\u2009\u00b1\u20091.75; bodily pain: 4.21\u2009\u00b1\u20092.17 vs. 0.10\u2009\u00b1\u20090.38) were significantly higher in the NCT group ( P\u2009<\u20090.05).\n## CONCLUSION\nNCT was superior to CCT for improving cognitive function and HRQoL of elderly adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Sensor-based balance training with motion feedback in people with mild cognitive impairment.",
        "key_reference_abstract": "Some individuals with mild cognitive impairment (MCI) experience not only cognitive deficits but also a decline in motor function, including postural balance. This pilot study sought to estimate the feasibility, user experience, and effects of a novel sensor-based balance training program. Patients with amnestic MCI (mean age 78.2 yr) were randomized to an intervention group (IG, n = 12) or control group (CG, n = 10). The IG underwent balance training (4 wk, twice a week) that included weight shifting and virtual obstacle crossing. Real-time visual/audio lower-limb motion feedback was provided from wearable sensors. The CG received no training. User experience was measured by a questionnaire. Postintervention effects on balance (center of mass sway during standing with eyes open [EO] and eyes closed), gait (speed, variability), cognition, and fear of falling were measured. Eleven participants (92%) completed the training and expressed fun, safety, and helpfulness of sensor feedback. Sway (EO, p = 0.04) and fear of falling (p = 0.02) were reduced in the IG compared to the CG. Changes in other measures were nonsignificant. Results suggest that the sensor-based training paradigm is well accepted in the target population and beneficial for improving postural control. Future studies should evaluate the added value of the sensor-based training compared to traditional training.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The Effect of a Virtual Reality-Based Intervention Program on Cognition in Older Adults with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "This study aimed to investigate the association between a virtual reality (VR) intervention program and cognitive, brain and physical functions in high-risk older adults. In a randomized controlled trial, we enrolled 68 individuals with mild cognitive impairment (MCI). The MCI diagnosis was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the Mini-Mental State Examination (MMSE) and frontal cognitive function: trail making test (TMT) A & B, and symbol digit substitute test (SDST). Resting state electroencephalogram (EEG) was measured in eyes open and eyes closed conditions for 5 minutes each, with a 19-channel wireless EEG device. The VR intervention program (3 times/week, 100 min each session) comprised four types of VR game-based content to improve the attention, memory and processing speed. Analysis of the subjects for group-time interactions revealed that the intervention group exhibited a significantly improved executive function and brain function at the resting state. Additionally, gait speed and mobility were also significantly improved between and after the follow-up. The VR-based training program improved cognitive and physical function in patients with MCI relative to controls. Encouraging patients to perform VR and game-based training may be beneficial to prevent cognitive decline.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The Effectiveness of a Virtual Reality-Based Intervention on Cognitive Functions in Older Adults with Mild Cognitive Impairment: A Single-Blind, Randomized Controlled Trial.",
        "key_reference_abstract": "Objective: Mild cognitive impairment (MCI) is a broad term for people at a stage between normal age-related cognitive decline and dementia, where cognitive problems are present but do not impair activities of daily living. This study aimed at evaluating the effectiveness of a virtual reality (VR)-based rehabilitation program on cognitive functions in MCI. Materials and Methods: Sixty-one older adults (25 men, 36 women) with MCI were randomized to the intervention group (n = 30; 70.12 \u00b1 2.57 years) or control (n = 31; 70.30 \u00b1 2.73 years) group. The intervention group received a VR (computer-generated interactive environments) intervention in addition to a conventional cognitive rehabilitation (CR) intervention, whereas the control group received only the CR intervention. Cognitive functions were assessed in both groups before and after the 12-week interventions by using the Loewenstein Occupational Therapy Cognitive Assessment-Geriatric. Results: Between-group comparisons revealed significantly greater improvements in orientation, visual-spatial perception, visuomotor organization, thinking operation, and attention/concentration functions in the VR group than in the control group (P < 0.001 for all). Conclusion: Our results showed that 12 weeks of VR-based rehabilitation enhanced cognitive functions in older adults with MCI. Using VR applications in CR is recommended to improve cognitive functions of older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Effects of Exergaming on Cognitive and Social Functioning of People with Dementia: A Randomized Controlled Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity in people with dementia (PwD) may enhance physical and mental functioning. Exergaming, which combines physical exercise with cognitive stimulation in a gaming environment, was developed to overcome barriers in performing physical activities. We evaluated the effects of exergaming in day care centers (DCCs) for PwD and informal caregivers (ICs).\n## DESIGN\nA randomized controlled trial among 23 DCCs across the Netherlands randomized to exergaming (interactive cycling during 6\u00a0months) or a care-as-usual control group.\n## SETTING AND PARTICIPANTS\nA total of 112 (73 exergaming, 39 control) community-dwelling dyads (PwD, IC), with the PwD visiting a DCC at least twice per week.\n## METHODS\nAll outcomes were assessed using structured questionnaires during interviews with PwD and ICs at baseline (T0), 3\u00a0months (T1), and 6 months (T2). Primary outcomes: physical activity and mobility of the PwD.\n## SECONDARY OUTCOMES\nphysical, cognitive, emotional and social functioning, and quality of life for PwD. For ICs: experienced burden, quality of life, and positive care experiences.\n## RESULTS\nMixed-model analyses showed no statistically significant effects on primary outcomes. There were statistically significant positive effects on PwD's secondary outcomes at T2 on cognition [Mini-Mental State Examination (MMSE): r\u00a0=\u00a02.30, 95% confidence interval (CI): 0.65, 3.96, P\u00a0=\u00a0.007; and Trail Making Test part A (TMT-A): r\u00a0=\u00a0-28.98, 95% CI:\u00a0-54.89,\u00a0-3.08, P\u00a0=\u00a0.029], social functioning (Behavior Observation Scale for Intramural Psychogeriatrics subscale 1 (GIP): r\u00a0=\u00a0-1.86, 95% CI:\u00a0-3.56,\u00a0-0.17, P\u00a0=\u00a0.031), and positive post-test effects in ICs on distress caused by the PwD's neuropsychiatric symptoms (NPI-Q total distress: r\u00a0=\u00a0-3.30, 95% CI:\u00a0-6.57,\u00a0-0.03, P\u00a0=\u00a0.048) and on sense of competence (SSCQ: r\u00a0=\u00a02.78, 95% CI: 0.85, 4.71, P\u00a0=\u00a0.005).\n## CONCLUSIONS AND IMPLICATIONS\nExergaming appeared not effective on the primary outcomes. Despite the study being underpowered, we found positive effects on secondary outcomes for PwD and ICs, and no negative effects. We therefore recommend further study, dissemination, and implementation.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "The Effects of Exergaming on Executive and Physical Functions in Older Adults With Dementia: Randomized Controlled Trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite increasing interest in the effects of exergaming on cognitive function, little is known about its effects on older adults with dementia.\n## OBJECTIVE\nThe purpose of this is to investigate the effects of exergaming on executive and physical functions in older adults with dementia compared to regular aerobic exercise.\n## METHODS\nIn total, 24 older adults with moderate dementia participated in the study. Participants were randomized into either the exergame group (EXG, n=13, 54%) or the aerobic exercise group (AEG, n=11, 46%). For 12 weeks, EXG engaged in a running-based exergame and AEG performed a cycling exercise. At baseline and postintervention, participants underwent the Ericksen flanker test (accuracy % and response time [RT]) while recording event-related potentials (ERPs) that included the N2 and P3b potentials. Participants also underwent the senior fitness test (SFT) and the body composition test pre- and postintervention. Repeated-measures ANOVA was performed to assess the effects of time (pre- vs postintervention), group (EXG vs AEG), and group\u00d7time interactions.\n## RESULTS\nCompared to AEG, EXG demonstrated greater improvements in the SFT (F\n## CONCLUSIONS\nOur results suggest that exergaming may be associated with greater improvements in brain neuronal activity and enhanced executive function task performance than regular aerobic exercise. Exergaming characterized by both aerobic exercise and cognitive stimulation can be used as an effective intervention to improve cognitive and physical functions in older adults with dementia.\n## TRIAL REGISTRATION\nClinical Research Information Service KCT0008238; https://cris.nih.go.kr/cris/search/detailSearch.do/24170.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "An Evaluation of the Effects of Active Game Play on Cognition, Quality of Life and Depression for Older People with Dementia.",
        "key_reference_abstract": "## OBJECTIVES\nThis pilot study was intended to evaluate the effects of active game play on cognition, quality of life, and depression for older people with dementia.\n## METHODS\nThirty-eight older people with dementia were recruited. Eighteen people received eight-week active game play using Xbox 360 Kinect. Twenty people received their usual care. The Mini Mental State Examination, Quality of Life-Alzheimer's Disease and Cornell Scale for Depression in Dementia were used to measure the outcomes.\n## RESULTS\nThe results showed that there was no significant improvement on the mean scores of Mini Mental State Examination (\n## CONCLUSIONS\nThe study demonstrated that the active game play was effective in improving quality of life and alleviating depression in older people with dementia.\n## CLINICAL IMPLICATIONS\nFindings highlight the potential for gaming as a non-pharmacological interventions for older people with dementia.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with mild cognitive impairment. - Video-gaming",
        "key_reference_title": "Assessing Virtual Reality Environments as Cognitive Stimulation Method for Patients with MCI",
        "key_reference_abstract": "Advances in technology in the last decade have created a diverse field of applications for the care of persons with cognitive impairment. This chapter is an attempt to introduce a virtual reality computer-based intervention, which can used for cognitive stimulating and disease progression evaluation of a wide range of cognitive disorders ranging from mild cognitive impairment (MCI) to Alzheimer\u2019s disease and various dementias. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. Nevertheless a holistic approach has been attempted, in order to view the research themes and applications that currently exist around the \u2018\u2018intelligent systems\u2019\u2019 healthcare given to the cognitively impaired persons, and thus looking at research directions, systems, technological frameworks and perhaps trends.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Xbox 360 Kinect Cognitive Games Improve Slowness, Complexity of EEG, and Cognitive Functions in Subjects with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity and cognitive training are effective to enhance cognition in older patients with mild cognitive impairment (MCI). Xbox 360 Kinect cognitive games are a combination of physical activity and cognitive training. The objective of this study was to determine the short- and long-term effects of Xbox 360 Kinect cognitive games on slowness and complexity of electroencephalography (EEG) and cognitive functions in older subjects with MCI.\n## MATERIALS AND METHODS\nA clinical trial was conducted on 44 MCI subjects. Both males and females were randomized into experimental group (participated in Xbox 360 Kinect cognitive games) and control group (range of motion exercises only and no Xbox 360 Kinect cognitive games). Subjects were assessed before and after one session of game intervention for short-term effects and after 6 weeks for long-term effects. The outcome measures were the mini-mental state examination (MMSE), Montreal cognitive assessment scale (MoCA), trail making test (TMT) A and B, and slowness and complexity of EEG.\n## RESULTS\nAfter one session of game intervention, delta (0.704\u2009\u00b1\u20090.025; P\u2009=\u20090.013), theta (0.128\u2009\u00b1\u20090.009; P\u2009=\u20090.00127) waves, and complexity of EEG (0.642\u2009\u00b1\u20090.042; P\u2009=\u20090.008) significantly improved, in eyes closed state. Whereas after 6 weeks intervention of games, delta (0.673\u2009\u00b1\u20090.029; P\u2009=\u20090.013), theta (0.129\u2009\u00b1\u20090.013; P\u2009=\u20090.002), beta2 waves (0.044\u2009\u00b1\u20090.009; P\u2009=\u20090.046), complexity of EEG (0.051\u2009\u00b1\u20090.042; P\u2009=\u20090.016), MMSE (26.25\u2009\u00b1\u20090.347 vs. 23.722\u2009\u00b1\u20090.731; P\u2009=\u20090.003), MoCA (25.65\u2009\u00b1\u20090.310 vs. 22.00\u2009\u00b1\u20090.504; P\u2009=\u20090.0001), TMT-A (1.429\u2009\u00b1\u20090.234 vs. 2.225\u2009\u00b1\u20090.259; P\u2009=\u20090.028), and TMT-B (2.393\u2009\u00b1\u20090.201 vs. 3.780\u2009\u00b1\u20090.195; P\u2009=\u20090.0001) improved significantly. These changes were not observed in the control group.\n## CONCLUSION\nXbox 360 Kinect games showed beneficial effects after short- and long-term intervention on MCI subjects. These games can serve as potential therapeutic candidates for MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Exergaming and older adult cognition: a cluster randomized clinical trial.",
        "key_reference_abstract": "## BACKGROUND\nDementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or \"exergames\" may elicit greater participation.\n## PURPOSE\nTo test the following hypotheses: (1) stationary cycling with virtual reality tours (\"cybercycle\") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain improvement; and (3) brain-derived neurotrophic growth factor (BDNF) will increase.\n## DESIGN\nMulti-site cluster randomized clinical trial (RCT) of the impact of 3 months of cybercycling versus traditional exercise, on cognitive function in older adults. Data were collected in 2008-2010; analyses were conducted in 2010-2011.\n## SETTING/PARTICIPANTS\n102 older adults from eight retirement communities enrolled; 79 were randomized and 63 completed.\n## INTERVENTIONS\nA recumbent stationary ergometer was utilized; virtual reality tours and competitors were enabled on the cybercycle.\n## MAIN OUTCOME MEASURES\nExecutive function (Color Trails Difference, Stroop C, Digits Backward); clinical status (mild cognitive impairment; MCI); exercise effort/fitness; and plasma BDNF.\n## RESULTS\nIntent-to-treat analyses, controlling for age, education, and cluster randomization, revealed a significant group X time interaction for composite executive function (p=0.002). Cybercycling yielded a medium effect over traditional exercise (d=0.50). Cybercyclists had a 23% relative risk reduction in clinical progression to MCI. Exercise effort and fitness were comparable, suggesting another underlying mechanism. A significant group X time interaction for BDNF (p=0.05) indicated enhanced neuroplasticity among cybercyclists.\n## CONCLUSIONS\nCybercycling older adults achieved better cognitive function than traditional exercisers, for the same effort, suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline.\n## TRIAL REGISTRATION\nThis study is registered at Clinicaltrials.gov NCT01167400.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The Effects of Virtual Kayak Paddling Exercise on Postural Balance, Muscle Performance, and Cognitive Function in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial.",
        "key_reference_abstract": "Deterioration of physical and psychological health is an important issue in older adults aged 65 years or more. This study aimed to determine whether a virtual kayak paddling (VKP) exercise could improve postural balance, muscle performance, and cognitive function in older adults with mild cognitive impairment. Sixty participants were randomly assigned to the VKP (",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The effect of cognitive-motor dual task training with the biorescue force platform on cognition, balance and dual task performance in institutionalized older adults: a randomized controlled trial.",
        "key_reference_abstract": "[Purpose] This study investigates whether cognition, balance and dual task performance in institutionalized older adults improves by a virtual reality dual task training. [Subjects and Methods] Randomized controlled trial; Twenty institutionalized older adults with mild cognitive impairment (13 female, 7 male; average age, 87.2 \u00b1 5.96\u2005years) were randomized to the intervention (i.e. Virtual reality dual-task training using the BioRescue) or control group (no additional training). The intervention group took part in a 6-week training program while the elderly in the control group maintained their daily activities. Balance was measured with the Instrumented Timed Up-and-Go Test with and without a cognitive task. The Observed Emotion Rating Scale and Intrinsic Motivation Inventory were administered to evaluate the emotions and motivation regarding the exergaming program. [Results] The intervention group improved significantly on the total Timed Up-and-Go duration and the turn-to-sit duration during single-task walking in comparison to the control group who received no additional training. Participants found the virtual reality dual task training pleasant and useful for their concentration, memory and balance. Pleasure and alertness were the two emotions which were mostly seen during the intervention. [Conclusion] The BioRescue is a pleasant and interesting treatment method, well suited for institutionalized older adults in need of lifelong physical therapy.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Interactive video gaming compared with health education in older adults with mild cognitive impairment: a feasibility study.",
        "key_reference_abstract": "## OBJECTIVE\nWe evaluated the feasibility of a trial of Wii interactive video gaming, and its potential efficacy at improving cognitive functioning compared with health education, in a community sample of older adults with neuropsychologically defined mild cognitive impairment.\n## METHODS\nTwenty older adults were equally randomized to either group-based interactive video gaming or health education for 90\u2009min each week for 24\u2009weeks. Although the primary outcomes were related to study feasibility, we also explored the effect of the intervention on neuropsychological performance and other secondary outcomes.\n## RESULTS\nAll 20 participants completed the intervention, and 18 attended at least 80% of the sessions. The majority (80%) of participants were \"very much\" satisfied with the intervention. Bowling was enjoyed by the most participants and was also rated the highest among the games for mental, social, and physical stimulation. We observed medium effect sizes for cognitive and physical functioning in favor of the interactive video gaming condition, but these effects were not statistically significant in this small sample.\n## CONCLUSION\nInteractive video gaming is feasible for older adults with mild cognitive impairment, and medium effect sizes in favor of the Wii group warrant a larger efficacy trial.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The quest for synergy between physical exercise and cognitive stimulation via exergaming in people with dementia: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nExercise is often proposed as a non-pharmacological intervention to delay cognitive decline in people\u00a0with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in older adults with dementia.\n## METHODS\nA three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized and individually trained three times a week during 12\u2009weeks. Cognitive functioning was measured at baseline, after the 12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of covariance.\n## RESULTS\nData from 115 people with dementia (mean (SD) age\u2009=\u200979.2 (6.9) years; mean (SD) MMSE score\u2009=\u200922.9 (3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103-0.637), p\u2009=\u20090.007; exergame versus control 0.326 (0.081-0.571), p\u2009=\u20090.009). The effect size was moderate (partial \u03b7\n## CONCLUSIONS\nTo our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training on cognitive functioning in people with dementia. We found that both exergame training and aerobic training improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as psychomotor speed is an important predictor for functional decline. No effects were found on executive function, episodic memory and working memory.\n## TRIAL REGISTRATION\nNetherlands Trial Register, NTR5581 . Registered on 7 October 2015.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Effects of Virtual Reality-Based Physical and Cognitive Training on Executive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "Background: Walking while performing cognitive and motor tasks simultaneously interferes with gait performance and may lead to falls in older adults with mild cognitive impairment (MCI). Executive function, which seems to play a key role in dual-task gait performance, can be improved by combined physical and cognitive training. Virtual reality (VR) has the potential to assist rehabilitation, and its effect on physical and cognitive function requires further investigation. The purpose of this study was to assess the effects of VR-based physical and cognitive training on executive function and dual-task gait performance in older adults with MCI, as well as to compare VR-based physical and cognitive training with traditional combined physical and cognitive training. Method: Thirty-four community-dwelling older adults with MCI were randomly assigned into either a VR-based physical and cognitive training (VR) group or a combined traditional physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Outcome measures included executive function [Stroop Color and Word Test (SCWT) and trail making test (TMT) A and B], gait performance (gait speed, stride length, and cadence) and dual-task costs (DTCs). Walking tasks were performed during single-task walking, walking while performing serial subtraction (cognitive dual task), and walking while carrying a tray (motor dual task). The GAIT Up system was used to evaluate gait parameters including speed, stride length, cadence and DTCs. DTC were defined as 100 * (single-task gait parameters - dual-task gait parameters)/single-task gait parameters. Results: Both groups showed significant improvements in the SCWT and single-task and motor dual-task gait performance measures. However, only the VR group showed improvements in cognitive dual-task gait performance and the DTC of cadence. Moreover, the VR group showed more improvements than the CPC group in the TMT-B and DTC of cadence with borderline significances. Conclusion: A 12-week VR-based physical and cognitive training program led to significant improvements in dual-task gait performance in older adults with MCI, which may be attributed to improvements in executive function.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Using virtual reality-based training to improve cognitive function, instrumental activities of daily living and neural efficiency in older adults with mild cognitive impairment.",
        "key_reference_abstract": "## BACKGROUND\nA combination of physical and cognitive training appears to be the effective intervention to improve cognitive function in older adults with mild cognitive impairment (MCI). Computing technology such as virtual reality (VR) may have the potential to assist rehabilitation in shaping brain health. However, little is known about the potential of VR-based physical and cognitive training designed as an intervention for cognition and brain activation in elderly patients with MCI. Moreover, whether a VR program designed around functional tasks can improve their instrumental activities of daily living (IADL) requires further investigation.\n## AIM\nThis study investigated the effects of 12 weeks of VR-based physical and cognitive training on cognitive function, brain activation and IADL and compared the VR intervention with combined physical and cognitive training.\n## DESIGN\nA single-blinded randomized controlled trial.\n## SETTING\nCommunities and day care centers in Taipei, Taiwan.\n## POPULATION\nOlder adults with mild cognitive impairment.\n## METHODS\nThirty-four community-dwelling older adults with MCI were randomized into either a VR-based physical and cognitive training (VR) group or a combined physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Participants were assessed for their cognitive function (global cognition, executive function and verbal memory) and IADL at pre- and postintervention. Changes in prefrontal cortex activation during the global cognition test were also captured by functional near-infrared spectroscopy (NIRS) to identify the potential mediating pathway of the intervention.\n## RESULTS\nBoth groups showed improved executive function and verbal memory (immediate recall). However, only the VR group showed significant improvements in global cognition (P<0.001), verbal memory (delayed recall, P=0.002), and IADL (P<0.001) after the intervention. The group \u00d7 time interaction effects further demonstrated that IADL were more significantly improved with VR training than with CPC training (P=0.006). The hemodynamic data revealed decreased activation in prefrontal areas after training (P=0.0015), indicative of increased neural efficiency, in the VR-trained subjects.\n## CONCLUSIONS\nVR-based physical and cognitive training improves cognitive function, IADL and neural efficiency in older adults with MCI.\n## CLINICAL REHABILITATION IMPACT\nVR training could be implemented for older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Effects of Exergaming-Based Tai Chi on Cognitive Function and Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "## BACKGROUND\nDeclined cognitive function interferes with dual-task walking ability and may result in falls in older adults with mild cognitive impairment (MCI). The mind-body exercise, Tai Chi (TC), improves cognition and dual-task ability. Exergaming is low-cost, safe, highly scalable, and feasible. Whether the effects of exergaming-based TC is beneficial than traditional TC has not been investigated yet.\n## OBJECTIVES\nThe objective of this study was to investigate effects of exergaming-based TC on cognitive function and dual-task walking among older adults with MCI.\n## METHODS\nFifty patients with MCI were randomly assigned to an exergaming-based TC (EXER-TC) group, a traditional TC (TC) group, or a control group. The EXER-TC and TC groups received 36 training sessions (three, 50-min sessions per week) during a 12-week period. The control group received no intervention and were instructed to maintain their usual daily physical activities. The outcome variables measured included those related to cognitive function, dual-task cost (DTC), and gait performance.\n## RESULTS\nThe EXER-TC and TC groups performed better than the control group on the Chinese version of the Stroop Color and Word Test, the Trail Making Test Parts A and B, the one-back test, gait speed, and DTC of gait speed in cognitive dual-task conditions after training. However, there were no significant differences between the EXER-TC and TC groups. Compared with the control group, only the EXER-TC group experienced beneficial effects for the Montreal Cognitive Assessment.\n## CONCLUSION\nEXER-TC was comparable to traditional TC for enhancement of dual-task gait performance and executive function. These results suggested that the EXER-TC approach has potential therapeutic use in older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Effects of Combined Physical and Cognitive Virtual Reality-Based Training on Cognitive Impairment and Oxidative Stress in MCI Patients: A Pilot Study.",
        "key_reference_abstract": "The growing elderly population and the increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) call for the improvement of the quality and the efficacy of the healthcare and social support services. Exercise and cognitive stimulation have been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) has been recognized as a factor that contributes to the advancement of neurodegenerative diseases. Taking these aspects into account, the impact of a novel virtual reality (VR)-based program combining aerobic exercise and cognitive training has been evaluated in the pilot study proposed here. Ten patients (aged 73.3 \u00b1 5.7 years) with MCI (Mini-Mental State Examination, MMSE: 23.0 \u00b1 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. The assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while CTR worsened. EXP group showed a greater improvement than CTR in the executive test, memory functions and verbal fluency. No statistical significance was obtained when comparing within and between both the groups, probably due to small number of subjects examined, which amplifies the effect of the slight heterogeneity in scores recorded. Despite a greater worsening of Daily Living Activities tests, all participants reported a better performance in real life, thanks to the elicited self-perceived improvement. After training intervention OxS (i.e., reactive oxygen species (ROS) production, oxidative damage of lipids and DNA) decreased resulting in significantly (range",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Wii-fit for improving gait and balance in an assisted living facility: a pilot study.",
        "key_reference_abstract": "Objectives. To determine the effects on balance and gait of a Wii-Fit program compared to a walking program in subjects with mild Alzheimer's dementia (AD). Methods. A prospective randomized (1\u2009:\u20091) pilot study with two intervention arms was conducted in an assisted living facility with twenty-two mild AD subjects. In both groups the intervention occurred under supervision for 30 minutes daily, five times a week for eight weeks. Repeated measures ANOVA and paired t-tests were used to analyze changes. Results. Both groups showed improvement in Berg Balance Scale (BBS), Tinetti Test (TT) and Timed Up and Go (TUG) over 8 weeks. However, there was no statistically significant difference between the groups over time. Intragroup analysis in the Wii-Fit group showed significant improvement on BBS (P = 0.003), and TT (P = 0.013). The walking group showed a trend towards improvement on BBS (P = 0.06) and TUG (P = 0.07) and significant improvement in TT (P = 0.06). Conclusion. This pilot study demonstrates the safety and efficacy of Wii-Fit in an assisted living facility in subjects with mild AD. Use of Wii-Fit resulted in significant improvements in balance and gait comparable to those in the robust monitored walking program. These results need to be confirmed in a larger, methodologically sound study.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study.",
        "key_reference_abstract": "## BACKGROUND/OBJECTIVE\nBalance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD.\n## METHODS\nA prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73\u00b16.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention).\n## RESULTS\nAt 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p\u200a<\u200a0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p\u200a<\u200a0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p\u200a<\u200a0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p\u200a=\u200a0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p\u200a=\u200a0.445).\n## CONCLUSION\nHome-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Does cognition-specific computer training have better clinical outcomes than non-specific computer training? A single-blind, randomized controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nThe purpose of this study was to investigate differences between non-specific computer training (NCT) and cognition-specific computer training (CCT).\n## DESIGN\nRandomized controlled experimental study.\n## SETTING\nLocal community welfare center.\n## SUBJECTS\nA total of 78 subjects with mild cognitive impairment (MCI) were randomly assigned to the NCT ( n\u2009=\u200939) or CCT group ( n\u2009=\u200939).\n## INTERVENTION\nThe NCT group underwent NCT using Nintendo Wii for improving functional performance, while the CCT group underwent CCT using CoTras for improving function of the cognitive domain specifically. Subjects in both groups received 30-minute intervention three times a week for 10\u2009weeks.\n## MAIN MEASURES\nTo identify effects on cognitive function, the Wechsler Adult Intelligence Scale (WAIS) digit span subtests, Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test-Part B (TMT-B), Rey-Osterrieth Complex Figure Test, and Modified Taylor Complex Figure (MTCF) were used. Health-related quality of life (HRQoL) was assessed using the Short-Form 36-item questionnaire.\n## RESULTS\nAfter 10\u2009weeks, the WAIS subtests (digit span forward: 0.48\u2009\u00b1\u20090.08 vs. 0.12\u2009\u00b1\u20090.04; digit span backward: 0.46\u2009\u00b1\u20090.09 vs. 0.11\u2009\u00b1\u20090.04) and HRQoL (vitality: 9.05\u2009\u00b1\u20091.17 vs. 2.69\u2009\u00b1\u20091.67; role-emotional: 8.31\u2009\u00b1\u20091.20 vs. 4.15\u2009\u00b1\u20090.71; mental health: 11.62\u2009\u00b1\u20091.63 vs. 6.95\u2009\u00b1\u20091.75; bodily pain: 4.21\u2009\u00b1\u20092.17 vs. 0.10\u2009\u00b1\u20090.38) were significantly higher in the NCT group ( P\u2009<\u20090.05).\n## CONCLUSION\nNCT was superior to CCT for improving cognitive function and HRQoL of elderly adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Sensor-based balance training with motion feedback in people with mild cognitive impairment.",
        "key_reference_abstract": "Some individuals with mild cognitive impairment (MCI) experience not only cognitive deficits but also a decline in motor function, including postural balance. This pilot study sought to estimate the feasibility, user experience, and effects of a novel sensor-based balance training program. Patients with amnestic MCI (mean age 78.2 yr) were randomized to an intervention group (IG, n = 12) or control group (CG, n = 10). The IG underwent balance training (4 wk, twice a week) that included weight shifting and virtual obstacle crossing. Real-time visual/audio lower-limb motion feedback was provided from wearable sensors. The CG received no training. User experience was measured by a questionnaire. Postintervention effects on balance (center of mass sway during standing with eyes open [EO] and eyes closed), gait (speed, variability), cognition, and fear of falling were measured. Eleven participants (92%) completed the training and expressed fun, safety, and helpfulness of sensor feedback. Sway (EO, p = 0.04) and fear of falling (p = 0.02) were reduced in the IG compared to the CG. Changes in other measures were nonsignificant. Results suggest that the sensor-based training paradigm is well accepted in the target population and beneficial for improving postural control. Future studies should evaluate the added value of the sensor-based training compared to traditional training.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The Effect of a Virtual Reality-Based Intervention Program on Cognition in Older Adults with Mild Cognitive Impairment: A Randomized Control Trial.",
        "key_reference_abstract": "This study aimed to investigate the association between a virtual reality (VR) intervention program and cognitive, brain and physical functions in high-risk older adults. In a randomized controlled trial, we enrolled 68 individuals with mild cognitive impairment (MCI). The MCI diagnosis was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the Mini-Mental State Examination (MMSE) and frontal cognitive function: trail making test (TMT) A & B, and symbol digit substitute test (SDST). Resting state electroencephalogram (EEG) was measured in eyes open and eyes closed conditions for 5 minutes each, with a 19-channel wireless EEG device. The VR intervention program (3 times/week, 100 min each session) comprised four types of VR game-based content to improve the attention, memory and processing speed. Analysis of the subjects for group-time interactions revealed that the intervention group exhibited a significantly improved executive function and brain function at the resting state. Additionally, gait speed and mobility were also significantly improved between and after the follow-up. The VR-based training program improved cognitive and physical function in patients with MCI relative to controls. Encouraging patients to perform VR and game-based training may be beneficial to prevent cognitive decline.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The Effectiveness of a Virtual Reality-Based Intervention on Cognitive Functions in Older Adults with Mild Cognitive Impairment: A Single-Blind, Randomized Controlled Trial.",
        "key_reference_abstract": "Objective: Mild cognitive impairment (MCI) is a broad term for people at a stage between normal age-related cognitive decline and dementia, where cognitive problems are present but do not impair activities of daily living. This study aimed at evaluating the effectiveness of a virtual reality (VR)-based rehabilitation program on cognitive functions in MCI. Materials and Methods: Sixty-one older adults (25 men, 36 women) with MCI were randomized to the intervention group (n = 30; 70.12 \u00b1 2.57 years) or control (n = 31; 70.30 \u00b1 2.73 years) group. The intervention group received a VR (computer-generated interactive environments) intervention in addition to a conventional cognitive rehabilitation (CR) intervention, whereas the control group received only the CR intervention. Cognitive functions were assessed in both groups before and after the 12-week interventions by using the Loewenstein Occupational Therapy Cognitive Assessment-Geriatric. Results: Between-group comparisons revealed significantly greater improvements in orientation, visual-spatial perception, visuomotor organization, thinking operation, and attention/concentration functions in the VR group than in the control group (P < 0.001 for all). Conclusion: Our results showed that 12 weeks of VR-based rehabilitation enhanced cognitive functions in older adults with MCI. Using VR applications in CR is recommended to improve cognitive functions of older adults with MCI.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Effects of Exergaming on Cognitive and Social Functioning of People with Dementia: A Randomized Controlled Trial.",
        "key_reference_abstract": "## OBJECTIVES\nPhysical activity in people with dementia (PwD) may enhance physical and mental functioning. Exergaming, which combines physical exercise with cognitive stimulation in a gaming environment, was developed to overcome barriers in performing physical activities. We evaluated the effects of exergaming in day care centers (DCCs) for PwD and informal caregivers (ICs).\n## DESIGN\nA randomized controlled trial among 23 DCCs across the Netherlands randomized to exergaming (interactive cycling during 6\u00a0months) or a care-as-usual control group.\n## SETTING AND PARTICIPANTS\nA total of 112 (73 exergaming, 39 control) community-dwelling dyads (PwD, IC), with the PwD visiting a DCC at least twice per week.\n## METHODS\nAll outcomes were assessed using structured questionnaires during interviews with PwD and ICs at baseline (T0), 3\u00a0months (T1), and 6 months (T2). Primary outcomes: physical activity and mobility of the PwD.\n## SECONDARY OUTCOMES\nphysical, cognitive, emotional and social functioning, and quality of life for PwD. For ICs: experienced burden, quality of life, and positive care experiences.\n## RESULTS\nMixed-model analyses showed no statistically significant effects on primary outcomes. There were statistically significant positive effects on PwD's secondary outcomes at T2 on cognition [Mini-Mental State Examination (MMSE): r\u00a0=\u00a02.30, 95% confidence interval (CI): 0.65, 3.96, P\u00a0=\u00a0.007; and Trail Making Test part A (TMT-A): r\u00a0=\u00a0-28.98, 95% CI:\u00a0-54.89,\u00a0-3.08, P\u00a0=\u00a0.029], social functioning (Behavior Observation Scale for Intramural Psychogeriatrics subscale 1 (GIP): r\u00a0=\u00a0-1.86, 95% CI:\u00a0-3.56,\u00a0-0.17, P\u00a0=\u00a0.031), and positive post-test effects in ICs on distress caused by the PwD's neuropsychiatric symptoms (NPI-Q total distress: r\u00a0=\u00a0-3.30, 95% CI:\u00a0-6.57,\u00a0-0.03, P\u00a0=\u00a0.048) and on sense of competence (SSCQ: r\u00a0=\u00a02.78, 95% CI: 0.85, 4.71, P\u00a0=\u00a0.005).\n## CONCLUSIONS AND IMPLICATIONS\nExergaming appeared not effective on the primary outcomes. Despite the study being underpowered, we found positive effects on secondary outcomes for PwD and ICs, and no negative effects. We therefore recommend further study, dissemination, and implementation.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "The Effects of Exergaming on Executive and Physical Functions in Older Adults With Dementia: Randomized Controlled Trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite increasing interest in the effects of exergaming on cognitive function, little is known about its effects on older adults with dementia.\n## OBJECTIVE\nThe purpose of this is to investigate the effects of exergaming on executive and physical functions in older adults with dementia compared to regular aerobic exercise.\n## METHODS\nIn total, 24 older adults with moderate dementia participated in the study. Participants were randomized into either the exergame group (EXG, n=13, 54%) or the aerobic exercise group (AEG, n=11, 46%). For 12 weeks, EXG engaged in a running-based exergame and AEG performed a cycling exercise. At baseline and postintervention, participants underwent the Ericksen flanker test (accuracy % and response time [RT]) while recording event-related potentials (ERPs) that included the N2 and P3b potentials. Participants also underwent the senior fitness test (SFT) and the body composition test pre- and postintervention. Repeated-measures ANOVA was performed to assess the effects of time (pre- vs postintervention), group (EXG vs AEG), and group\u00d7time interactions.\n## RESULTS\nCompared to AEG, EXG demonstrated greater improvements in the SFT (F\n## CONCLUSIONS\nOur results suggest that exergaming may be associated with greater improvements in brain neuronal activity and enhanced executive function task performance than regular aerobic exercise. Exergaming characterized by both aerobic exercise and cognitive stimulation can be used as an effective intervention to improve cognitive and physical functions in older adults with dementia.\n## TRIAL REGISTRATION\nClinical Research Information Service KCT0008238; https://cris.nih.go.kr/cris/search/detailSearch.do/24170.",
        "truth": "False"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "An Evaluation of the Effects of Active Game Play on Cognition, Quality of Life and Depression for Older People with Dementia.",
        "key_reference_abstract": "## OBJECTIVES\nThis pilot study was intended to evaluate the effects of active game play on cognition, quality of life, and depression for older people with dementia.\n## METHODS\nThirty-eight older people with dementia were recruited. Eighteen people received eight-week active game play using Xbox 360 Kinect. Twenty people received their usual care. The Mini Mental State Examination, Quality of Life-Alzheimer's Disease and Cornell Scale for Depression in Dementia were used to measure the outcomes.\n## RESULTS\nThe results showed that there was no significant improvement on the mean scores of Mini Mental State Examination (\n## CONCLUSIONS\nThe study demonstrated that the active game play was effective in improving quality of life and alleviating depression in older people with dementia.\n## CLINICAL IMPLICATIONS\nFindings highlight the potential for gaming as a non-pharmacological interventions for older people with dementia.",
        "truth": "True"
    },
    {
        "pmid": "38879695",
        "meta_analysis_title": "Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.",
        "meta_analysis_question": "Does exergaming improve cognitive functions in people with mild cognitive impairment (MCI) or dementia?",
        "criteria": "RCTs were included if they (i) recruited participants with MCI or dementia in any type of clinical or community setting; (ii) evaluated any type of exergaming intervention, such as video gaming or VR-based exergaming and compared with a non-exergaming intervention as control; (iii) measured the change of cognitive score between pre-and-post intervention; and (iv) reported at least one of the cognitive domains, including global cognitive function, learning and memory, working memory, verbal fluency, complex attention, and executive function. Studies were excluded if they focused on cognitive decline in patients with Parkinson\u2019s disease, stroke, Huntington\u2019s disease, epilepsy, multiple sclerosis, diabetes, or psychiatric illness.",
        "subgroup": "Effect of exergaming intervention on global cognitive function in people with dementia. - Video-gaming",
        "key_reference_title": "Assessing Virtual Reality Environments as Cognitive Stimulation Method for Patients with MCI",
        "key_reference_abstract": "Advances in technology in the last decade have created a diverse field of applications for the care of persons with cognitive impairment. This chapter is an attempt to introduce a virtual reality computer-based intervention, which can used for cognitive stimulating and disease progression evaluation of a wide range of cognitive disorders ranging from mild cognitive impairment (MCI) to Alzheimer\u2019s disease and various dementias. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. Nevertheless a holistic approach has been attempted, in order to view the research themes and applications that currently exist around the \u2018\u2018intelligent systems\u2019\u2019 healthcare given to the cognitively impaired persons, and thus looking at research directions, systems, technological frameworks and perhaps trends.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation.",
        "key_reference_abstract": "## BACKGROUND\nDespite extensive training of citizens of Seattle in cardiopulmonary resuscitation (CPR), bystanders do not perform CPR in almost half of witnessed cardiac arrests. Instructions in chest compression plus mouth-to-mouth ventilation given by dispatchers over the telephone can require 2.4 minutes. In experimental studies, chest compression alone is associated with survival rates similar to those with chest compression plus mouth-to-mouth ventilation. We conducted a randomized study to compare CPR by chest compression alone with CPR by chest compression plus mouth-to-mouth ventilation.\n## METHODS\nThe setting of the trial was an urban, fire-department-based, emergency-medical-care system with central dispatching. In a randomized manner, telephone dispatchers gave bystanders at the scene of apparent cardiac arrest instructions in either chest compression alone or chest compression plus mouth-to-mouth ventilation. The primary end point was survival to hospital discharge.\n## RESULTS\nData were analyzed for 241 patients randomly assigned to receive chest compression alone and 279 assigned to chest compression plus mouth-to-mouth ventilation. Complete instructions were delivered in 62 percent of episodes for the group receiving chest compression plus mouth-to-mouth ventilation and 81 percent of episodes for the group receiving chest compression alone (P=0.005). Instructions for compression required 1.4 minutes less to complete than instructions for compression plus mouth-to-mouth ventilation. Survival to hospital discharge was better among patients assigned to chest compression alone than among those assigned to chest compression plus mouth-to-mouth ventilation (14.6 percent vs. 10.4 percent), but the difference was not statistically significant (P=0.18).\n## CONCLUSIONS\nThe outcome after CPR with chest compression alone is similar to that after chest compression with mouth-to-mouth ventilation, and chest compression alone may be the preferred approach for bystanders inexperienced in CPR.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "CPR with chest compression alone or with rescue breathing.",
        "key_reference_abstract": "## BACKGROUND\nThe role of rescue breathing in cardiopulmonary resuscitation (CPR) performed by a layperson is uncertain. We hypothesized that the dispatcher instructions to bystanders to provide chest compression alone would result in improved survival as compared with instructions to provide chest compression plus rescue breathing.\n## METHODS\nWe conducted a multicenter, randomized trial of dispatcher instructions to bystanders for performing CPR. The patients were persons 18 years of age or older with out-of-hospital cardiac arrest for whom dispatchers initiated CPR instruction to bystanders. Patients were randomly assigned to receive chest compression alone or chest compression plus rescue breathing. The primary outcome was survival to hospital discharge. Secondary outcomes included a favorable neurologic outcome at discharge.\n## RESULTS\nOf the 1941 patients who met the inclusion criteria, 981 were randomly assigned to receive chest compression alone and 960 to receive chest compression plus rescue breathing. We observed no significant difference between the two groups in the proportion of patients who survived to hospital discharge (12.5% with chest compression alone and 11.0% with chest compression plus rescue breathing, P=0.31) or in the proportion who survived with a favorable neurologic outcome in the two sites that assessed this secondary outcome (14.4% and 11.5%, respectively; P=0.13). Prespecified subgroup analyses showed a trend toward a higher proportion of patients surviving to hospital discharge with chest compression alone as compared with chest compression plus rescue breathing for patients with a cardiac cause of arrest (15.5% vs. 12.3%, P=0.09) and for those with shockable rhythms (31.9% vs. 25.7%, P=0.09).\n## CONCLUSIONS\nDispatcher instruction consisting of chest compression alone did not increase the survival rate overall, although there was a trend toward better outcomes in key clinical subgroups. The results support a strategy for CPR performed by laypersons that emphasizes chest compression and minimizes the role of rescue breathing. (Funded in part by the Laerdal Foundation for Acute Medicine and the Medic One Foundation; ClinicalTrials.gov number, NCT00219687.)",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Compression-only CPR or standard CPR in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nEmergency medical dispatchers give instructions on how to perform cardiopulmonary resuscitation (CPR) over the telephone to callers requesting help for a patient with suspected cardiac arrest, before the arrival of emergency medical services (EMS) personnel. A previous study indicated that instructions to perform CPR consisting of only chest compression result in a treatment efficacy that is similar or even superior to that associated with instructions given to perform standard CPR, which consists of both compression and ventilation. That study, however, was not powered to assess a possible difference in survival. The aim of this prospective, randomized study was to evaluate the possible superiority of compression-only CPR over standard CPR with respect to survival.\n## METHODS\nPatients with suspected, witnessed, out-of-hospital cardiac arrest were randomly assigned to undergo either compression-only CPR or standard CPR. The primary end point was 30-day survival.\n## RESULTS\nData for the primary analysis were collected from February 2005 through January 2009 for a total of 1276 patients. Of these, 620 patients had been assigned to receive compression-only CPR and 656 patients had been assigned to receive standard CPR. The rate of 30-day survival was similar in the two groups: 8.7% (54 of 620 patients) in the group receiving compression-only CPR and 7.0% (46 of 656 patients) in the group receiving standard CPR (absolute difference for compression-only vs. standard CPR, 1.7 percentage points; 95% confidence interval, -1.2 to 4.6; P=0.29).\n## CONCLUSIONS\nThis prospective, randomized study showed no significant difference with respect to survival at 30 days between instructions given by an emergency medical dispatcher, before the arrival of EMS personnel, for compression-only CPR and instructions for standard CPR in patients with suspected, witnessed, out-of-hospital cardiac arrest. (Funded by the Swedish Heart\u2013Lung Foundation and others; Karolinska Clinical Trial Registration number, CT20080012.)",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Quality and efficiency of bystander CPR. Belgian Cerebral Resuscitation Study Group.",
        "key_reference_abstract": "Incorrectly performed bystander CPR might compromise survival of the cardiac arrest patient. We therefore evaluated the outcome in 3306 out-of-hospital primary cardiac arrests of which 885 received bystander CPR. bystanders performed CPR correctly in 52%, incorrectly in 11%, 31% performed only external chest compressions (ECC) and 6% only mouth-to-mouth ventilation (MMV). The initial ECG in cases without bystander CPR was ventricular fibrillation in 28% (95% confidence interval: 27-30%); 45% (41-50%) and 39% (29-48%), respectively when bystander CPR was performed correctly or incorrectly; 43% (37-49%) when only ECC was applied and 22% (11-33%) when only MMV was practiced. Long term survival, defined as being awake 14 days after CPR, was 16% (13-19%) in patients with correct bystander CPR; 10% (7-14%) and 2% (0-9%), respectively when only ECC or only MMV was performed; 7% (6-8%) when no bystander was involved; 4% (0-8%) when bystander CPR was performed incorrectly. Bystander CPR might have a beneficial effect on survival by maintaining the heart in ventricular fibrillation by ECC. A negative effect of badly performed bystander CPR was not observed compared to cases which had not received bystander CPR.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Bystander initiated actions in out-of-hospital cardiopulmonary resuscitation: results from the Amsterdam Resuscitation Study (ARRESUST).",
        "key_reference_abstract": "The objective of this study was to analyze the functioning of the first two links of the chain of survival: 'access' and 'basic cardiopulmonary resuscitation (CPR)'. In a prospective study, all bystander witnessed circulatory arrests resuscitated by emergency medical service (EMS) personnel, were recorded consecutively. Univariate differences in survival were calculated for various witnesses, the performance of basic CPR, the quality of CPR, the performers of CPR and the delays. A logistic regression model for survival was developed from all potential predictors of these first two links. From the 922 included patients, 93 survived to hospital discharge. In 21% of the cases, the witness did not immediately call 112, but first called others, resulting in a longer delay and a lower survival. Family members were frequent witnesses of the arrest (44%), but seldom started basic CPR (11%). Survival, when basic CPR performers were untrained and had no previous experience, was similar to that when no basic CPR was performed (6%). Not performing basic CPR, delay in basic CPR, the interval between basic CPR and EMS arrival, and being both untrained and inexperienced in basic CPR were independent predictors for survival. Basic CPR performed by persons trained a long time ago did not appear to have a negative influence on outcome, nor did basic CPR limited to chest compressions alone. The mere reporting that basic CPR has been performed does not describe adequately the actual value of basic CPR. The interval from collapse to initiation of basic CPR, and the training and experience of the performer must be taken into account. Policy makers for basic CPR training should focus on partners of the patients, who are most likely witness of an arrest.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study.",
        "key_reference_abstract": "## BACKGROUND\nMouth-to-mouth ventilation is a barrier to bystanders doing cardiopulmonary resuscitation (CPR), but few clinical studies have investigated the efficacy of bystander resuscitation by chest compressions without mouth-to-mouth ventilation (cardiac-only resuscitation).\n## METHODS\nWe did a prospective, multicentre, observational study of patients who had out-of-hospital cardiac arrest. On arrival at the scene, paramedics assessed the technique of bystander resuscitation. The primary endpoint was favourable neurological outcome 30 days after cardiac arrest.\n## FINDINGS\n4068 adult patients who had out-of-hospital cardiac arrest witnessed by bystanders were included; 439 (11%) received cardiac-only resuscitation from bystanders, 712 (18%) conventional CPR, and 2917 (72%) received no bystander CPR. Any resuscitation attempt was associated with a higher proportion having favourable neurological outcomes than no resuscitation (5.0%vs 2.2%, p<0.0001). Cardiac-only resuscitation resulted in a higher proportion of patients with favourable neurological outcomes than conventional CPR in patients with apnoea (6.2%vs 3.1%; p=0.0195), with shockable rhythm (19.4%vs 11.2%, p=0.041), and with resuscitation that started within 4 min of arrest (10.1%vs 5.1%, p=0.0221). However, there was no evidence for any benefit from the addition of mouth-to-mouth ventilation in any subgroup. The adjusted odds ratio for a favourable neurological outcome after cardiac-only resuscitation was 2.2 (95% CI 1.2-4.2) in patients who received any resuscitation from bystanders.\n## INTERPRETATION\nCardiac-only resuscitation by bystanders is the preferable approach to resuscitation for adult patients with witnessed out-of-hospital cardiac arrest, especially those with apnoea, shockable rhythm, or short periods of untreated arrest.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation.",
        "key_reference_abstract": "## BACKGROUND\nWe sought to compare the 1-month survival rates among patients after out-of-hospital cardiac arrest who had been given bystander cardiopulmonary resuscitation (CPR) in relation to whether they had received standard CPR with chest compression plus mouth-to-mouth ventilation or chest compression only.\n## METHODS AND RESULTS\nAll patients with out-of-hospital cardiac arrest who received bystander CPR and who were reported to the Swedish Cardiac Arrest Register between 1990 and 2005 were included. Crew-witnessed cases were excluded. Among 11,275 patients, 73% (n=8209) received standard CPR, and 10% (n=1145) received chest compression only. There was no significant difference in 1-month survival between patients who received standard CPR (1-month survival=7.2%) and those who received chest compression only (1-month survival=6.7%).\n## CONCLUSIONS\nAmong patients with out-of-hospital cardiac arrest who received bystander CPR, there was no significant difference in 1-month survival between a standard CPR program with chest compression plus mouth-to-mouth ventilation and a simplified version of CPR with chest compression only.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Effectiveness of bystander-initiated cardiac-only resuscitation for patients with out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nPrevious animal and clinical studies suggest that bystander-initiated cardiac-only resuscitation may be superior to conventional cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrests. Our hypothesis was that both cardiac-only bystander resuscitation and conventional bystander CPR would improve outcomes from out-of-hospital cardiac arrests of < or = 15 minutes' duration, whereas the addition of rescue breathing would improve outcomes for cardiac arrests lasting > 15 minutes.\n## METHODS AND RESULTS\nWe carried out a prospective, population-based, observational study involving consecutive patients with emergency responder resuscitation attempts from May 1, 1998, through April 30, 2003. The primary outcome measure was 1-year survival with favorable neurological outcome. Multivariable logistic regression analysis was performed to evaluate the relationship between type of CPR and outcomes. Among the 4902 witnessed cardiac arrests, 783 received conventional CPR, and 544 received cardiac-only resuscitation. Excluding very-long-duration cardiac arrests (> 15 minutes), the cardiac-only resuscitation yielded a higher rate of 1-year survival with favorable neurological outcome than no bystander CPR (4.3% versus 2.5%; odds ratio, 1.72; 95% CI, 1.01 to 2.95), and conventional CPR showed similar effectiveness (4.1%; odds ratio, 1.57; 95% CI, 0.95 to 2.60). For the very-long-duration arrests, neurologically favorable 1-year survival was greater in the conventional CPR group, but there were few survivors regardless of the type of bystander CPR (0.3% [2 of 624], 0% [0 of 92], and 2.2% [3 of 139] in the no bystander CPR, cardiac-only CPR, and conventional CPR groups, respectively; P<0.05).\n## CONCLUSIONS\nBystander-initiated cardiac-only resuscitation and conventional CPR are similarly effective for most adult out-of-hospital cardiac arrests. For very prolonged cardiac arrests, the addition of rescue breathing may be of some help.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Standard basic life support vs. continuous chest compressions only in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nThe importance of ventilations after cardiac arrest has been much debated recently and eliminating mouth-to-mouth ventilations for bystanders has been suggested as a means to increase bystander cardiopulmonary resuscitation (CPR). Standard basic life support (S-BLS) is not documented to be superior to continuous chest compressions (CCC).\n## METHODS\nRetrospective, observational study of all non-traumatic cardiac arrest patients older than 18 years between May 2003 and December 2006 treated by the community-run emergency medical service (EMS) in Oslo. Outcome for patients receiving S-BLS was compared with patients receiving CCC. All Utstein characteristics were registered for both patient groups as well as for patients not receiving any bystander CPR by reviewing Ambulance run sheets, Utstein forms and hospital records. Method of bystander CPR as well as dispatcher instruction was registered by first-arriving ambulance personnel.\n## RESULTS\nSix-hundred ninety-five out of 809 cardiac arrests in our EMS were included in this study. Two-hundred eighty-one (40%) received S-CPR and 145 (21%) received CCC. There were no differences in outcome between the two patient groups, with 35 (13%) discharged with a favourable outcome for the S-BLS group and 15 (10%) in the CCC group (P=0.859). Similarly, there was no difference in survival subgroup analysis of patients presenting with initial ventricular fibrillation/ventricular tachycardia after witnessed arrest, with 32 (29%) and 10 (28%) patients discharged from hospital in the S-BLS and CCC groups, respectively (P=0.972).\n## CONCLUSIONS\nPatients receiving CCC from bystanders did not have a worse outcome than patients receiving standard CPR, even with a tendency towards a higher distribution of known negative predictive features.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Primary Analysis of Randomized Controlled Trials in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Comparison of chest compression only and standard cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Singapore.",
        "key_reference_abstract": "## OBJECTIVE\nChest compression only cardiopulmonary resuscitation (CC-CPR) without ventilation has been proposed as an alternative to standard cardiopulmonary resuscitation (CPR) for bystanders. However, there has been controversy regarding the relative effectiveness of both of these techniques. We aim to compare the outcomes of cardiac arrest patients in the cardiac arrest and resuscitation epidemiology study who either received CC-CPR, standard CPR or no bystander CPR.\n## METHODS\nThis prospective cohort study involved all out-of-hospital cardiac arrest (OHCA) patients attended to by emergency medical service (EMS) providers in a large urban centre. The data analyses were conducted secondarily on these collected data. The technique of bystander CPR was reported by paramedics who arrived at the scene.\n## RESULTS\nFrom 1 October 2001 to 14 October 2004, 2428 patients were enrolled into the study. Of these, 255 were EMS-witnessed arrests and were excluded. 1695 cases did not receive any bystander CPR, 287 had standard CPR and 154 CC-CPR. Patient characteristics were similar in both the standard and CC-CPR groups except for a higher incidence of residential arrests and previous heart disease sufferers in the CC-CPR group. Patients who received standard CPR (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.1-14.0) or CC-CPR (OR 5.0, 95% CI 1.5-16.4) were more likely to survive to discharge than those who had no bystander CPR. There was no significant difference in survival to discharge between those who received CC-CPR and standard CPR (OR 0.9, 95% CI 0.3-3.1).\n## CONCLUSION\nWe found that patients were more likely to survive with any form of bystander CPR than without. This emphasises the importance of chest compressions for OHCA patients, whether with or without ventilation.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation.",
        "key_reference_abstract": "## BACKGROUND\nDespite extensive training of citizens of Seattle in cardiopulmonary resuscitation (CPR), bystanders do not perform CPR in almost half of witnessed cardiac arrests. Instructions in chest compression plus mouth-to-mouth ventilation given by dispatchers over the telephone can require 2.4 minutes. In experimental studies, chest compression alone is associated with survival rates similar to those with chest compression plus mouth-to-mouth ventilation. We conducted a randomized study to compare CPR by chest compression alone with CPR by chest compression plus mouth-to-mouth ventilation.\n## METHODS\nThe setting of the trial was an urban, fire-department-based, emergency-medical-care system with central dispatching. In a randomized manner, telephone dispatchers gave bystanders at the scene of apparent cardiac arrest instructions in either chest compression alone or chest compression plus mouth-to-mouth ventilation. The primary end point was survival to hospital discharge.\n## RESULTS\nData were analyzed for 241 patients randomly assigned to receive chest compression alone and 279 assigned to chest compression plus mouth-to-mouth ventilation. Complete instructions were delivered in 62 percent of episodes for the group receiving chest compression plus mouth-to-mouth ventilation and 81 percent of episodes for the group receiving chest compression alone (P=0.005). Instructions for compression required 1.4 minutes less to complete than instructions for compression plus mouth-to-mouth ventilation. Survival to hospital discharge was better among patients assigned to chest compression alone than among those assigned to chest compression plus mouth-to-mouth ventilation (14.6 percent vs. 10.4 percent), but the difference was not statistically significant (P=0.18).\n## CONCLUSIONS\nThe outcome after CPR with chest compression alone is similar to that after chest compression with mouth-to-mouth ventilation, and chest compression alone may be the preferred approach for bystanders inexperienced in CPR.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "CPR with chest compression alone or with rescue breathing.",
        "key_reference_abstract": "## BACKGROUND\nThe role of rescue breathing in cardiopulmonary resuscitation (CPR) performed by a layperson is uncertain. We hypothesized that the dispatcher instructions to bystanders to provide chest compression alone would result in improved survival as compared with instructions to provide chest compression plus rescue breathing.\n## METHODS\nWe conducted a multicenter, randomized trial of dispatcher instructions to bystanders for performing CPR. The patients were persons 18 years of age or older with out-of-hospital cardiac arrest for whom dispatchers initiated CPR instruction to bystanders. Patients were randomly assigned to receive chest compression alone or chest compression plus rescue breathing. The primary outcome was survival to hospital discharge. Secondary outcomes included a favorable neurologic outcome at discharge.\n## RESULTS\nOf the 1941 patients who met the inclusion criteria, 981 were randomly assigned to receive chest compression alone and 960 to receive chest compression plus rescue breathing. We observed no significant difference between the two groups in the proportion of patients who survived to hospital discharge (12.5% with chest compression alone and 11.0% with chest compression plus rescue breathing, P=0.31) or in the proportion who survived with a favorable neurologic outcome in the two sites that assessed this secondary outcome (14.4% and 11.5%, respectively; P=0.13). Prespecified subgroup analyses showed a trend toward a higher proportion of patients surviving to hospital discharge with chest compression alone as compared with chest compression plus rescue breathing for patients with a cardiac cause of arrest (15.5% vs. 12.3%, P=0.09) and for those with shockable rhythms (31.9% vs. 25.7%, P=0.09).\n## CONCLUSIONS\nDispatcher instruction consisting of chest compression alone did not increase the survival rate overall, although there was a trend toward better outcomes in key clinical subgroups. The results support a strategy for CPR performed by laypersons that emphasizes chest compression and minimizes the role of rescue breathing. (Funded in part by the Laerdal Foundation for Acute Medicine and the Medic One Foundation; ClinicalTrials.gov number, NCT00219687.)",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Compression-only CPR or standard CPR in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nEmergency medical dispatchers give instructions on how to perform cardiopulmonary resuscitation (CPR) over the telephone to callers requesting help for a patient with suspected cardiac arrest, before the arrival of emergency medical services (EMS) personnel. A previous study indicated that instructions to perform CPR consisting of only chest compression result in a treatment efficacy that is similar or even superior to that associated with instructions given to perform standard CPR, which consists of both compression and ventilation. That study, however, was not powered to assess a possible difference in survival. The aim of this prospective, randomized study was to evaluate the possible superiority of compression-only CPR over standard CPR with respect to survival.\n## METHODS\nPatients with suspected, witnessed, out-of-hospital cardiac arrest were randomly assigned to undergo either compression-only CPR or standard CPR. The primary end point was 30-day survival.\n## RESULTS\nData for the primary analysis were collected from February 2005 through January 2009 for a total of 1276 patients. Of these, 620 patients had been assigned to receive compression-only CPR and 656 patients had been assigned to receive standard CPR. The rate of 30-day survival was similar in the two groups: 8.7% (54 of 620 patients) in the group receiving compression-only CPR and 7.0% (46 of 656 patients) in the group receiving standard CPR (absolute difference for compression-only vs. standard CPR, 1.7 percentage points; 95% confidence interval, -1.2 to 4.6; P=0.29).\n## CONCLUSIONS\nThis prospective, randomized study showed no significant difference with respect to survival at 30 days between instructions given by an emergency medical dispatcher, before the arrival of EMS personnel, for compression-only CPR and instructions for standard CPR in patients with suspected, witnessed, out-of-hospital cardiac arrest. (Funded by the Swedish Heart\u2013Lung Foundation and others; Karolinska Clinical Trial Registration number, CT20080012.)",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Quality and efficiency of bystander CPR. Belgian Cerebral Resuscitation Study Group.",
        "key_reference_abstract": "Incorrectly performed bystander CPR might compromise survival of the cardiac arrest patient. We therefore evaluated the outcome in 3306 out-of-hospital primary cardiac arrests of which 885 received bystander CPR. bystanders performed CPR correctly in 52%, incorrectly in 11%, 31% performed only external chest compressions (ECC) and 6% only mouth-to-mouth ventilation (MMV). The initial ECG in cases without bystander CPR was ventricular fibrillation in 28% (95% confidence interval: 27-30%); 45% (41-50%) and 39% (29-48%), respectively when bystander CPR was performed correctly or incorrectly; 43% (37-49%) when only ECC was applied and 22% (11-33%) when only MMV was practiced. Long term survival, defined as being awake 14 days after CPR, was 16% (13-19%) in patients with correct bystander CPR; 10% (7-14%) and 2% (0-9%), respectively when only ECC or only MMV was performed; 7% (6-8%) when no bystander was involved; 4% (0-8%) when bystander CPR was performed incorrectly. Bystander CPR might have a beneficial effect on survival by maintaining the heart in ventricular fibrillation by ECC. A negative effect of badly performed bystander CPR was not observed compared to cases which had not received bystander CPR.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Bystander initiated actions in out-of-hospital cardiopulmonary resuscitation: results from the Amsterdam Resuscitation Study (ARRESUST).",
        "key_reference_abstract": "The objective of this study was to analyze the functioning of the first two links of the chain of survival: 'access' and 'basic cardiopulmonary resuscitation (CPR)'. In a prospective study, all bystander witnessed circulatory arrests resuscitated by emergency medical service (EMS) personnel, were recorded consecutively. Univariate differences in survival were calculated for various witnesses, the performance of basic CPR, the quality of CPR, the performers of CPR and the delays. A logistic regression model for survival was developed from all potential predictors of these first two links. From the 922 included patients, 93 survived to hospital discharge. In 21% of the cases, the witness did not immediately call 112, but first called others, resulting in a longer delay and a lower survival. Family members were frequent witnesses of the arrest (44%), but seldom started basic CPR (11%). Survival, when basic CPR performers were untrained and had no previous experience, was similar to that when no basic CPR was performed (6%). Not performing basic CPR, delay in basic CPR, the interval between basic CPR and EMS arrival, and being both untrained and inexperienced in basic CPR were independent predictors for survival. Basic CPR performed by persons trained a long time ago did not appear to have a negative influence on outcome, nor did basic CPR limited to chest compressions alone. The mere reporting that basic CPR has been performed does not describe adequately the actual value of basic CPR. The interval from collapse to initiation of basic CPR, and the training and experience of the performer must be taken into account. Policy makers for basic CPR training should focus on partners of the patients, who are most likely witness of an arrest.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study.",
        "key_reference_abstract": "## BACKGROUND\nMouth-to-mouth ventilation is a barrier to bystanders doing cardiopulmonary resuscitation (CPR), but few clinical studies have investigated the efficacy of bystander resuscitation by chest compressions without mouth-to-mouth ventilation (cardiac-only resuscitation).\n## METHODS\nWe did a prospective, multicentre, observational study of patients who had out-of-hospital cardiac arrest. On arrival at the scene, paramedics assessed the technique of bystander resuscitation. The primary endpoint was favourable neurological outcome 30 days after cardiac arrest.\n## FINDINGS\n4068 adult patients who had out-of-hospital cardiac arrest witnessed by bystanders were included; 439 (11%) received cardiac-only resuscitation from bystanders, 712 (18%) conventional CPR, and 2917 (72%) received no bystander CPR. Any resuscitation attempt was associated with a higher proportion having favourable neurological outcomes than no resuscitation (5.0%vs 2.2%, p<0.0001). Cardiac-only resuscitation resulted in a higher proportion of patients with favourable neurological outcomes than conventional CPR in patients with apnoea (6.2%vs 3.1%; p=0.0195), with shockable rhythm (19.4%vs 11.2%, p=0.041), and with resuscitation that started within 4 min of arrest (10.1%vs 5.1%, p=0.0221). However, there was no evidence for any benefit from the addition of mouth-to-mouth ventilation in any subgroup. The adjusted odds ratio for a favourable neurological outcome after cardiac-only resuscitation was 2.2 (95% CI 1.2-4.2) in patients who received any resuscitation from bystanders.\n## INTERPRETATION\nCardiac-only resuscitation by bystanders is the preferable approach to resuscitation for adult patients with witnessed out-of-hospital cardiac arrest, especially those with apnoea, shockable rhythm, or short periods of untreated arrest.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation.",
        "key_reference_abstract": "## BACKGROUND\nWe sought to compare the 1-month survival rates among patients after out-of-hospital cardiac arrest who had been given bystander cardiopulmonary resuscitation (CPR) in relation to whether they had received standard CPR with chest compression plus mouth-to-mouth ventilation or chest compression only.\n## METHODS AND RESULTS\nAll patients with out-of-hospital cardiac arrest who received bystander CPR and who were reported to the Swedish Cardiac Arrest Register between 1990 and 2005 were included. Crew-witnessed cases were excluded. Among 11,275 patients, 73% (n=8209) received standard CPR, and 10% (n=1145) received chest compression only. There was no significant difference in 1-month survival between patients who received standard CPR (1-month survival=7.2%) and those who received chest compression only (1-month survival=6.7%).\n## CONCLUSIONS\nAmong patients with out-of-hospital cardiac arrest who received bystander CPR, there was no significant difference in 1-month survival between a standard CPR program with chest compression plus mouth-to-mouth ventilation and a simplified version of CPR with chest compression only.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Effectiveness of bystander-initiated cardiac-only resuscitation for patients with out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nPrevious animal and clinical studies suggest that bystander-initiated cardiac-only resuscitation may be superior to conventional cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrests. Our hypothesis was that both cardiac-only bystander resuscitation and conventional bystander CPR would improve outcomes from out-of-hospital cardiac arrests of < or = 15 minutes' duration, whereas the addition of rescue breathing would improve outcomes for cardiac arrests lasting > 15 minutes.\n## METHODS AND RESULTS\nWe carried out a prospective, population-based, observational study involving consecutive patients with emergency responder resuscitation attempts from May 1, 1998, through April 30, 2003. The primary outcome measure was 1-year survival with favorable neurological outcome. Multivariable logistic regression analysis was performed to evaluate the relationship between type of CPR and outcomes. Among the 4902 witnessed cardiac arrests, 783 received conventional CPR, and 544 received cardiac-only resuscitation. Excluding very-long-duration cardiac arrests (> 15 minutes), the cardiac-only resuscitation yielded a higher rate of 1-year survival with favorable neurological outcome than no bystander CPR (4.3% versus 2.5%; odds ratio, 1.72; 95% CI, 1.01 to 2.95), and conventional CPR showed similar effectiveness (4.1%; odds ratio, 1.57; 95% CI, 0.95 to 2.60). For the very-long-duration arrests, neurologically favorable 1-year survival was greater in the conventional CPR group, but there were few survivors regardless of the type of bystander CPR (0.3% [2 of 624], 0% [0 of 92], and 2.2% [3 of 139] in the no bystander CPR, cardiac-only CPR, and conventional CPR groups, respectively; P<0.05).\n## CONCLUSIONS\nBystander-initiated cardiac-only resuscitation and conventional CPR are similarly effective for most adult out-of-hospital cardiac arrests. For very prolonged cardiac arrests, the addition of rescue breathing may be of some help.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Standard basic life support vs. continuous chest compressions only in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nThe importance of ventilations after cardiac arrest has been much debated recently and eliminating mouth-to-mouth ventilations for bystanders has been suggested as a means to increase bystander cardiopulmonary resuscitation (CPR). Standard basic life support (S-BLS) is not documented to be superior to continuous chest compressions (CCC).\n## METHODS\nRetrospective, observational study of all non-traumatic cardiac arrest patients older than 18 years between May 2003 and December 2006 treated by the community-run emergency medical service (EMS) in Oslo. Outcome for patients receiving S-BLS was compared with patients receiving CCC. All Utstein characteristics were registered for both patient groups as well as for patients not receiving any bystander CPR by reviewing Ambulance run sheets, Utstein forms and hospital records. Method of bystander CPR as well as dispatcher instruction was registered by first-arriving ambulance personnel.\n## RESULTS\nSix-hundred ninety-five out of 809 cardiac arrests in our EMS were included in this study. Two-hundred eighty-one (40%) received S-CPR and 145 (21%) received CCC. There were no differences in outcome between the two patient groups, with 35 (13%) discharged with a favourable outcome for the S-BLS group and 15 (10%) in the CCC group (P=0.859). Similarly, there was no difference in survival subgroup analysis of patients presenting with initial ventricular fibrillation/ventricular tachycardia after witnessed arrest, with 32 (29%) and 10 (28%) patients discharged from hospital in the S-BLS and CCC groups, respectively (P=0.972).\n## CONCLUSIONS\nPatients receiving CCC from bystanders did not have a worse outcome than patients receiving standard CPR, even with a tendency towards a higher distribution of known negative predictive features.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Secondary Analysis of Observational Cohort Studies in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Comparison of chest compression only and standard cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Singapore.",
        "key_reference_abstract": "## OBJECTIVE\nChest compression only cardiopulmonary resuscitation (CC-CPR) without ventilation has been proposed as an alternative to standard cardiopulmonary resuscitation (CPR) for bystanders. However, there has been controversy regarding the relative effectiveness of both of these techniques. We aim to compare the outcomes of cardiac arrest patients in the cardiac arrest and resuscitation epidemiology study who either received CC-CPR, standard CPR or no bystander CPR.\n## METHODS\nThis prospective cohort study involved all out-of-hospital cardiac arrest (OHCA) patients attended to by emergency medical service (EMS) providers in a large urban centre. The data analyses were conducted secondarily on these collected data. The technique of bystander CPR was reported by paramedics who arrived at the scene.\n## RESULTS\nFrom 1 October 2001 to 14 October 2004, 2428 patients were enrolled into the study. Of these, 255 were EMS-witnessed arrests and were excluded. 1695 cases did not receive any bystander CPR, 287 had standard CPR and 154 CC-CPR. Patient characteristics were similar in both the standard and CC-CPR groups except for a higher incidence of residential arrests and previous heart disease sufferers in the CC-CPR group. Patients who received standard CPR (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.1-14.0) or CC-CPR (OR 5.0, 95% CI 1.5-16.4) were more likely to survive to discharge than those who had no bystander CPR. There was no significant difference in survival to discharge between those who received CC-CPR and standard CPR (OR 0.9, 95% CI 0.3-3.1).\n## CONCLUSION\nWe found that patients were more likely to survive with any form of bystander CPR than without. This emphasises the importance of chest compressions for OHCA patients, whether with or without ventilation.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation.",
        "key_reference_abstract": "## BACKGROUND\nDespite extensive training of citizens of Seattle in cardiopulmonary resuscitation (CPR), bystanders do not perform CPR in almost half of witnessed cardiac arrests. Instructions in chest compression plus mouth-to-mouth ventilation given by dispatchers over the telephone can require 2.4 minutes. In experimental studies, chest compression alone is associated with survival rates similar to those with chest compression plus mouth-to-mouth ventilation. We conducted a randomized study to compare CPR by chest compression alone with CPR by chest compression plus mouth-to-mouth ventilation.\n## METHODS\nThe setting of the trial was an urban, fire-department-based, emergency-medical-care system with central dispatching. In a randomized manner, telephone dispatchers gave bystanders at the scene of apparent cardiac arrest instructions in either chest compression alone or chest compression plus mouth-to-mouth ventilation. The primary end point was survival to hospital discharge.\n## RESULTS\nData were analyzed for 241 patients randomly assigned to receive chest compression alone and 279 assigned to chest compression plus mouth-to-mouth ventilation. Complete instructions were delivered in 62 percent of episodes for the group receiving chest compression plus mouth-to-mouth ventilation and 81 percent of episodes for the group receiving chest compression alone (P=0.005). Instructions for compression required 1.4 minutes less to complete than instructions for compression plus mouth-to-mouth ventilation. Survival to hospital discharge was better among patients assigned to chest compression alone than among those assigned to chest compression plus mouth-to-mouth ventilation (14.6 percent vs. 10.4 percent), but the difference was not statistically significant (P=0.18).\n## CONCLUSIONS\nThe outcome after CPR with chest compression alone is similar to that after chest compression with mouth-to-mouth ventilation, and chest compression alone may be the preferred approach for bystanders inexperienced in CPR.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "CPR with chest compression alone or with rescue breathing.",
        "key_reference_abstract": "## BACKGROUND\nThe role of rescue breathing in cardiopulmonary resuscitation (CPR) performed by a layperson is uncertain. We hypothesized that the dispatcher instructions to bystanders to provide chest compression alone would result in improved survival as compared with instructions to provide chest compression plus rescue breathing.\n## METHODS\nWe conducted a multicenter, randomized trial of dispatcher instructions to bystanders for performing CPR. The patients were persons 18 years of age or older with out-of-hospital cardiac arrest for whom dispatchers initiated CPR instruction to bystanders. Patients were randomly assigned to receive chest compression alone or chest compression plus rescue breathing. The primary outcome was survival to hospital discharge. Secondary outcomes included a favorable neurologic outcome at discharge.\n## RESULTS\nOf the 1941 patients who met the inclusion criteria, 981 were randomly assigned to receive chest compression alone and 960 to receive chest compression plus rescue breathing. We observed no significant difference between the two groups in the proportion of patients who survived to hospital discharge (12.5% with chest compression alone and 11.0% with chest compression plus rescue breathing, P=0.31) or in the proportion who survived with a favorable neurologic outcome in the two sites that assessed this secondary outcome (14.4% and 11.5%, respectively; P=0.13). Prespecified subgroup analyses showed a trend toward a higher proportion of patients surviving to hospital discharge with chest compression alone as compared with chest compression plus rescue breathing for patients with a cardiac cause of arrest (15.5% vs. 12.3%, P=0.09) and for those with shockable rhythms (31.9% vs. 25.7%, P=0.09).\n## CONCLUSIONS\nDispatcher instruction consisting of chest compression alone did not increase the survival rate overall, although there was a trend toward better outcomes in key clinical subgroups. The results support a strategy for CPR performed by laypersons that emphasizes chest compression and minimizes the role of rescue breathing. (Funded in part by the Laerdal Foundation for Acute Medicine and the Medic One Foundation; ClinicalTrials.gov number, NCT00219687.)",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Compression-only CPR or standard CPR in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nEmergency medical dispatchers give instructions on how to perform cardiopulmonary resuscitation (CPR) over the telephone to callers requesting help for a patient with suspected cardiac arrest, before the arrival of emergency medical services (EMS) personnel. A previous study indicated that instructions to perform CPR consisting of only chest compression result in a treatment efficacy that is similar or even superior to that associated with instructions given to perform standard CPR, which consists of both compression and ventilation. That study, however, was not powered to assess a possible difference in survival. The aim of this prospective, randomized study was to evaluate the possible superiority of compression-only CPR over standard CPR with respect to survival.\n## METHODS\nPatients with suspected, witnessed, out-of-hospital cardiac arrest were randomly assigned to undergo either compression-only CPR or standard CPR. The primary end point was 30-day survival.\n## RESULTS\nData for the primary analysis were collected from February 2005 through January 2009 for a total of 1276 patients. Of these, 620 patients had been assigned to receive compression-only CPR and 656 patients had been assigned to receive standard CPR. The rate of 30-day survival was similar in the two groups: 8.7% (54 of 620 patients) in the group receiving compression-only CPR and 7.0% (46 of 656 patients) in the group receiving standard CPR (absolute difference for compression-only vs. standard CPR, 1.7 percentage points; 95% confidence interval, -1.2 to 4.6; P=0.29).\n## CONCLUSIONS\nThis prospective, randomized study showed no significant difference with respect to survival at 30 days between instructions given by an emergency medical dispatcher, before the arrival of EMS personnel, for compression-only CPR and instructions for standard CPR in patients with suspected, witnessed, out-of-hospital cardiac arrest. (Funded by the Swedish Heart\u2013Lung Foundation and others; Karolinska Clinical Trial Registration number, CT20080012.)",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Quality and efficiency of bystander CPR. Belgian Cerebral Resuscitation Study Group.",
        "key_reference_abstract": "Incorrectly performed bystander CPR might compromise survival of the cardiac arrest patient. We therefore evaluated the outcome in 3306 out-of-hospital primary cardiac arrests of which 885 received bystander CPR. bystanders performed CPR correctly in 52%, incorrectly in 11%, 31% performed only external chest compressions (ECC) and 6% only mouth-to-mouth ventilation (MMV). The initial ECG in cases without bystander CPR was ventricular fibrillation in 28% (95% confidence interval: 27-30%); 45% (41-50%) and 39% (29-48%), respectively when bystander CPR was performed correctly or incorrectly; 43% (37-49%) when only ECC was applied and 22% (11-33%) when only MMV was practiced. Long term survival, defined as being awake 14 days after CPR, was 16% (13-19%) in patients with correct bystander CPR; 10% (7-14%) and 2% (0-9%), respectively when only ECC or only MMV was performed; 7% (6-8%) when no bystander was involved; 4% (0-8%) when bystander CPR was performed incorrectly. Bystander CPR might have a beneficial effect on survival by maintaining the heart in ventricular fibrillation by ECC. A negative effect of badly performed bystander CPR was not observed compared to cases which had not received bystander CPR.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Bystander initiated actions in out-of-hospital cardiopulmonary resuscitation: results from the Amsterdam Resuscitation Study (ARRESUST).",
        "key_reference_abstract": "The objective of this study was to analyze the functioning of the first two links of the chain of survival: 'access' and 'basic cardiopulmonary resuscitation (CPR)'. In a prospective study, all bystander witnessed circulatory arrests resuscitated by emergency medical service (EMS) personnel, were recorded consecutively. Univariate differences in survival were calculated for various witnesses, the performance of basic CPR, the quality of CPR, the performers of CPR and the delays. A logistic regression model for survival was developed from all potential predictors of these first two links. From the 922 included patients, 93 survived to hospital discharge. In 21% of the cases, the witness did not immediately call 112, but first called others, resulting in a longer delay and a lower survival. Family members were frequent witnesses of the arrest (44%), but seldom started basic CPR (11%). Survival, when basic CPR performers were untrained and had no previous experience, was similar to that when no basic CPR was performed (6%). Not performing basic CPR, delay in basic CPR, the interval between basic CPR and EMS arrival, and being both untrained and inexperienced in basic CPR were independent predictors for survival. Basic CPR performed by persons trained a long time ago did not appear to have a negative influence on outcome, nor did basic CPR limited to chest compressions alone. The mere reporting that basic CPR has been performed does not describe adequately the actual value of basic CPR. The interval from collapse to initiation of basic CPR, and the training and experience of the performer must be taken into account. Policy makers for basic CPR training should focus on partners of the patients, who are most likely witness of an arrest.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study.",
        "key_reference_abstract": "## BACKGROUND\nMouth-to-mouth ventilation is a barrier to bystanders doing cardiopulmonary resuscitation (CPR), but few clinical studies have investigated the efficacy of bystander resuscitation by chest compressions without mouth-to-mouth ventilation (cardiac-only resuscitation).\n## METHODS\nWe did a prospective, multicentre, observational study of patients who had out-of-hospital cardiac arrest. On arrival at the scene, paramedics assessed the technique of bystander resuscitation. The primary endpoint was favourable neurological outcome 30 days after cardiac arrest.\n## FINDINGS\n4068 adult patients who had out-of-hospital cardiac arrest witnessed by bystanders were included; 439 (11%) received cardiac-only resuscitation from bystanders, 712 (18%) conventional CPR, and 2917 (72%) received no bystander CPR. Any resuscitation attempt was associated with a higher proportion having favourable neurological outcomes than no resuscitation (5.0%vs 2.2%, p<0.0001). Cardiac-only resuscitation resulted in a higher proportion of patients with favourable neurological outcomes than conventional CPR in patients with apnoea (6.2%vs 3.1%; p=0.0195), with shockable rhythm (19.4%vs 11.2%, p=0.041), and with resuscitation that started within 4 min of arrest (10.1%vs 5.1%, p=0.0221). However, there was no evidence for any benefit from the addition of mouth-to-mouth ventilation in any subgroup. The adjusted odds ratio for a favourable neurological outcome after cardiac-only resuscitation was 2.2 (95% CI 1.2-4.2) in patients who received any resuscitation from bystanders.\n## INTERPRETATION\nCardiac-only resuscitation by bystanders is the preferable approach to resuscitation for adult patients with witnessed out-of-hospital cardiac arrest, especially those with apnoea, shockable rhythm, or short periods of untreated arrest.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation.",
        "key_reference_abstract": "## BACKGROUND\nWe sought to compare the 1-month survival rates among patients after out-of-hospital cardiac arrest who had been given bystander cardiopulmonary resuscitation (CPR) in relation to whether they had received standard CPR with chest compression plus mouth-to-mouth ventilation or chest compression only.\n## METHODS AND RESULTS\nAll patients with out-of-hospital cardiac arrest who received bystander CPR and who were reported to the Swedish Cardiac Arrest Register between 1990 and 2005 were included. Crew-witnessed cases were excluded. Among 11,275 patients, 73% (n=8209) received standard CPR, and 10% (n=1145) received chest compression only. There was no significant difference in 1-month survival between patients who received standard CPR (1-month survival=7.2%) and those who received chest compression only (1-month survival=6.7%).\n## CONCLUSIONS\nAmong patients with out-of-hospital cardiac arrest who received bystander CPR, there was no significant difference in 1-month survival between a standard CPR program with chest compression plus mouth-to-mouth ventilation and a simplified version of CPR with chest compression only.",
        "truth": "False"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Effectiveness of bystander-initiated cardiac-only resuscitation for patients with out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nPrevious animal and clinical studies suggest that bystander-initiated cardiac-only resuscitation may be superior to conventional cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrests. Our hypothesis was that both cardiac-only bystander resuscitation and conventional bystander CPR would improve outcomes from out-of-hospital cardiac arrests of < or = 15 minutes' duration, whereas the addition of rescue breathing would improve outcomes for cardiac arrests lasting > 15 minutes.\n## METHODS AND RESULTS\nWe carried out a prospective, population-based, observational study involving consecutive patients with emergency responder resuscitation attempts from May 1, 1998, through April 30, 2003. The primary outcome measure was 1-year survival with favorable neurological outcome. Multivariable logistic regression analysis was performed to evaluate the relationship between type of CPR and outcomes. Among the 4902 witnessed cardiac arrests, 783 received conventional CPR, and 544 received cardiac-only resuscitation. Excluding very-long-duration cardiac arrests (> 15 minutes), the cardiac-only resuscitation yielded a higher rate of 1-year survival with favorable neurological outcome than no bystander CPR (4.3% versus 2.5%; odds ratio, 1.72; 95% CI, 1.01 to 2.95), and conventional CPR showed similar effectiveness (4.1%; odds ratio, 1.57; 95% CI, 0.95 to 2.60). For the very-long-duration arrests, neurologically favorable 1-year survival was greater in the conventional CPR group, but there were few survivors regardless of the type of bystander CPR (0.3% [2 of 624], 0% [0 of 92], and 2.2% [3 of 139] in the no bystander CPR, cardiac-only CPR, and conventional CPR groups, respectively; P<0.05).\n## CONCLUSIONS\nBystander-initiated cardiac-only resuscitation and conventional CPR are similarly effective for most adult out-of-hospital cardiac arrests. For very prolonged cardiac arrests, the addition of rescue breathing may be of some help.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Standard basic life support vs. continuous chest compressions only in out-of-hospital cardiac arrest.",
        "key_reference_abstract": "## BACKGROUND\nThe importance of ventilations after cardiac arrest has been much debated recently and eliminating mouth-to-mouth ventilations for bystanders has been suggested as a means to increase bystander cardiopulmonary resuscitation (CPR). Standard basic life support (S-BLS) is not documented to be superior to continuous chest compressions (CCC).\n## METHODS\nRetrospective, observational study of all non-traumatic cardiac arrest patients older than 18 years between May 2003 and December 2006 treated by the community-run emergency medical service (EMS) in Oslo. Outcome for patients receiving S-BLS was compared with patients receiving CCC. All Utstein characteristics were registered for both patient groups as well as for patients not receiving any bystander CPR by reviewing Ambulance run sheets, Utstein forms and hospital records. Method of bystander CPR as well as dispatcher instruction was registered by first-arriving ambulance personnel.\n## RESULTS\nSix-hundred ninety-five out of 809 cardiac arrests in our EMS were included in this study. Two-hundred eighty-one (40%) received S-CPR and 145 (21%) received CCC. There were no differences in outcome between the two patient groups, with 35 (13%) discharged with a favourable outcome for the S-BLS group and 15 (10%) in the CCC group (P=0.859). Similarly, there was no difference in survival subgroup analysis of patients presenting with initial ventricular fibrillation/ventricular tachycardia after witnessed arrest, with 32 (29%) and 10 (28%) patients discharged from hospital in the S-BLS and CCC groups, respectively (P=0.972).\n## CONCLUSIONS\nPatients receiving CCC from bystanders did not have a worse outcome than patients receiving standard CPR, even with a tendency towards a higher distribution of known negative predictive features.",
        "truth": "True"
    },
    {
        "pmid": "20951422",
        "meta_analysis_title": "Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.",
        "meta_analysis_question": "Is chest-compression-only bystander CPR associated with improved survival outcomes compared to standard bystander CPR in adults with out-of-hospital cardiac arrest?",
        "criteria": "We separated the systematic review and meta-analysis into two parts: in the primary analysis, randomized clinical trials were included and in the secondary, observational cohort studies. Only three randomized clinical trials have been conducted where adult patients suffering from out-of-hospital cardiac arrest received randomized instructions by a dispatcher for either chest compression-only CPR or standard CPR, and all three trials were included in the systematic review and meta-analysis. For observational studies, the following eligibility criteria were required for inclusion: (1) observational cohort studies (no case series); (2) comparison between chest-compression-only CPR and standard CPR; (3) survival data available; (3) adult population; (4) unstratified cohort (e.g., arrests of non-cardiac origin only); (5) bystander CPR; (6) out-of-hospital arrest. Articles were considered if published in English and German; this notwithstanding, no other foreign language study was found.",
        "subgroup": "Return of Spontaneous Circulation in Chest Compression-Only CPR - Meta Analysis",
        "key_reference_title": "Comparison of chest compression only and standard cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Singapore.",
        "key_reference_abstract": "## OBJECTIVE\nChest compression only cardiopulmonary resuscitation (CC-CPR) without ventilation has been proposed as an alternative to standard cardiopulmonary resuscitation (CPR) for bystanders. However, there has been controversy regarding the relative effectiveness of both of these techniques. We aim to compare the outcomes of cardiac arrest patients in the cardiac arrest and resuscitation epidemiology study who either received CC-CPR, standard CPR or no bystander CPR.\n## METHODS\nThis prospective cohort study involved all out-of-hospital cardiac arrest (OHCA) patients attended to by emergency medical service (EMS) providers in a large urban centre. The data analyses were conducted secondarily on these collected data. The technique of bystander CPR was reported by paramedics who arrived at the scene.\n## RESULTS\nFrom 1 October 2001 to 14 October 2004, 2428 patients were enrolled into the study. Of these, 255 were EMS-witnessed arrests and were excluded. 1695 cases did not receive any bystander CPR, 287 had standard CPR and 154 CC-CPR. Patient characteristics were similar in both the standard and CC-CPR groups except for a higher incidence of residential arrests and previous heart disease sufferers in the CC-CPR group. Patients who received standard CPR (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.1-14.0) or CC-CPR (OR 5.0, 95% CI 1.5-16.4) were more likely to survive to discharge than those who had no bystander CPR. There was no significant difference in survival to discharge between those who received CC-CPR and standard CPR (OR 0.9, 95% CI 0.3-3.1).\n## CONCLUSION\nWe found that patients were more likely to survive with any form of bystander CPR than without. This emphasises the importance of chest compressions for OHCA patients, whether with or without ventilation.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## BACKGROUND\nDespite anecdotal evidence suggesting that heavy physical exertion can trigger the onset of acute myocardial infarction, there have been no controlled studies of the risk of myocardial infarction during and after heavy exertion, the length of time between heavy exertion and the onset of symptoms (induction time), and whether the risk can be modified by regular physical exertion. To address these questions, we collected data from patients with confirmed myocardial infarction on their activities one hour before the onset of myocardial infarction and during control periods.\n## METHODS\nInterviews with 1228 patients conducted an average of four days after myocardial infarction provided data on their usual annual frequency of physical activity and the time, type, and intensity of physical exertion in the 26 hours before the onset of myocardial infarction. We compared the observed frequency of heavy exertion (6 or more metabolic equivalents) with the expected values using two types of self-matched analyses based on a new case-crossover study design. The low frequency of heavy exertion during the control periods was validated by data from a population-based control group of 218 subjects.\n## RESULTS\nOf the patients, 4.4 percent reported heavy exertion within one hour before the onset of myocardial infarction. The estimated relative risk of myocardial infarction in the hour after heavy physical exertion, as compared with less strenuous physical exertion or none, was 5.9 (95 percent confidence interval, 4.6 to 7.7), Among people who usually exercised less than one, one to two, three to four, or five or more times per week, the respective relative risks were 107 (95 percent confidence interval, 67 to 171), 19.4 (9.9 to 38.1), 8.6 (3.6 to 20.5), and 2.4 (1.5 to 3.7). Thus, increasing levels of habitual physical activity were associated with progressively lower relative risks. The induction time from heavy exertion to the onset of myocardial infarction was less than one hour, and symptoms usually began during the activity.\n## CONCLUSIONS\nHeavy physical exertion can trigger the onset of acute myocardial infarction, particularly in people who are habitually sedentary. Improved understanding of the mechanisms by which heavy physical exertion triggers the onset of myocardial infarction and the manner in which regular exertion protects against it would facilitate the design of new preventive approaches.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Physical exertion as a trigger of acute myocardial infarction. Triggers and Mechanisms of Myocardial Infarction Study Group.",
        "key_reference_abstract": "## BACKGROUND\nIt is controversial whether the onset of myocardial infarction occurs randomly or is precipitated by identifiable stimuli. Previous studies have suggested a higher risk of cardiac events in association with exertion.\n## METHODS\nConsecutive patients with acute myocardial infarction were identified by recording all admissions to our hospital in Berlin and by monitoring a general population of 330,000 residents in Augsburg, Germany. Information on the circumstances of each infarction was obtained by means of standardized interviews. The data analysis included a comparison of patients with matched controls and a case-crossover comparison (one in which each patient serves as his or her own control) of the patient's usual frequency of exertion with the last episode of exertion before the onset of myocardial infarction.\n## RESULTS\nFrom January 1989 through December 1991, 1194 patients (74 percent of whom were men; mean age [+/- SD], 61 +/- 9 years) completed the interview 13 +/- 6 days after infarction. We found that 7.1 percent of the case patients had engaged in physical exertion (> or = 6 metabolic equivalents) at the onset of infarction, as compared with 3.9 percent of the controls at the onset of the control event. For the patients as compared with the matched controls, the adjusted relative risk of having engaged in strenuous physical activity at the onset of infarction or the control event was 2.1 (95 percent confidence interval, 1.1 to 3.6). The case-crossover comparison yielded a similar relative risk of 2.1 (95 percent confidence interval, 1.6 to 3.1) for having engaged in strenuous physical activity within one hour before myocardial infarction. Patients whose frequency of regular exercise was less than four and four or more times per week had relative risks of 6.9 and 1.3, respectively (P < 0.01).\n## CONCLUSIONS\nA period of strenuous physical activity is associated with a temporary increase in the risk of having a myocardial infarction, particularly among patients who exercise infrequently. These findings should aid in the identification of the triggering mechanisms for myocardial infarction and improve prevention of this common and serious disorder.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Clinical and angiographic characteristics of exertion-related acute myocardial infarction.",
        "key_reference_abstract": "## CONTEXT\nVigorous physical exertion transiently increases the risk of acute myocardial infarction (MI), but little is known about the clinical characteristics of exertion-related MI.\n## OBJECTIVE\nTo compare the clinical and angiographic characteristics of patients who had an exertion-related acute MI vs those who experienced an MI not related to exertion.\n## DESIGN AND SETTING\nProspective observational cohort study of patients with an acute MI referred to a tertiary care hospital for primary angioplasty.\n## PATIENTS\nOf 1048 patients with acute MI, 640 (64 who experienced an exertion-related MI and 576 who did not) were selected for treatment with primary angioplasty and admitted between August 1995 and November 1998.\n## MAIN OUTCOME MEASURES\nClinical characteristics of the patients, including their habitual physical activity (determined by the Framingham Physical Activity Index and the Lipid Research Clinic Physical Activity Questionnaire), angiographic findings during coronary angiography, and the relative risk (RR) of MI during exertion.\n## RESULTS\nPatients who experienced exertion-related MI were more frequently men (86% vs 68%), hyperlipidemic (62% vs 40%), and smokers (59% vs 37%), were more likely to present with ventricular fibrillation (20% vs 11%), Killip classification III or IV heart failure (44% vs 22%), single-vessel disease (50% vs 28%), and a large thrombus in the infarct artery (64% vs 35%) and were more likely to be classified as having very low or low activity (84% vs 66%). The RR of experiencing an MI during exertion was 10.1 times greater than the risk at other times (95% confidence interval [CI], 1.6-65.6), with the highest risk among patients classified as very low active (RR, 30.5; 95% CI, 4.4-209.9) and low active (RR, 20.9; 95% CI, 3.1-142.1).\n## CONCLUSION\nThese results show that exertion-related MIs occur in habitually inactive people with multiple cardiac risk factors. These individuals may benefit from modest exercise training and aggressive risk-factor modification before they perform vigorous physical activity.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a population-based case-referent study.",
        "key_reference_abstract": "To study possible triggering of first events of acute myocardial infarction by heavy physical exertion, the authors conducted a case-crossover analysis (1993-1994) within a population-based case-referent study in Stockholm County, Sweden (the Stockholm Heart Epidemiology Program). Interviews were carried out with 699 myocardial infarction patients after onset of the disease. These cases represented 47 percent of all cases in the study base, and 70 percent of all nonfatal cases. The relative risk from vigorous exertion was 6.1 (95% confidence interval: 4.2, 9.0). The rate difference was 1.5 per million person-hours, and the attributable proportion was 5.7 percent. The risk was modified by physical fitness, with an increased risk being seen among sedentary subjects as in earlier studies, but the data also suggested a U-shaped association. In addition, the trigger effect was modified by socioeconomic status. Premonitory symptoms were common, and this implies risks of reverse causation bias and misclassification of case exposure information that require methodological consideration. Different techniques (the use of the usual-frequency type of control information, a pair-matched analysis, and a standard case-referent analysis) were applied to overcome the threat of misclassification of control exposure information. A case-crossover analysis in a random sample of healthy subjects resulted in a relative risk close to unity, as expected.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Triggers of nonfatal myocardial infarction in Costa Rica: heavy physical exertion, sexual activity, and infection.",
        "key_reference_abstract": "## PURPOSE\nThere are no data for factors that could trigger myocardial infarction (MI) in the context of lifestyles in developing countries.\n## METHODS\nUsing a case-crossover design, we assessed the effect of heavy physical exertion, sexual activity, acute respiratory tract infections, and gastroenteritis as triggers for MI in 530 survivors of a first MI from Costa Rica.\n## RESULTS\nRelative risks (RRs) for MI in the hour after heavy physical exertion and 2 hours after sexual activity were 4.94 (95% confidence interval [CI], 3.73-6.54) and 5.47 (95% CI, 2.71-11.02). Risk for MI after heavy physical exertion was greater for patients with poor physical fitness or elevated underlying cardiovascular risk (p < 0.0001 and p = 0.06, tests of homogeneity). RRs for acute respiratory tract infection and gastroenteritis were 1.48 (95% CI, 0.92-2.38) and 1.27 (95% CI, 0.95-1.69), respectively. Patients with three or more risk factors had an RR for MI for gastroenteritis of 2.08 (95% CI, 1.31-3.28).\n## CONCLUSIONS\nOur results confirm previous studies in developed countries showing that heavy physical exertion and sexual activity are potential triggers for MI, and their effect is modified by physical fitness and underlying cardiovascular risk. Additional studies that explore the biologic effects of gastroenteritis as triggers of MI are warranted.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Intensity of physical exertion and triggering of myocardial infarction: a case-crossover study.",
        "key_reference_abstract": "## AIMS\nAcute myocardial infarction (AMI) can be precipitated or triggered by discrete transient exposures including physical exertion. We evaluated whether the risk of having an AMI triggered by physical exertion exhibits an exposure-response relationship, and whether it varies by ambient temperature or by taking place indoors or outdoors.\n## METHODS AND RESULTS\nWe conducted a case-crossover study within the Myocardial Infarction Registry in Augsburg, Germany in 1999-2003. One thousand three hundred and one patients reported levels of activity and time spent outdoors on the day of AMI and three preceding days in an interview. The case-crossover analyses showed an association of physical exertion with AMI symptom onset within 2 h, which was strong for strenuous exertion (METs >or= 6) [relative risk (RR) 5.7, 95% confidence interval (CI) 3.6-9.0), and still significant for moderate exertion (METs = 5) (RR 1.6, 95% CI 1.2-2.1) compared to very light or no exertion. Strenuous exertion outside was associated with a four-fold larger RR of AMI symptom onset than exertion performed indoors, which was not explained by temperature.\n## CONCLUSION\nThis study confirms previous results and shows a graded exposure-response relationship between physical exertion intensity and triggering of AMI onset. These findings may have implications for behavioural guidance of people at risk of AMI.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Physical exertion, exercise, and sudden cardiac death in women.",
        "key_reference_abstract": "## CONTEXT\nExercise is associated with a lower risk of cardiovascular events but may transiently increase the risk of ventricular arrhythmias. Its short-term and long-term associations with risk of sudden cardiac death among women are unclear.\n## OBJECTIVES\nTo compare the risk of sudden cardiac death in women during moderate to vigorous exertion with the risk of sudden cardiac death during lighter or no exertion; and to assess the long-term association between moderate to vigorous exercise and sudden cardiac death.\n## DESIGN, SETTING, AND PARTICIPANTS\nProspective, nested case-crossover study of 288 cases of sudden cardiac death within the Nurses' Health Study (1980-2004); and a prospective cohort analysis of 69,693 participants without prior cardiovascular disease followed up from 1986-2004.\n## MAIN OUTCOME MEASURE\nRisk of sudden cardiac death associated with moderate to vigorous exertion.\n## RESULTS\nThe absolute risk of sudden cardiac death associated with moderate to vigorous exertion was exceedingly low at 1 per 36.5 million hours of exertion. In case-crossover analyses, the risk of sudden cardiac death was transiently elevated during moderate to vigorous exertion (relative risk [RR], 2.38; 95% confidence interval [CI], 1.23-4.60; P = .01) compared with the risk during lesser or no exertion. Habitual moderate to vigorous exertion modified this transient risk (P = .005 for interaction) and the risk was no longer significantly elevated among those who exercised 2 or more hours per week. In the cohort analyses, an increasing amount of moderate to vigorous exercise was associated with a lower long-term risk of sudden cardiac death in age-adjusted and multivariable models that excluded biological intermediates (P = .006 for trend). This relationship was attenuated when biological intermediates were included (P = .06 for trend); however, the reduction in risk remained significant among women who exercised 4 or more hours per week (adjusted RR, 0.41; 95% CI, 0.20-0.83; P = .01) compared with women who did not exercise.\n## CONCLUSIONS\nThese prospective data suggest that sudden cardiac death during exertion is an extremely rare event in women. Regular exercise may significantly minimize this small transient risk and may lower the overall long-term risk of sudden cardiac death.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Triggering of sudden death from cardiac causes by vigorous exertion.",
        "key_reference_abstract": "## BACKGROUND\nRetrospective and cross-sectional data suggest that vigorous exertion can trigger cardiac arrest or sudden death and that habitual exercise may diminish this risk. However, the role of physical activity in precipitating or preventing sudden death has not been assessed prospectively in a large number of subjects.\n## METHODS\nWe used a prospective, nested case-crossover design within the Physicians' Health Study to compare the risk of sudden death during and up to 30 minutes after an episode of vigorous exertion with that during periods of lighter exertion or none. We then evaluated whether habitual vigorous exercise modified the risk of sudden death that was associated with vigorous exertion. In addition, the relation of vigorous exercise to the overall risk of sudden death and nonsudden death from coronary heart disease was assessed.\n## RESULTS\nDuring 12 years of follow-up, 122 sudden deaths were confirmed among the 21,481 male physicians who were initially free of self-reported cardiovascular disease and who provided information on their habitual level of exercise at base line. The relative risk of-sudden death during and up to 30 minutes after vigorous exertion was 16.9 (95 percent confidence interval, 10.5 to 27.0; P<0.001). However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (1 sudden death per 1.51 million episodes of exertion). Habitual vigorous exercise attenuated the relative risk of sudden death that was associated with an episode of vigorous exertion (P value for trend=0.006). The base-line level of exercise was not associated with the overall risk of subsequent sudden death.\n## CONCLUSIONS\nThese prospective data from a study of U.S. male physicians suggest that habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics.",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate the role of vigorous physical exertion and anger as triggers of acute coronary syndromes (ACS) and to identify the clinical and sociodemographic correlates of triggering.\n## DESIGN\nProspective observational clinical cohort study.\n## SETTING\nFour coronary care units in the London area.\n## PATIENTS\n295 men and women with electrocardiographically and biochemically verified ACS.\n## MAIN OUTCOME MEASURES\nPhysical exertion in the 1 h and anger in the 2 h before symptom onset were assessed with structured interviews. Control periods were the equivalent hours one day earlier and usual rates over the past six months. Data were analysed by case-crossover methods.\n## RESULTS\nPhysical exertion was reported by 10% and anger by 17.4% of patients in the hazard period. The risk of ACS onset after physical exertion compared with light or no activity was 3.50 (95% confidence interval (CI) 1.37 to 10.6). The risk of onset with anger was 2.06 (95% CI 1.12 to 3.92). Physical exertion during the hazard period was related to an absence of premonitory symptoms, presentation with an ST elevation myocardial infarction (STEMI), low socioeconomic deprivation and higher future cardiovascular risk. Anger during the hazard period was more common in younger, socioeconomically deprived patients who presented with a STEMI.\n## CONCLUSIONS\nTriggers are relevant across the spectrum of ACS. The distinct clinical and sociodemographic factors associated with physical exertion and anger suggest that different pathophysiological processes may be involved.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the relative risks of nonfatal myocardial infarction (MI) triggered by sexual activity among the general population and in patients with prior coronary heart disease.\n## DESIGN\nRelative risks and effect modification were calculated by the case-crossover method, a new epidemiologic technique designed to quantify the transient change in risk following exposure to a potential disease trigger.\n## SETTING/PARTICIPANTS\nA total of 1774 patients with MI were interviewed in 45 hospitals throughout the United States. Data were gathered on potential triggers of MI occurring immediately prior to the event and during the previous year. Results are presented for the 858 patients who were sexually active in the year prior to the MI, with attention to the 273 patients who had coronary artery disease prior to their index MI, and the effect of regular exertion on risk.\n## MAIN OUTCOME MEASURE\nThe relative risk of nonfatal MI following sexual activity.\n## RESULTS\nOf the 858 patients, 79(9%) reported sexual activity in the 24 hours preceding MI, and 27(3%) reported sexual activity in the 2 hours preceding onset of symptoms of MI. The relative risk of MI occurring in the 2 hours after sexual activity was 2.5(95% confidence interval [CI], 1.7-3.7). The relative risk of triggering onset of MI among patients with a history of prior angina (2.1 [95% CI, 0.8-5.8]) or prior MI (2.9 [95% CI, 1.3-6.5]) was not greater than that observed in those without prior cardiac disease. Sexual activity was a likely contributor to the onset of MI in only 0.9% of cases and regular exertion was associated with decreasing risk.\n## CONCLUSIONS\nSexual activity can trigger the onset of MI. However, the relative risk is low, and since the absolute hourly risk of MI is extremely low, the absolute risk increase caused by sexual activity also is extremely low (1 chance in a million for a healthy individual). Moreover, the relative risk is not increased in patients with a prior history of cardiac disease and regular exercise appears to prevent triggering. These findings should be useful for counseling patients and decreasing the fear of sexual activity that often prevents complete rehabilitation from cardiovascular disease.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Sexual activity as a trigger of myocardial infarction. A case-crossover analysis in the Stockholm Heart Epidemiology Programme (SHEEP).",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate sexual activity as a trigger of myocardial infarction and the potential effect modification of physical fitness.\n## DESIGN\nA case-crossover study nested in the Stockholm Heart Epidemiology Programme (SHEEP).\n## SETTING\nStockholm County from April 1993 to December 1994.\n## PATIENTS\nAll patients with a first episode of non-fatal acute myocardial infarction admitted to coronary care units were eligible, and 699 patients participated in an interview.\n## MAIN OUTCOME MEASURES\nRelative risks with 95% confidence intervals.\n## RESULTS\nOnly 1.3% of the patients without premonitory symptoms had sexual activity during two hours before the onset of myocardial infarction. The relative risk of myocardial infarction was 2.1 (95% confidence interval (CI) 0.7 to 6.5) during one hour after sexual activity, and the risk among patients with a sedentary life was 4.4 (95% CI 1.5 to 12.9).\n## CONCLUSIONS\nThe increased risk of myocardial infarction after sexual activity and the further increase in risk among the less physically fit support the hypothesis of causal triggering by sexual activity. However, the absolute risk per hour is very low, and exposure is relatively infrequent. Thus having sex once a week only increases the annual risk of myocardial infarction slightly. Counselling should focus on encouraging patients to live a physically active life and not on abstaining from sexual activity.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Sex differences in potential daily triggers of the onset of acute myocardial infarction: a case-crossover analysis among an Iranian population.",
        "key_reference_abstract": "## OBJECTIVE\nDespite an increasing knowledge of the importance of triggering in cardiac events and their mortality and morbidity, awareness concerning the types of physical and psychological triggers is unsatisfactory. This study aimed to address the main daily triggers of typical chest pain as a marker of acute coronary syndrome onset and assessed the sex-related differences regarding these triggers among Iranians.\n## BASIC METHODS\nA case-crossover study was conducted on 198 consecutive patients with a first event of acute myocardial infarction admitted to the coronary care unit of Shafa hospital in Kerman. Patients were interviewed about the baseline characteristics as well as potential triggers of chest pain experienced over the day before the diagnosed onset of disease. The start of diagnostic chest pain was used as a marker of disease onset. The hazard period was defined as 12-h period of onset of chest pain.\n## MAIN RESULTS\nAmong probable triggers, only unsuspected sudden bad news and sexual activity had significant relationships with chest pain appearance during the hazard period. Among patients with the experience of bad news, the risk of chest pain occurrence during the hazard period was 6.9 [95% confidence interval (CI) 1.5-31.8]. Also, among those who were exposed to sexual activity, this risk was 3.4 (95% CI 1.1-10.4). Risk of chest pain following bad news was specific to men with a risk of 9.9 (95% CI 1.1-87.6) and risk of event following sexual activity was specific to women with a risk of 13.3 (95% CI 1.4-120.9).\n## CONCLUSION\nUnsuspected sudden bad news can be an important trigger for acute cardiac events in men, whereas sexual activity can act as a strong trigger for these events among women. Counseling in high-risk groups should be focused on men with considerable sudden emotional stressors in their lives and also on women during the ages of active sexual function.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: myocardial infarction",
        "key_reference_title": "Out of Hospital Sudden Cardiac Death Among Physically Active and Inactive Married Persons Younger than 65 Years in Slovenia",
        "key_reference_abstract": "Methods: A sedentary life style has been shown to increase the risk of coronary artery disease, a precursor of sudden cardiac death, while regular physical activity prevents atherosclerosis. In an out of hospital cardiac death study in Slovenia, case crossover design was used to investigate physical activity as a potential trigger of sudden cardiac death in connection with certain life style, biological and social risk factors.\nResults: In the study, 206 sudden cardiac deaths were selected: 166 men and 40 women with median age at death 57.8 and 59.0 years, respectively. The relative risk of dying during or within one hour after terminating physical activity of at least 6 metabolic equivalents was 3.0 in comparison to time without activity. The relative risk of people who performed 1.5 hours or more physical activity per week was 2.55 (95 % confidence limits: 1.69\u20133.84), opposed to 49.90 (confidence limits: 18.73\u2013132.96) for persons who performed less activity. According to the observed characteristics the risk of dying for inactive sudden cardiac victims was 17.13 to 25.89 (95 % confidence limits: 11.28\u201344.60) times higher in comparison to physically active persons. Persons who drank more than 4 international units of alcohol per day, positive family history, ischaemic heart disease and a heart rate of more than 90 beats/minute had the highest risk.\nConclusion: The results confirmed that the risk of dying due to sudden cardiac death during physical activity depends on the degree of physical activity regularly performed and the existing risk factors. J Clin Basic Cardiol 2003; 6: 63\u20137.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## BACKGROUND\nDespite anecdotal evidence suggesting that heavy physical exertion can trigger the onset of acute myocardial infarction, there have been no controlled studies of the risk of myocardial infarction during and after heavy exertion, the length of time between heavy exertion and the onset of symptoms (induction time), and whether the risk can be modified by regular physical exertion. To address these questions, we collected data from patients with confirmed myocardial infarction on their activities one hour before the onset of myocardial infarction and during control periods.\n## METHODS\nInterviews with 1228 patients conducted an average of four days after myocardial infarction provided data on their usual annual frequency of physical activity and the time, type, and intensity of physical exertion in the 26 hours before the onset of myocardial infarction. We compared the observed frequency of heavy exertion (6 or more metabolic equivalents) with the expected values using two types of self-matched analyses based on a new case-crossover study design. The low frequency of heavy exertion during the control periods was validated by data from a population-based control group of 218 subjects.\n## RESULTS\nOf the patients, 4.4 percent reported heavy exertion within one hour before the onset of myocardial infarction. The estimated relative risk of myocardial infarction in the hour after heavy physical exertion, as compared with less strenuous physical exertion or none, was 5.9 (95 percent confidence interval, 4.6 to 7.7), Among people who usually exercised less than one, one to two, three to four, or five or more times per week, the respective relative risks were 107 (95 percent confidence interval, 67 to 171), 19.4 (9.9 to 38.1), 8.6 (3.6 to 20.5), and 2.4 (1.5 to 3.7). Thus, increasing levels of habitual physical activity were associated with progressively lower relative risks. The induction time from heavy exertion to the onset of myocardial infarction was less than one hour, and symptoms usually began during the activity.\n## CONCLUSIONS\nHeavy physical exertion can trigger the onset of acute myocardial infarction, particularly in people who are habitually sedentary. Improved understanding of the mechanisms by which heavy physical exertion triggers the onset of myocardial infarction and the manner in which regular exertion protects against it would facilitate the design of new preventive approaches.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Physical exertion as a trigger of acute myocardial infarction. Triggers and Mechanisms of Myocardial Infarction Study Group.",
        "key_reference_abstract": "## BACKGROUND\nIt is controversial whether the onset of myocardial infarction occurs randomly or is precipitated by identifiable stimuli. Previous studies have suggested a higher risk of cardiac events in association with exertion.\n## METHODS\nConsecutive patients with acute myocardial infarction were identified by recording all admissions to our hospital in Berlin and by monitoring a general population of 330,000 residents in Augsburg, Germany. Information on the circumstances of each infarction was obtained by means of standardized interviews. The data analysis included a comparison of patients with matched controls and a case-crossover comparison (one in which each patient serves as his or her own control) of the patient's usual frequency of exertion with the last episode of exertion before the onset of myocardial infarction.\n## RESULTS\nFrom January 1989 through December 1991, 1194 patients (74 percent of whom were men; mean age [+/- SD], 61 +/- 9 years) completed the interview 13 +/- 6 days after infarction. We found that 7.1 percent of the case patients had engaged in physical exertion (> or = 6 metabolic equivalents) at the onset of infarction, as compared with 3.9 percent of the controls at the onset of the control event. For the patients as compared with the matched controls, the adjusted relative risk of having engaged in strenuous physical activity at the onset of infarction or the control event was 2.1 (95 percent confidence interval, 1.1 to 3.6). The case-crossover comparison yielded a similar relative risk of 2.1 (95 percent confidence interval, 1.6 to 3.1) for having engaged in strenuous physical activity within one hour before myocardial infarction. Patients whose frequency of regular exercise was less than four and four or more times per week had relative risks of 6.9 and 1.3, respectively (P < 0.01).\n## CONCLUSIONS\nA period of strenuous physical activity is associated with a temporary increase in the risk of having a myocardial infarction, particularly among patients who exercise infrequently. These findings should aid in the identification of the triggering mechanisms for myocardial infarction and improve prevention of this common and serious disorder.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Clinical and angiographic characteristics of exertion-related acute myocardial infarction.",
        "key_reference_abstract": "## CONTEXT\nVigorous physical exertion transiently increases the risk of acute myocardial infarction (MI), but little is known about the clinical characteristics of exertion-related MI.\n## OBJECTIVE\nTo compare the clinical and angiographic characteristics of patients who had an exertion-related acute MI vs those who experienced an MI not related to exertion.\n## DESIGN AND SETTING\nProspective observational cohort study of patients with an acute MI referred to a tertiary care hospital for primary angioplasty.\n## PATIENTS\nOf 1048 patients with acute MI, 640 (64 who experienced an exertion-related MI and 576 who did not) were selected for treatment with primary angioplasty and admitted between August 1995 and November 1998.\n## MAIN OUTCOME MEASURES\nClinical characteristics of the patients, including their habitual physical activity (determined by the Framingham Physical Activity Index and the Lipid Research Clinic Physical Activity Questionnaire), angiographic findings during coronary angiography, and the relative risk (RR) of MI during exertion.\n## RESULTS\nPatients who experienced exertion-related MI were more frequently men (86% vs 68%), hyperlipidemic (62% vs 40%), and smokers (59% vs 37%), were more likely to present with ventricular fibrillation (20% vs 11%), Killip classification III or IV heart failure (44% vs 22%), single-vessel disease (50% vs 28%), and a large thrombus in the infarct artery (64% vs 35%) and were more likely to be classified as having very low or low activity (84% vs 66%). The RR of experiencing an MI during exertion was 10.1 times greater than the risk at other times (95% confidence interval [CI], 1.6-65.6), with the highest risk among patients classified as very low active (RR, 30.5; 95% CI, 4.4-209.9) and low active (RR, 20.9; 95% CI, 3.1-142.1).\n## CONCLUSION\nThese results show that exertion-related MIs occur in habitually inactive people with multiple cardiac risk factors. These individuals may benefit from modest exercise training and aggressive risk-factor modification before they perform vigorous physical activity.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a population-based case-referent study.",
        "key_reference_abstract": "To study possible triggering of first events of acute myocardial infarction by heavy physical exertion, the authors conducted a case-crossover analysis (1993-1994) within a population-based case-referent study in Stockholm County, Sweden (the Stockholm Heart Epidemiology Program). Interviews were carried out with 699 myocardial infarction patients after onset of the disease. These cases represented 47 percent of all cases in the study base, and 70 percent of all nonfatal cases. The relative risk from vigorous exertion was 6.1 (95% confidence interval: 4.2, 9.0). The rate difference was 1.5 per million person-hours, and the attributable proportion was 5.7 percent. The risk was modified by physical fitness, with an increased risk being seen among sedentary subjects as in earlier studies, but the data also suggested a U-shaped association. In addition, the trigger effect was modified by socioeconomic status. Premonitory symptoms were common, and this implies risks of reverse causation bias and misclassification of case exposure information that require methodological consideration. Different techniques (the use of the usual-frequency type of control information, a pair-matched analysis, and a standard case-referent analysis) were applied to overcome the threat of misclassification of control exposure information. A case-crossover analysis in a random sample of healthy subjects resulted in a relative risk close to unity, as expected.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Triggers of nonfatal myocardial infarction in Costa Rica: heavy physical exertion, sexual activity, and infection.",
        "key_reference_abstract": "## PURPOSE\nThere are no data for factors that could trigger myocardial infarction (MI) in the context of lifestyles in developing countries.\n## METHODS\nUsing a case-crossover design, we assessed the effect of heavy physical exertion, sexual activity, acute respiratory tract infections, and gastroenteritis as triggers for MI in 530 survivors of a first MI from Costa Rica.\n## RESULTS\nRelative risks (RRs) for MI in the hour after heavy physical exertion and 2 hours after sexual activity were 4.94 (95% confidence interval [CI], 3.73-6.54) and 5.47 (95% CI, 2.71-11.02). Risk for MI after heavy physical exertion was greater for patients with poor physical fitness or elevated underlying cardiovascular risk (p < 0.0001 and p = 0.06, tests of homogeneity). RRs for acute respiratory tract infection and gastroenteritis were 1.48 (95% CI, 0.92-2.38) and 1.27 (95% CI, 0.95-1.69), respectively. Patients with three or more risk factors had an RR for MI for gastroenteritis of 2.08 (95% CI, 1.31-3.28).\n## CONCLUSIONS\nOur results confirm previous studies in developed countries showing that heavy physical exertion and sexual activity are potential triggers for MI, and their effect is modified by physical fitness and underlying cardiovascular risk. Additional studies that explore the biologic effects of gastroenteritis as triggers of MI are warranted.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Intensity of physical exertion and triggering of myocardial infarction: a case-crossover study.",
        "key_reference_abstract": "## AIMS\nAcute myocardial infarction (AMI) can be precipitated or triggered by discrete transient exposures including physical exertion. We evaluated whether the risk of having an AMI triggered by physical exertion exhibits an exposure-response relationship, and whether it varies by ambient temperature or by taking place indoors or outdoors.\n## METHODS AND RESULTS\nWe conducted a case-crossover study within the Myocardial Infarction Registry in Augsburg, Germany in 1999-2003. One thousand three hundred and one patients reported levels of activity and time spent outdoors on the day of AMI and three preceding days in an interview. The case-crossover analyses showed an association of physical exertion with AMI symptom onset within 2 h, which was strong for strenuous exertion (METs >or= 6) [relative risk (RR) 5.7, 95% confidence interval (CI) 3.6-9.0), and still significant for moderate exertion (METs = 5) (RR 1.6, 95% CI 1.2-2.1) compared to very light or no exertion. Strenuous exertion outside was associated with a four-fold larger RR of AMI symptom onset than exertion performed indoors, which was not explained by temperature.\n## CONCLUSION\nThis study confirms previous results and shows a graded exposure-response relationship between physical exertion intensity and triggering of AMI onset. These findings may have implications for behavioural guidance of people at risk of AMI.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Physical exertion, exercise, and sudden cardiac death in women.",
        "key_reference_abstract": "## CONTEXT\nExercise is associated with a lower risk of cardiovascular events but may transiently increase the risk of ventricular arrhythmias. Its short-term and long-term associations with risk of sudden cardiac death among women are unclear.\n## OBJECTIVES\nTo compare the risk of sudden cardiac death in women during moderate to vigorous exertion with the risk of sudden cardiac death during lighter or no exertion; and to assess the long-term association between moderate to vigorous exercise and sudden cardiac death.\n## DESIGN, SETTING, AND PARTICIPANTS\nProspective, nested case-crossover study of 288 cases of sudden cardiac death within the Nurses' Health Study (1980-2004); and a prospective cohort analysis of 69,693 participants without prior cardiovascular disease followed up from 1986-2004.\n## MAIN OUTCOME MEASURE\nRisk of sudden cardiac death associated with moderate to vigorous exertion.\n## RESULTS\nThe absolute risk of sudden cardiac death associated with moderate to vigorous exertion was exceedingly low at 1 per 36.5 million hours of exertion. In case-crossover analyses, the risk of sudden cardiac death was transiently elevated during moderate to vigorous exertion (relative risk [RR], 2.38; 95% confidence interval [CI], 1.23-4.60; P = .01) compared with the risk during lesser or no exertion. Habitual moderate to vigorous exertion modified this transient risk (P = .005 for interaction) and the risk was no longer significantly elevated among those who exercised 2 or more hours per week. In the cohort analyses, an increasing amount of moderate to vigorous exercise was associated with a lower long-term risk of sudden cardiac death in age-adjusted and multivariable models that excluded biological intermediates (P = .006 for trend). This relationship was attenuated when biological intermediates were included (P = .06 for trend); however, the reduction in risk remained significant among women who exercised 4 or more hours per week (adjusted RR, 0.41; 95% CI, 0.20-0.83; P = .01) compared with women who did not exercise.\n## CONCLUSIONS\nThese prospective data suggest that sudden cardiac death during exertion is an extremely rare event in women. Regular exercise may significantly minimize this small transient risk and may lower the overall long-term risk of sudden cardiac death.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Triggering of sudden death from cardiac causes by vigorous exertion.",
        "key_reference_abstract": "## BACKGROUND\nRetrospective and cross-sectional data suggest that vigorous exertion can trigger cardiac arrest or sudden death and that habitual exercise may diminish this risk. However, the role of physical activity in precipitating or preventing sudden death has not been assessed prospectively in a large number of subjects.\n## METHODS\nWe used a prospective, nested case-crossover design within the Physicians' Health Study to compare the risk of sudden death during and up to 30 minutes after an episode of vigorous exertion with that during periods of lighter exertion or none. We then evaluated whether habitual vigorous exercise modified the risk of sudden death that was associated with vigorous exertion. In addition, the relation of vigorous exercise to the overall risk of sudden death and nonsudden death from coronary heart disease was assessed.\n## RESULTS\nDuring 12 years of follow-up, 122 sudden deaths were confirmed among the 21,481 male physicians who were initially free of self-reported cardiovascular disease and who provided information on their habitual level of exercise at base line. The relative risk of-sudden death during and up to 30 minutes after vigorous exertion was 16.9 (95 percent confidence interval, 10.5 to 27.0; P<0.001). However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (1 sudden death per 1.51 million episodes of exertion). Habitual vigorous exercise attenuated the relative risk of sudden death that was associated with an episode of vigorous exertion (P value for trend=0.006). The base-line level of exercise was not associated with the overall risk of subsequent sudden death.\n## CONCLUSIONS\nThese prospective data from a study of U.S. male physicians suggest that habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics.",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate the role of vigorous physical exertion and anger as triggers of acute coronary syndromes (ACS) and to identify the clinical and sociodemographic correlates of triggering.\n## DESIGN\nProspective observational clinical cohort study.\n## SETTING\nFour coronary care units in the London area.\n## PATIENTS\n295 men and women with electrocardiographically and biochemically verified ACS.\n## MAIN OUTCOME MEASURES\nPhysical exertion in the 1 h and anger in the 2 h before symptom onset were assessed with structured interviews. Control periods were the equivalent hours one day earlier and usual rates over the past six months. Data were analysed by case-crossover methods.\n## RESULTS\nPhysical exertion was reported by 10% and anger by 17.4% of patients in the hazard period. The risk of ACS onset after physical exertion compared with light or no activity was 3.50 (95% confidence interval (CI) 1.37 to 10.6). The risk of onset with anger was 2.06 (95% CI 1.12 to 3.92). Physical exertion during the hazard period was related to an absence of premonitory symptoms, presentation with an ST elevation myocardial infarction (STEMI), low socioeconomic deprivation and higher future cardiovascular risk. Anger during the hazard period was more common in younger, socioeconomically deprived patients who presented with a STEMI.\n## CONCLUSIONS\nTriggers are relevant across the spectrum of ACS. The distinct clinical and sociodemographic factors associated with physical exertion and anger suggest that different pathophysiological processes may be involved.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the relative risks of nonfatal myocardial infarction (MI) triggered by sexual activity among the general population and in patients with prior coronary heart disease.\n## DESIGN\nRelative risks and effect modification were calculated by the case-crossover method, a new epidemiologic technique designed to quantify the transient change in risk following exposure to a potential disease trigger.\n## SETTING/PARTICIPANTS\nA total of 1774 patients with MI were interviewed in 45 hospitals throughout the United States. Data were gathered on potential triggers of MI occurring immediately prior to the event and during the previous year. Results are presented for the 858 patients who were sexually active in the year prior to the MI, with attention to the 273 patients who had coronary artery disease prior to their index MI, and the effect of regular exertion on risk.\n## MAIN OUTCOME MEASURE\nThe relative risk of nonfatal MI following sexual activity.\n## RESULTS\nOf the 858 patients, 79(9%) reported sexual activity in the 24 hours preceding MI, and 27(3%) reported sexual activity in the 2 hours preceding onset of symptoms of MI. The relative risk of MI occurring in the 2 hours after sexual activity was 2.5(95% confidence interval [CI], 1.7-3.7). The relative risk of triggering onset of MI among patients with a history of prior angina (2.1 [95% CI, 0.8-5.8]) or prior MI (2.9 [95% CI, 1.3-6.5]) was not greater than that observed in those without prior cardiac disease. Sexual activity was a likely contributor to the onset of MI in only 0.9% of cases and regular exertion was associated with decreasing risk.\n## CONCLUSIONS\nSexual activity can trigger the onset of MI. However, the relative risk is low, and since the absolute hourly risk of MI is extremely low, the absolute risk increase caused by sexual activity also is extremely low (1 chance in a million for a healthy individual). Moreover, the relative risk is not increased in patients with a prior history of cardiac disease and regular exercise appears to prevent triggering. These findings should be useful for counseling patients and decreasing the fear of sexual activity that often prevents complete rehabilitation from cardiovascular disease.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Sexual activity as a trigger of myocardial infarction. A case-crossover analysis in the Stockholm Heart Epidemiology Programme (SHEEP).",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate sexual activity as a trigger of myocardial infarction and the potential effect modification of physical fitness.\n## DESIGN\nA case-crossover study nested in the Stockholm Heart Epidemiology Programme (SHEEP).\n## SETTING\nStockholm County from April 1993 to December 1994.\n## PATIENTS\nAll patients with a first episode of non-fatal acute myocardial infarction admitted to coronary care units were eligible, and 699 patients participated in an interview.\n## MAIN OUTCOME MEASURES\nRelative risks with 95% confidence intervals.\n## RESULTS\nOnly 1.3% of the patients without premonitory symptoms had sexual activity during two hours before the onset of myocardial infarction. The relative risk of myocardial infarction was 2.1 (95% confidence interval (CI) 0.7 to 6.5) during one hour after sexual activity, and the risk among patients with a sedentary life was 4.4 (95% CI 1.5 to 12.9).\n## CONCLUSIONS\nThe increased risk of myocardial infarction after sexual activity and the further increase in risk among the less physically fit support the hypothesis of causal triggering by sexual activity. However, the absolute risk per hour is very low, and exposure is relatively infrequent. Thus having sex once a week only increases the annual risk of myocardial infarction slightly. Counselling should focus on encouraging patients to live a physically active life and not on abstaining from sexual activity.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Sex differences in potential daily triggers of the onset of acute myocardial infarction: a case-crossover analysis among an Iranian population.",
        "key_reference_abstract": "## OBJECTIVE\nDespite an increasing knowledge of the importance of triggering in cardiac events and their mortality and morbidity, awareness concerning the types of physical and psychological triggers is unsatisfactory. This study aimed to address the main daily triggers of typical chest pain as a marker of acute coronary syndrome onset and assessed the sex-related differences regarding these triggers among Iranians.\n## BASIC METHODS\nA case-crossover study was conducted on 198 consecutive patients with a first event of acute myocardial infarction admitted to the coronary care unit of Shafa hospital in Kerman. Patients were interviewed about the baseline characteristics as well as potential triggers of chest pain experienced over the day before the diagnosed onset of disease. The start of diagnostic chest pain was used as a marker of disease onset. The hazard period was defined as 12-h period of onset of chest pain.\n## MAIN RESULTS\nAmong probable triggers, only unsuspected sudden bad news and sexual activity had significant relationships with chest pain appearance during the hazard period. Among patients with the experience of bad news, the risk of chest pain occurrence during the hazard period was 6.9 [95% confidence interval (CI) 1.5-31.8]. Also, among those who were exposed to sexual activity, this risk was 3.4 (95% CI 1.1-10.4). Risk of chest pain following bad news was specific to men with a risk of 9.9 (95% CI 1.1-87.6) and risk of event following sexual activity was specific to women with a risk of 13.3 (95% CI 1.4-120.9).\n## CONCLUSION\nUnsuspected sudden bad news can be an important trigger for acute cardiac events in men, whereas sexual activity can act as a strong trigger for these events among women. Counseling in high-risk groups should be focused on men with considerable sudden emotional stressors in their lives and also on women during the ages of active sexual function.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Physical activity: sudden cardiac death",
        "key_reference_title": "Out of Hospital Sudden Cardiac Death Among Physically Active and Inactive Married Persons Younger than 65 Years in Slovenia",
        "key_reference_abstract": "Methods: A sedentary life style has been shown to increase the risk of coronary artery disease, a precursor of sudden cardiac death, while regular physical activity prevents atherosclerosis. In an out of hospital cardiac death study in Slovenia, case crossover design was used to investigate physical activity as a potential trigger of sudden cardiac death in connection with certain life style, biological and social risk factors.\nResults: In the study, 206 sudden cardiac deaths were selected: 166 men and 40 women with median age at death 57.8 and 59.0 years, respectively. The relative risk of dying during or within one hour after terminating physical activity of at least 6 metabolic equivalents was 3.0 in comparison to time without activity. The relative risk of people who performed 1.5 hours or more physical activity per week was 2.55 (95 % confidence limits: 1.69\u20133.84), opposed to 49.90 (confidence limits: 18.73\u2013132.96) for persons who performed less activity. According to the observed characteristics the risk of dying for inactive sudden cardiac victims was 17.13 to 25.89 (95 % confidence limits: 11.28\u201344.60) times higher in comparison to physically active persons. Persons who drank more than 4 international units of alcohol per day, positive family history, ischaemic heart disease and a heart rate of more than 90 beats/minute had the highest risk.\nConclusion: The results confirmed that the risk of dying due to sudden cardiac death during physical activity depends on the degree of physical activity regularly performed and the existing risk factors. J Clin Basic Cardiol 2003; 6: 63\u20137.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## BACKGROUND\nDespite anecdotal evidence suggesting that heavy physical exertion can trigger the onset of acute myocardial infarction, there have been no controlled studies of the risk of myocardial infarction during and after heavy exertion, the length of time between heavy exertion and the onset of symptoms (induction time), and whether the risk can be modified by regular physical exertion. To address these questions, we collected data from patients with confirmed myocardial infarction on their activities one hour before the onset of myocardial infarction and during control periods.\n## METHODS\nInterviews with 1228 patients conducted an average of four days after myocardial infarction provided data on their usual annual frequency of physical activity and the time, type, and intensity of physical exertion in the 26 hours before the onset of myocardial infarction. We compared the observed frequency of heavy exertion (6 or more metabolic equivalents) with the expected values using two types of self-matched analyses based on a new case-crossover study design. The low frequency of heavy exertion during the control periods was validated by data from a population-based control group of 218 subjects.\n## RESULTS\nOf the patients, 4.4 percent reported heavy exertion within one hour before the onset of myocardial infarction. The estimated relative risk of myocardial infarction in the hour after heavy physical exertion, as compared with less strenuous physical exertion or none, was 5.9 (95 percent confidence interval, 4.6 to 7.7), Among people who usually exercised less than one, one to two, three to four, or five or more times per week, the respective relative risks were 107 (95 percent confidence interval, 67 to 171), 19.4 (9.9 to 38.1), 8.6 (3.6 to 20.5), and 2.4 (1.5 to 3.7). Thus, increasing levels of habitual physical activity were associated with progressively lower relative risks. The induction time from heavy exertion to the onset of myocardial infarction was less than one hour, and symptoms usually began during the activity.\n## CONCLUSIONS\nHeavy physical exertion can trigger the onset of acute myocardial infarction, particularly in people who are habitually sedentary. Improved understanding of the mechanisms by which heavy physical exertion triggers the onset of myocardial infarction and the manner in which regular exertion protects against it would facilitate the design of new preventive approaches.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Physical exertion as a trigger of acute myocardial infarction. Triggers and Mechanisms of Myocardial Infarction Study Group.",
        "key_reference_abstract": "## BACKGROUND\nIt is controversial whether the onset of myocardial infarction occurs randomly or is precipitated by identifiable stimuli. Previous studies have suggested a higher risk of cardiac events in association with exertion.\n## METHODS\nConsecutive patients with acute myocardial infarction were identified by recording all admissions to our hospital in Berlin and by monitoring a general population of 330,000 residents in Augsburg, Germany. Information on the circumstances of each infarction was obtained by means of standardized interviews. The data analysis included a comparison of patients with matched controls and a case-crossover comparison (one in which each patient serves as his or her own control) of the patient's usual frequency of exertion with the last episode of exertion before the onset of myocardial infarction.\n## RESULTS\nFrom January 1989 through December 1991, 1194 patients (74 percent of whom were men; mean age [+/- SD], 61 +/- 9 years) completed the interview 13 +/- 6 days after infarction. We found that 7.1 percent of the case patients had engaged in physical exertion (> or = 6 metabolic equivalents) at the onset of infarction, as compared with 3.9 percent of the controls at the onset of the control event. For the patients as compared with the matched controls, the adjusted relative risk of having engaged in strenuous physical activity at the onset of infarction or the control event was 2.1 (95 percent confidence interval, 1.1 to 3.6). The case-crossover comparison yielded a similar relative risk of 2.1 (95 percent confidence interval, 1.6 to 3.1) for having engaged in strenuous physical activity within one hour before myocardial infarction. Patients whose frequency of regular exercise was less than four and four or more times per week had relative risks of 6.9 and 1.3, respectively (P < 0.01).\n## CONCLUSIONS\nA period of strenuous physical activity is associated with a temporary increase in the risk of having a myocardial infarction, particularly among patients who exercise infrequently. These findings should aid in the identification of the triggering mechanisms for myocardial infarction and improve prevention of this common and serious disorder.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Clinical and angiographic characteristics of exertion-related acute myocardial infarction.",
        "key_reference_abstract": "## CONTEXT\nVigorous physical exertion transiently increases the risk of acute myocardial infarction (MI), but little is known about the clinical characteristics of exertion-related MI.\n## OBJECTIVE\nTo compare the clinical and angiographic characteristics of patients who had an exertion-related acute MI vs those who experienced an MI not related to exertion.\n## DESIGN AND SETTING\nProspective observational cohort study of patients with an acute MI referred to a tertiary care hospital for primary angioplasty.\n## PATIENTS\nOf 1048 patients with acute MI, 640 (64 who experienced an exertion-related MI and 576 who did not) were selected for treatment with primary angioplasty and admitted between August 1995 and November 1998.\n## MAIN OUTCOME MEASURES\nClinical characteristics of the patients, including their habitual physical activity (determined by the Framingham Physical Activity Index and the Lipid Research Clinic Physical Activity Questionnaire), angiographic findings during coronary angiography, and the relative risk (RR) of MI during exertion.\n## RESULTS\nPatients who experienced exertion-related MI were more frequently men (86% vs 68%), hyperlipidemic (62% vs 40%), and smokers (59% vs 37%), were more likely to present with ventricular fibrillation (20% vs 11%), Killip classification III or IV heart failure (44% vs 22%), single-vessel disease (50% vs 28%), and a large thrombus in the infarct artery (64% vs 35%) and were more likely to be classified as having very low or low activity (84% vs 66%). The RR of experiencing an MI during exertion was 10.1 times greater than the risk at other times (95% confidence interval [CI], 1.6-65.6), with the highest risk among patients classified as very low active (RR, 30.5; 95% CI, 4.4-209.9) and low active (RR, 20.9; 95% CI, 3.1-142.1).\n## CONCLUSION\nThese results show that exertion-related MIs occur in habitually inactive people with multiple cardiac risk factors. These individuals may benefit from modest exercise training and aggressive risk-factor modification before they perform vigorous physical activity.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a population-based case-referent study.",
        "key_reference_abstract": "To study possible triggering of first events of acute myocardial infarction by heavy physical exertion, the authors conducted a case-crossover analysis (1993-1994) within a population-based case-referent study in Stockholm County, Sweden (the Stockholm Heart Epidemiology Program). Interviews were carried out with 699 myocardial infarction patients after onset of the disease. These cases represented 47 percent of all cases in the study base, and 70 percent of all nonfatal cases. The relative risk from vigorous exertion was 6.1 (95% confidence interval: 4.2, 9.0). The rate difference was 1.5 per million person-hours, and the attributable proportion was 5.7 percent. The risk was modified by physical fitness, with an increased risk being seen among sedentary subjects as in earlier studies, but the data also suggested a U-shaped association. In addition, the trigger effect was modified by socioeconomic status. Premonitory symptoms were common, and this implies risks of reverse causation bias and misclassification of case exposure information that require methodological consideration. Different techniques (the use of the usual-frequency type of control information, a pair-matched analysis, and a standard case-referent analysis) were applied to overcome the threat of misclassification of control exposure information. A case-crossover analysis in a random sample of healthy subjects resulted in a relative risk close to unity, as expected.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Triggers of nonfatal myocardial infarction in Costa Rica: heavy physical exertion, sexual activity, and infection.",
        "key_reference_abstract": "## PURPOSE\nThere are no data for factors that could trigger myocardial infarction (MI) in the context of lifestyles in developing countries.\n## METHODS\nUsing a case-crossover design, we assessed the effect of heavy physical exertion, sexual activity, acute respiratory tract infections, and gastroenteritis as triggers for MI in 530 survivors of a first MI from Costa Rica.\n## RESULTS\nRelative risks (RRs) for MI in the hour after heavy physical exertion and 2 hours after sexual activity were 4.94 (95% confidence interval [CI], 3.73-6.54) and 5.47 (95% CI, 2.71-11.02). Risk for MI after heavy physical exertion was greater for patients with poor physical fitness or elevated underlying cardiovascular risk (p < 0.0001 and p = 0.06, tests of homogeneity). RRs for acute respiratory tract infection and gastroenteritis were 1.48 (95% CI, 0.92-2.38) and 1.27 (95% CI, 0.95-1.69), respectively. Patients with three or more risk factors had an RR for MI for gastroenteritis of 2.08 (95% CI, 1.31-3.28).\n## CONCLUSIONS\nOur results confirm previous studies in developed countries showing that heavy physical exertion and sexual activity are potential triggers for MI, and their effect is modified by physical fitness and underlying cardiovascular risk. Additional studies that explore the biologic effects of gastroenteritis as triggers of MI are warranted.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Intensity of physical exertion and triggering of myocardial infarction: a case-crossover study.",
        "key_reference_abstract": "## AIMS\nAcute myocardial infarction (AMI) can be precipitated or triggered by discrete transient exposures including physical exertion. We evaluated whether the risk of having an AMI triggered by physical exertion exhibits an exposure-response relationship, and whether it varies by ambient temperature or by taking place indoors or outdoors.\n## METHODS AND RESULTS\nWe conducted a case-crossover study within the Myocardial Infarction Registry in Augsburg, Germany in 1999-2003. One thousand three hundred and one patients reported levels of activity and time spent outdoors on the day of AMI and three preceding days in an interview. The case-crossover analyses showed an association of physical exertion with AMI symptom onset within 2 h, which was strong for strenuous exertion (METs >or= 6) [relative risk (RR) 5.7, 95% confidence interval (CI) 3.6-9.0), and still significant for moderate exertion (METs = 5) (RR 1.6, 95% CI 1.2-2.1) compared to very light or no exertion. Strenuous exertion outside was associated with a four-fold larger RR of AMI symptom onset than exertion performed indoors, which was not explained by temperature.\n## CONCLUSION\nThis study confirms previous results and shows a graded exposure-response relationship between physical exertion intensity and triggering of AMI onset. These findings may have implications for behavioural guidance of people at risk of AMI.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Physical exertion, exercise, and sudden cardiac death in women.",
        "key_reference_abstract": "## CONTEXT\nExercise is associated with a lower risk of cardiovascular events but may transiently increase the risk of ventricular arrhythmias. Its short-term and long-term associations with risk of sudden cardiac death among women are unclear.\n## OBJECTIVES\nTo compare the risk of sudden cardiac death in women during moderate to vigorous exertion with the risk of sudden cardiac death during lighter or no exertion; and to assess the long-term association between moderate to vigorous exercise and sudden cardiac death.\n## DESIGN, SETTING, AND PARTICIPANTS\nProspective, nested case-crossover study of 288 cases of sudden cardiac death within the Nurses' Health Study (1980-2004); and a prospective cohort analysis of 69,693 participants without prior cardiovascular disease followed up from 1986-2004.\n## MAIN OUTCOME MEASURE\nRisk of sudden cardiac death associated with moderate to vigorous exertion.\n## RESULTS\nThe absolute risk of sudden cardiac death associated with moderate to vigorous exertion was exceedingly low at 1 per 36.5 million hours of exertion. In case-crossover analyses, the risk of sudden cardiac death was transiently elevated during moderate to vigorous exertion (relative risk [RR], 2.38; 95% confidence interval [CI], 1.23-4.60; P = .01) compared with the risk during lesser or no exertion. Habitual moderate to vigorous exertion modified this transient risk (P = .005 for interaction) and the risk was no longer significantly elevated among those who exercised 2 or more hours per week. In the cohort analyses, an increasing amount of moderate to vigorous exercise was associated with a lower long-term risk of sudden cardiac death in age-adjusted and multivariable models that excluded biological intermediates (P = .006 for trend). This relationship was attenuated when biological intermediates were included (P = .06 for trend); however, the reduction in risk remained significant among women who exercised 4 or more hours per week (adjusted RR, 0.41; 95% CI, 0.20-0.83; P = .01) compared with women who did not exercise.\n## CONCLUSIONS\nThese prospective data suggest that sudden cardiac death during exertion is an extremely rare event in women. Regular exercise may significantly minimize this small transient risk and may lower the overall long-term risk of sudden cardiac death.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Triggering of sudden death from cardiac causes by vigorous exertion.",
        "key_reference_abstract": "## BACKGROUND\nRetrospective and cross-sectional data suggest that vigorous exertion can trigger cardiac arrest or sudden death and that habitual exercise may diminish this risk. However, the role of physical activity in precipitating or preventing sudden death has not been assessed prospectively in a large number of subjects.\n## METHODS\nWe used a prospective, nested case-crossover design within the Physicians' Health Study to compare the risk of sudden death during and up to 30 minutes after an episode of vigorous exertion with that during periods of lighter exertion or none. We then evaluated whether habitual vigorous exercise modified the risk of sudden death that was associated with vigorous exertion. In addition, the relation of vigorous exercise to the overall risk of sudden death and nonsudden death from coronary heart disease was assessed.\n## RESULTS\nDuring 12 years of follow-up, 122 sudden deaths were confirmed among the 21,481 male physicians who were initially free of self-reported cardiovascular disease and who provided information on their habitual level of exercise at base line. The relative risk of-sudden death during and up to 30 minutes after vigorous exertion was 16.9 (95 percent confidence interval, 10.5 to 27.0; P<0.001). However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (1 sudden death per 1.51 million episodes of exertion). Habitual vigorous exercise attenuated the relative risk of sudden death that was associated with an episode of vigorous exertion (P value for trend=0.006). The base-line level of exercise was not associated with the overall risk of subsequent sudden death.\n## CONCLUSIONS\nThese prospective data from a study of U.S. male physicians suggest that habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics.",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate the role of vigorous physical exertion and anger as triggers of acute coronary syndromes (ACS) and to identify the clinical and sociodemographic correlates of triggering.\n## DESIGN\nProspective observational clinical cohort study.\n## SETTING\nFour coronary care units in the London area.\n## PATIENTS\n295 men and women with electrocardiographically and biochemically verified ACS.\n## MAIN OUTCOME MEASURES\nPhysical exertion in the 1 h and anger in the 2 h before symptom onset were assessed with structured interviews. Control periods were the equivalent hours one day earlier and usual rates over the past six months. Data were analysed by case-crossover methods.\n## RESULTS\nPhysical exertion was reported by 10% and anger by 17.4% of patients in the hazard period. The risk of ACS onset after physical exertion compared with light or no activity was 3.50 (95% confidence interval (CI) 1.37 to 10.6). The risk of onset with anger was 2.06 (95% CI 1.12 to 3.92). Physical exertion during the hazard period was related to an absence of premonitory symptoms, presentation with an ST elevation myocardial infarction (STEMI), low socioeconomic deprivation and higher future cardiovascular risk. Anger during the hazard period was more common in younger, socioeconomically deprived patients who presented with a STEMI.\n## CONCLUSIONS\nTriggers are relevant across the spectrum of ACS. The distinct clinical and sociodemographic factors associated with physical exertion and anger suggest that different pathophysiological processes may be involved.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the relative risks of nonfatal myocardial infarction (MI) triggered by sexual activity among the general population and in patients with prior coronary heart disease.\n## DESIGN\nRelative risks and effect modification were calculated by the case-crossover method, a new epidemiologic technique designed to quantify the transient change in risk following exposure to a potential disease trigger.\n## SETTING/PARTICIPANTS\nA total of 1774 patients with MI were interviewed in 45 hospitals throughout the United States. Data were gathered on potential triggers of MI occurring immediately prior to the event and during the previous year. Results are presented for the 858 patients who were sexually active in the year prior to the MI, with attention to the 273 patients who had coronary artery disease prior to their index MI, and the effect of regular exertion on risk.\n## MAIN OUTCOME MEASURE\nThe relative risk of nonfatal MI following sexual activity.\n## RESULTS\nOf the 858 patients, 79(9%) reported sexual activity in the 24 hours preceding MI, and 27(3%) reported sexual activity in the 2 hours preceding onset of symptoms of MI. The relative risk of MI occurring in the 2 hours after sexual activity was 2.5(95% confidence interval [CI], 1.7-3.7). The relative risk of triggering onset of MI among patients with a history of prior angina (2.1 [95% CI, 0.8-5.8]) or prior MI (2.9 [95% CI, 1.3-6.5]) was not greater than that observed in those without prior cardiac disease. Sexual activity was a likely contributor to the onset of MI in only 0.9% of cases and regular exertion was associated with decreasing risk.\n## CONCLUSIONS\nSexual activity can trigger the onset of MI. However, the relative risk is low, and since the absolute hourly risk of MI is extremely low, the absolute risk increase caused by sexual activity also is extremely low (1 chance in a million for a healthy individual). Moreover, the relative risk is not increased in patients with a prior history of cardiac disease and regular exercise appears to prevent triggering. These findings should be useful for counseling patients and decreasing the fear of sexual activity that often prevents complete rehabilitation from cardiovascular disease.",
        "truth": "False"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Sexual activity as a trigger of myocardial infarction. A case-crossover analysis in the Stockholm Heart Epidemiology Programme (SHEEP).",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate sexual activity as a trigger of myocardial infarction and the potential effect modification of physical fitness.\n## DESIGN\nA case-crossover study nested in the Stockholm Heart Epidemiology Programme (SHEEP).\n## SETTING\nStockholm County from April 1993 to December 1994.\n## PATIENTS\nAll patients with a first episode of non-fatal acute myocardial infarction admitted to coronary care units were eligible, and 699 patients participated in an interview.\n## MAIN OUTCOME MEASURES\nRelative risks with 95% confidence intervals.\n## RESULTS\nOnly 1.3% of the patients without premonitory symptoms had sexual activity during two hours before the onset of myocardial infarction. The relative risk of myocardial infarction was 2.1 (95% confidence interval (CI) 0.7 to 6.5) during one hour after sexual activity, and the risk among patients with a sedentary life was 4.4 (95% CI 1.5 to 12.9).\n## CONCLUSIONS\nThe increased risk of myocardial infarction after sexual activity and the further increase in risk among the less physically fit support the hypothesis of causal triggering by sexual activity. However, the absolute risk per hour is very low, and exposure is relatively infrequent. Thus having sex once a week only increases the annual risk of myocardial infarction slightly. Counselling should focus on encouraging patients to live a physically active life and not on abstaining from sexual activity.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Sex differences in potential daily triggers of the onset of acute myocardial infarction: a case-crossover analysis among an Iranian population.",
        "key_reference_abstract": "## OBJECTIVE\nDespite an increasing knowledge of the importance of triggering in cardiac events and their mortality and morbidity, awareness concerning the types of physical and psychological triggers is unsatisfactory. This study aimed to address the main daily triggers of typical chest pain as a marker of acute coronary syndrome onset and assessed the sex-related differences regarding these triggers among Iranians.\n## BASIC METHODS\nA case-crossover study was conducted on 198 consecutive patients with a first event of acute myocardial infarction admitted to the coronary care unit of Shafa hospital in Kerman. Patients were interviewed about the baseline characteristics as well as potential triggers of chest pain experienced over the day before the diagnosed onset of disease. The start of diagnostic chest pain was used as a marker of disease onset. The hazard period was defined as 12-h period of onset of chest pain.\n## MAIN RESULTS\nAmong probable triggers, only unsuspected sudden bad news and sexual activity had significant relationships with chest pain appearance during the hazard period. Among patients with the experience of bad news, the risk of chest pain occurrence during the hazard period was 6.9 [95% confidence interval (CI) 1.5-31.8]. Also, among those who were exposed to sexual activity, this risk was 3.4 (95% CI 1.1-10.4). Risk of chest pain following bad news was specific to men with a risk of 9.9 (95% CI 1.1-87.6) and risk of event following sexual activity was specific to women with a risk of 13.3 (95% CI 1.4-120.9).\n## CONCLUSION\nUnsuspected sudden bad news can be an important trigger for acute cardiac events in men, whereas sexual activity can act as a strong trigger for these events among women. Counseling in high-risk groups should be focused on men with considerable sudden emotional stressors in their lives and also on women during the ages of active sexual function.",
        "truth": "True"
    },
    {
        "pmid": "21427375",
        "meta_analysis_title": "Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis.",
        "meta_analysis_question": "Are episodic physical and sexual activities associated with an increased risk of acute cardiac events, and how does habitual physical activity level modify this association?",
        "criteria": "One reviewer screened all abstracts (I.J.D.) to identify potentially eligible studies, and 2 reviewers (I.J.D. and J.K.P.) screened all potentially eligible studies in full text to determine eligibility for the review. Eligible studies had to have a case-crossover design, as described by Maclure,10 and had to examine the effect of episodic physical or sexual activity (exposures) on the risk of acute coronary syndrome (including MI) and SCD (outcomes). Given that we expected studies conducted over a period of several years to be eligible for this analysis, we considered the definitions and diagnostic criteria used in the primary studies for the outcomes of interest. We excluded studies with an experimental design, ie, studies where exposure status was assigned by the investigators, including studies of induced exertion. Finally, we excluded observational studies not using a case-crossover design, including those with ecological, case-control, and cohort designs. We did not use any language restrictions, and we did not consider abstracts presented at scientific meetings, since they are frequently not peer reviewed.",
        "subgroup": "Forest Plot of Studies Assessing the Association of Episodic Physical and Sexual Activity With Myocardial Infarction and Sudden Cardiac Death - Sexual activity: myocardial infarction",
        "key_reference_title": "Out of Hospital Sudden Cardiac Death Among Physically Active and Inactive Married Persons Younger than 65 Years in Slovenia",
        "key_reference_abstract": "Methods: A sedentary life style has been shown to increase the risk of coronary artery disease, a precursor of sudden cardiac death, while regular physical activity prevents atherosclerosis. In an out of hospital cardiac death study in Slovenia, case crossover design was used to investigate physical activity as a potential trigger of sudden cardiac death in connection with certain life style, biological and social risk factors.\nResults: In the study, 206 sudden cardiac deaths were selected: 166 men and 40 women with median age at death 57.8 and 59.0 years, respectively. The relative risk of dying during or within one hour after terminating physical activity of at least 6 metabolic equivalents was 3.0 in comparison to time without activity. The relative risk of people who performed 1.5 hours or more physical activity per week was 2.55 (95 % confidence limits: 1.69\u20133.84), opposed to 49.90 (confidence limits: 18.73\u2013132.96) for persons who performed less activity. According to the observed characteristics the risk of dying for inactive sudden cardiac victims was 17.13 to 25.89 (95 % confidence limits: 11.28\u201344.60) times higher in comparison to physically active persons. Persons who drank more than 4 international units of alcohol per day, positive family history, ischaemic heart disease and a heart rate of more than 90 beats/minute had the highest risk.\nConclusion: The results confirmed that the risk of dying due to sudden cardiac death during physical activity depends on the degree of physical activity regularly performed and the existing risk factors. J Clin Basic Cardiol 2003; 6: 63\u20137.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Calcium Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Hip Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Nonvertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Vertebral Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial.",
        "key_reference_abstract": "In a double-blind trial, 327 patients (57 men) over 65 (mean age 79.5) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, methandienone 2.5 mg and/or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed: the greatest changes occurred with methandienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant (P less than 0.001) in those receiving vitamin D3 and methandienone.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study.",
        "key_reference_abstract": "Daily treatment with 30 mg of sodium fluoride (NaF) and 1 g of calcium over a 3-year period increased the bone mineral content (BMC) in the spines of women (n = 25) with osteoporosis. Determination of the BMC was followed with dual photon absorptiometry (137Cs-241Am) in the third lumbar vertebra. No increase in BMC was found with only 10 mg sodium fluoride in combination with calcium (n = 25), with calcium alone (n = 25), or with placebo (n = 25). No serious side effects were registered. There was, however, minor gastrointestinal distress in one-fifth of the patients taking 30 mg NaF daily.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium supplementation on bone loss in postmenopausal women.",
        "key_reference_abstract": "## BACKGROUND\nThe use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known.\n## METHODS\nWe studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months.\n## RESULTS\nThe mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Ward's triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations.\n## CONCLUSIONS\nCalcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Correcting calcium nutritional deficiency prevents spine fractures in elderly women.",
        "key_reference_abstract": "We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women.",
        "key_reference_abstract": "We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age +/- SE, 66.3+/-0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: -18.9% (p = 0.002) for parathyroid hormone (PTH), -11.9% (p = 0.026) for serum osteocalcin, and -32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.",
        "key_reference_abstract": "## BACKGROUND AND METHODS\nLaboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.\n## RESULTS\nThe subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.\n## CONCLUSIONS\nCalcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.",
        "key_reference_abstract": "This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60.",
        "key_reference_abstract": "Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.",
        "key_reference_abstract": "## BACKGROUND\nIn randomized trials there may be no overriding reason whether or not to have a placebo control.\n## PURPOSE\nWe assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.\n## METHODS\nWe undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.\n## RESULTS\nFrom 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).\n## CONCLUSIONS\nWe conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nElderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.\n## METHODS\nIn a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.\n## FINDINGS\n698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.\n## INTERPRETATION\nThe findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.",
        "key_reference_abstract": "## BACKGROUND\nIncreased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.\n## METHODS\nFive-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.\n## RESULTS\nAmong our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).\n## CONCLUSION\nSupplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomized controlled trial of calcium in healthy older women.",
        "key_reference_abstract": "## PURPOSE\nCalcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.\n## METHODS\nA randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.\n## RESULTS\nFollow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.\n## CONCLUSIONS\nCalcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of vitamin D and calcium supplementation on pancreatic \u03b2 cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.\n## OBJECTIVE\nWe determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.\n## DESIGN\nNinety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic \u03b2 cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.\n## RESULTS\nParticipants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D \u00d7 calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change \u00b1 SE: 300 \u00b1 130 compared with -126 \u00b1 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 \u00b1 39 compared with -36 \u00b1 37 mU \u00b7 L(-1) \u00b7 min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 \u00b1 0.03% compared with 0.14 \u00b1 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.\n## CONCLUSION\nIn adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved \u03b2 cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium and vitamin d supplementation in postmenopausal women.",
        "key_reference_abstract": "## CONTEXT\nBone health is influenced by the intake of both calcium and vitamin D.\n## OBJECTIVE\nOur objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.\n## INTERVENTIONS\nSubjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 \u03bcg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months.\n## MAIN OUTCOME MEASURES\nSerum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured.\n## RESULTS\nBefore study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium.\n## CONCLUSIONS\nFasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 \u03bcg vitamin D3/d does not.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.\n## DESIGN\nProspective, double-blind trial.\n## SETTING\nCommunity setting (Amsterdam and surrounding area).\n## PATIENTS\n2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.\n## INTERVENTION\nParticipants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.\n## MEASUREMENTS\nDietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.\n## RESULTS\nMean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).\n## CONCLUSION\nOur results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.",
        "key_reference_abstract": "## OBJECTIVE\nTo determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.\n## DESIGN\nRandomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.\n## SETTING AND PARTICIPANTS\n2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.\n## MAIN OUTCOME MEASURES\nFracture incidence and total mortality by cause.\n## RESULTS\nAfter five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.\n## CONCLUSION\nFour monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study.",
        "key_reference_abstract": "## BACKGROUND\nsurvivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.\n## OBJECTIVE\nto compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.\n## DESIGN\nrandomised controlled trial.\n## SETTING\northogeriatric rehabilitation ward.\n## METHODS\n150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.\n## RESULTS\nmean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.\n## CONCLUSION\nVitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nLow trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.\n## METHODS\nRandomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.\n## RESULTS\n585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.\n## CONCLUSIONS\nAn annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nImproving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.\n## OBJECTIVE\nTo determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.\n## DESIGN, SETTING, AND PARTICIPANTS\nA double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.\n## INTERVENTION\n500,000 IU of cholecalciferol or placebo.\n## MAIN OUTCOME MEASURES\nFalls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.\n## RESULTS\nWomen in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.\n## CONCLUSION\nAmong older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.\n## TRIAL REGISTRATION\nanzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.",
        "key_reference_abstract": "Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3-monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9-month randomized, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n\u2009=\u2009353) or an identical placebo (n\u2009=\u2009333). All participants were advised to increase dietary calcium intake. Falls data were collected 3-monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7\u2009\u00b1\u20094.1 years. The average serum 25OHD value at baseline was 65.8\u2009\u00b1\u200922.7\u2009nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15\u2009nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864\u2009\u00b1\u2009412\u2009mg/day) and 9 months (855\u2009\u00b1\u2009357\u2009mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high-dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.",
        "key_reference_abstract": "## AIMS/OBJECTIVE\nConflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.\n## METHODS\nA large multicentre 3 \u00d7 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged \u2265 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n =\u2009541), rosiglitazone 4-8 mg/day (n\u2009=\u2009399) or pioglitazone 30-45 mg/day (n\u2009=\u2009392); 1,221 participants were randomised to placebo (n\u2009=\u2009614) or vitamin D 1,000 IU/day (n\u2009=\u2009607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.\n## RESULTS\nFrom the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.\n## CONCLUSIONS/INTERPRETATION\nUncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.",
        "key_reference_abstract": "## IMPORTANCE\nObservational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people.\n## OBJECTIVE\nTo test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension.\n## DESIGN\nParallel group, double-blind, placebo-controlled randomized trial.\n## SETTING\nPrimary care clinics and hospital clinics.\n## PARTICIPANTS\nPatients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011.\n## INTERVENTIONS\nA total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.\n## MAIN OUTCOMES AND MEASURES\nDifference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months.\n## RESULTS\nA total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P\u2009<\u2009.001). No significant treatment effect was seen for mean (95% CI) office blood pressure (\u22121 [\u22126 to 4]/\u22122 [\u22124 to 1] mm Hg at 3 months and 1 [\u22122 to 4]/0 [\u22122 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P\u2009=\u2009.24).\n## CONCLUSIONS AND RELEVANCE\nVitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension.\n## TRIAL REGISTRATION\nisrctn.org Identifier: ISRCTN92186858.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.",
        "key_reference_abstract": "## BACKGROUND\nThe 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol.\n## STUDY DESIGN\n2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study.\n## SETTING & PARTICIPANTS\n55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October\u00a02009.\n## INTERVENTION\nCholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines.\n## OUTCOMES\nPrimary end point was the percentage of patients with 25(OH)D levels\u226530ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid\u00a0hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D.\n## MEASUREMENTS\nBlood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and\u00a039.\n## RESULTS\nThe primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level\u226530ng/mL in patients issued from the placebo group.\n## LIMITATIONS\nSmall size of the study population.\n## CONCLUSIONS\nOral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.",
        "key_reference_abstract": "## IMPORTANCE\nWhile vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory.\n## OBJECTIVE\nTo determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women.\n## DESIGN, SETTING, AND PARTICIPANTS\nA 2-year randomized, double-blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home-dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise.\n## INTERVENTIONS\nFour study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed.\n## RESULTS\nIntent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.\n## CONCLUSIONS AND RELEVANCE\nThe rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00986466.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.",
        "key_reference_abstract": "## UNLABELLED\nThis trial compared the effects of daily treatment with vitamin D or placebo for 1\u00a0year on blood tests of vitamin D status. The results demonstrated that daily 4000\u00a0IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.\n## INTRODUCTION\nThe aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000\u00a0IU (100\u00a0\u03bcg), 2000\u00a0IU (50\u00a0\u03bcg) or placebo for 1\u00a0year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes.\n## METHODS\nThis is a randomized placebo-controlled trial in 305 community-dwelling people aged 65\u00a0years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function.\n## RESULTS\nMean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12\u00a0months in those allocated 4000\u00a0IU, 2000\u00a0IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90\u00a0nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000\u00a0IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function.\n## CONCLUSIONS\nAfter accounting for average 70% compliance in long-term trials, doses of 4000\u00a0IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.",
        "key_reference_abstract": "## BACKGROUND\nAdults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls.\n## METHODS\nThe Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200\u2008000 IU (5\u00b70 mg) colecalciferol (vitamin D\n## FINDINGS\nBetween April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65\u00b79 years (SD 8\u00b73) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3\u00b74 years (SD 0\u00b74, range 2\u00b75-4\u00b72). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0\u00b799 (95% CI 0\u00b792-1\u00b707; p=0\u00b782) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1\u00b719 (95% CI 0\u00b794-1\u00b750; p=0\u00b715) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant.\n## INTERPRETATION\nHigh-dose bolus vitamin D supplementation of 100\u2008000 IU colecalciferol monthly over 2\u00b75-4\u00b72 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium.\n## FUNDING\nHealth Research Council of New Zealand and Accident Compensation Corporation of New Zealand.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.",
        "key_reference_abstract": "## BACKGROUND\nInadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.\n## METHODS\nWe studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records.\n## RESULTS\nThe mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02).\n## CONCLUSIONS\nIn men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n## DESIGN\nPragmatic open randomised controlled trial.\n## SETTING\nPractice nurse led clinics in primary care.\n## PARTICIPANTS\n3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n## INTERVENTION\nDaily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n## MAIN OUTCOME MEASURES\nPrimary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n## RESULTS\n69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n## CONCLUSION\nWe found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Calcium plus vitamin D supplementation and the risk of fractures.",
        "key_reference_abstract": "## BACKGROUND\nThe efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.\n## METHODS\nWe recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.\n## RESULTS\nHip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.\n## CONCLUSIONS\nAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.",
        "key_reference_abstract": "## UNLABELLED\nDietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.\n## INTRODUCTION\nThe putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.\n## MATERIALS AND METHODS\nHealthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.\n## RESULTS\nSignificant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).\n## CONCLUSIONS\nThese results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS.",
        "key_reference_abstract": "Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women.",
        "truth": "True"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial.",
        "key_reference_abstract": "Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n\u200a=\u200a198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE\u200a+\u200aCa. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE\u200a+\u200aCa group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one-leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE\u200a+\u200aCa group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE\u200a+\u200aCa groups. For the balance capacity, the subjects in MESE and MESE\u200a+\u200aCa groups secured much better performance than those in Ca and control group after the treatment for 12 months (P\u200a<\u200a0.001, P\u200a<\u200a0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women.",
        "truth": "False"
    },
    {
        "pmid": "29279934",
        "meta_analysis_title": "Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?",
        "criteria": "Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.",
        "subgroup": "Meta-analysis Results of Combined Calcium and Vitamin D Supplementation for the Incidence of Hip, Nonvertebral, Vertebral, and Total Fractures - Total Fracture",
        "key_reference_title": "Effects of Enhanced Exercise and Combined Vitamin D and Calcium Supplementation on Muscle Strength and Fracture Risk in Postmenopausal Chinese Women.",
        "key_reference_abstract": "Objective To observe the effects of enhanced exercise and combined vitamin D and calcium supplementation on muscular strength and fracture occurrence in postmenopausal women with a high risk of osteoporosis.Methods Totally 614 postmenopausal women at high risk factors of osteoporosis were enrolled in Dongcheng district of Beijing and randomized into four groups:group A(control group,n=173),group B(regular Tai Chi exercise,n=171),group C(calcium 600 mg/d+VitD",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Conducting a fully mobile and randomised clinical trial for depression: access, engagement and expense.",
        "key_reference_abstract": "## IMPORTANCE\nAdvances in mobile technology have resulted in federal and industry-level initiatives to facilitate large-scale clinical research using smart devices. Although the benefits of technology to expand data collection are obvious, assumptions about the reach of mobile research methods (\n## OBJECTIVE\nTo assess the feasibility of a fully mobile randomised controlled trial using assessments and treatments delivered entirely through mobile devices to depressed individuals.\n## DESIGN\nUsing a web-based research portal, adult participants with depression who also owned a smart device were screened, consented and randomised to 1 of 3 mental health apps for treatment. Assessments of self-reported mood and cognitive function were conducted at baseline, 4, 8 and 12\u2005weeks. Physical and social activity was monitored daily using passively collected phone use data. All treatment and assessment tools were housed on each participant's smart phone or tablet.\n## INTERVENTIONS\nA cognitive training application, an application based on problem-solving therapy, and a mobile-sensing application promoting daily activities.\n## RESULTS\nNone\n## CONCLUSIONS AND RELEVANCE\nThese findings suggest that mobile randomised control trials can recruit large numbers of participants in a short period of time and with minimal cost, but study engagement remains challenging.\n## TRIAL REGISTRATION NUMBER\nNCT00540865.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "mHealth for Schizophrenia: Patient Engagement With a Mobile Phone Intervention Following Hospital Discharge.",
        "key_reference_abstract": "## BACKGROUND\nmHealth interventions that use mobile phones as instruments for illness management are gaining popularity. Research examining mobile phone\u2012based mHealth programs for people with psychosis has shown that these approaches are feasible, acceptable, and clinically promising. However, most mHealth initiatives involving people with schizophrenia have spanned periods ranging from a few days to several weeks and have typically involved participants who were clinically stable.\n## OBJECTIVE\nOur aim was to evaluate the viability of extended mHealth interventions for people with schizophrenia-spectrum disorders following hospital discharge. Specifically, we set out to examine the following: (1) Can individuals be engaged with a mobile phone intervention program during this high-risk period?, (2) Are age, gender, racial background, or hospitalization history associated with their engagement or persistence in using a mobile phone intervention over time?, and (3) Does engagement differ by characteristics of the mHealth intervention itself (ie, pre-programmed vs on-demand functions)?\n## METHODS\nWe examined mHealth intervention use and demographic and clinical predictors of engagement in 342 individuals with schizophrenia-spectrum disorders who were given the FOCUS mobile phone intervention as part of a technology-assisted relapse prevention program during the 6-month high-risk period following hospitalization.\n## RESULTS\nOn average, participants engaged with FOCUS for 82% of the weeks they had the mobile phone. People who used FOCUS more often continued using it over longer periods: 44% used the intervention over 5-6 months, on average 4.3 days a week. Gender, race, age, and number of past psychiatric hospitalizations were associated with engagement. Females used FOCUS on average 0.4 more days a week than males. White participants engaged on average 0.7 days more a week than African-Americans and responded to prompts on 0.7 days more a week than Hispanic participants. Younger participants (age 18-29) had 0.4 fewer days of on-demand use a week than individuals who were 30-45 years old and 0.5 fewer days a week than older participants (age 46-60). Participants with fewer past hospitalizations (1-6) engaged on average 0.2 more days a week than those with seven or more. mHealth program functions were associated with engagement. Participants responded to prompts more often than they self-initiated on-demand tools, but both FOCUS functions were used regularly. Both types of intervention use declined over time (on-demand use had a steeper decline). Although mHealth use declined, the majority of individuals used both on-demand and system-prompted functions regularly throughout their participation. Therefore, neither function is extraneous.\n## CONCLUSIONS\nThe findings demonstrated that individuals with schizophrenia-spectrum disorders can actively engage with a clinically supported mobile phone intervention for up to 6 months following hospital discharge. mHealth may be useful in reaching a clinical population that is typically difficult to engage during high-risk periods.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A multi-faceted approach to characterizing user behavior and experience in a digital mental health intervention.",
        "key_reference_abstract": "Digital interventions offer great promise for supporting health-related behavior change. However, there is much that we have yet to learn about how people respond to them. In this study, we present a novel mixed-methods approach to analysis of the complex and rich data that digital interventions collect. We perform secondary analysis of IntelliCare, an intervention in which participants are able to try 14 different mental health apps over the course of eight weeks. The goal of our analysis is to characterize users' app use behavior and experiences, and is rooted in theoretical conceptualizations of engagement as both usage and user experience. In the first aim, we employ cluster analysis to identify subgroups of participants that share similarities in terms of the frequency of their usage of particular apps, and then employ other engagement measures to compare the clusters. We identified four clusters with different app usage patterns: Low Usage, High Usage, Daily Feats Users, and Day to Day users. Each cluster was distinguished by its overall frequency of app use, or the main app that participants used. In the second aim, we developed a computer-assisted text analysis and visualization method - message highlighting - to facilitate comparison of the clusters. Last, we performed a qualitative analysis using participant messages to better understand the mechanisms of change and usability of salient apps from the cluster analysis. Our novel approach, integrating text and visual analytics with more traditional qualitative analysis techniques, can be used to generate insights concerning the behavior and experience of users in digital health contexts, for subsequent personalization and to identify areas for improvement of intervention technologies.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Pilot Randomized Trial of a Self-Help Behavioral Activation Mobile App for Utilization in Primary Care.",
        "key_reference_abstract": "Mobile technologies can be leveraged to meet the need for evidence-based psychological depression treatment via primary care. The purpose of the present study was to preliminarily examine the feasibility and efficacy of a self-help brief behavioral activation mobile application (app; \"Moodivate\") for depressive symptoms among adults treated via primary care. Participants (N = 52) were recruited from primary care practices between January and December 2017 and were randomized 2:2:1 to receive (a) Moodivate, (b) an active control cognitive-behavioral therapy-based mobile app (\"MoodKit\"), or (c) treatment as usual (TAU; no app). Participants completed assessments of depressive symptoms weekly for 8 weeks. App analytics data were captured to examine Moodivate feasibility (analytics unavailable for control app). Moodivate participants on average had 46.76 (SD = 30.10) app sessions throughout the trial duration, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total throughout the trial. Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period. A generalized estimating equation model examining change in depressive symptoms over time by treatment condition indicated a significant interaction between time and treatment condition (\u03c7",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Pilot randomized controlled trial of a Spanish-language Behavioral Activation mobile app (\u00a1Apt\u00edvate!) for the treatment of depressive symptoms among united states Latinx adults with limited English proficiency.",
        "key_reference_abstract": "## BACKGROUND\nTo address the need for disseminable, evidence-based depression treatment options for Latinx adults with limited English proficiency (LEP), our team developed \u00a1Apt\u00edvate!, a Spanish-language Behavioral Activation self-help mobile application. Primary aims of this study were to: 1) examine feasibility and uptake of \u00a1Apt\u00edvate! among depressed Latinx adults with LEP and 2) preliminarily examine \u00a1Apt\u00edvate! efficacy for depression treatment.\n## METHODS\nParticipants (N\u202f=\u202f42) with elevated depressive symptoms were randomized 2:1:1 to: 1) \u00a1Apt\u00edvate! (n\u202f=\u202f22), 2) an active control Spanish-language app (\"iCouch CBT\"; n\u202f=\u202f9), or 3) Treatment As Usual (i.e., no app; n\u202f=\u202f11). Feasibility was assessed via self-reported app utilization and app analytics data. Depressive symptoms were assessed weekly for eight weeks via self report.\n## RESULTS\nAll \u00a1Apt\u00edvate! participants used the app at least once, 81.8% of participants used the app \u22658 times, and 36.4% of participants used the app \u226556 times. Weekly retention was strong: 72.7% and 50% of participants continued to use the app at one- and two-months post-enrollment, respectively. Generalized Estimating Equation models indicated a significant interaction between time and treatment, such that \u00a1Apt\u00edvate! participants reported significantly lower depressive symptoms over time than TAU. Depressive symptoms did not differ on average across time between the iCouch and TAU conditions, nor between iCouch and \u00a1Apt\u00edvate!.\n## LIMITATIONS\nLimitations include small sample size, limited follow-up, and lack of analytics data for the active control condition.\n## CONCLUSIONS\nWith further research, \u00a1Apt\u00edvate! may offer a feasible, efficacious approach to extend the reach of evidence-based depression treatment for Latinx adults with LEP.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A Scenario-Based Cognitive Behavioral Therapy Mobile App to Reduce Dysfunctional Beliefs in Individuals with Depression: A Randomized Controlled Trial.",
        "key_reference_abstract": "## INTRODUCTION\nWhile self-administered mobile app-based cognitive behavioral therapy (CBT) has shown efficiency and effectiveness over the past decade, attempts to address automatic and negative beliefs have been lacking. The purpose of this study was to introduce and verify a mobile app that directly intervenes in dysfunctional thoughts. This app-based treatment includes recognizing automatic and negative thoughts of the protagonist of scenarios, writing advice directly to the main character, and sharing advice provided by other participants.\n## MATERIALS AND METHODS\nThirty-four participants diagnosed with Other Specified Depressive Disorder were recruited and randomly allocated to a CBT-based mobile-app program, the Todac Todac (TT group), or a daily mood chart app program (control group). Participants were asked to use the software for 3 weeks. Assessments for autonomic thoughts and clinical symptoms were administered at baseline and at a follow-up evaluation.\n## RESULTS\nAfter completing the 3-week program, Dysfunctional Attitude Scale (DAS) scores in TT group were lower than they were in the control group. In clinical measures, both TT group and control group showed reduced Beck Depression Inventory-II (BDI-II) scores and situation-dependent trait version of State-Trait Anxiety Inventory (STAI-X2) at follow-up. However, TT group showed significantly reduced STAI-X2 scores compared to control group. For all participants, changes in DAS scores were correlated with BDI-II and STAI-X2 scores.\n## CONCLUSIONS\nOur preliminary findings provide promising evidence that scenario-based CBT mobile apps can be used to deliver feasible and efficacious cognitive therapy. Long-term research is needed to determine the impact and effectiveness of this new treatment format.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "An Empathy-Driven, Conversational Artificial Intelligence Agent (Wysa) for Digital Mental Well-Being: Real-World Data Evaluation Mixed-Methods Study.",
        "key_reference_abstract": "## BACKGROUND\nA World Health Organization 2017 report stated that major depression affects almost 5% of the human population. Major depression is associated with impaired psychosocial functioning and reduced quality of life. Challenges such as shortage of mental health personnel, long waiting times, perceived stigma, and lower government spends pose barriers to the alleviation of mental health problems. Face-to-face psychotherapy alone provides only point-in-time support and cannot scale quickly enough to address this growing global public health challenge. Artificial intelligence (AI)-enabled, empathetic, and evidence-driven conversational mobile app technologies could play an active role in filling this gap by increasing adoption and enabling reach. Although such a technology can help manage these barriers, they should never replace time with a health care professional for more severe mental health problems. However, app technologies could act as a supplementary or intermediate support system. Mobile mental well-being apps need to uphold privacy and foster both short- and long-term positive outcomes.\n## OBJECTIVE\nThis study aimed to present a preliminary real-world data evaluation of the effectiveness and engagement levels of an AI-enabled, empathetic, text-based conversational mobile mental well-being app, Wysa, on users with self-reported symptoms of depression.\n## METHODS\nIn the study, a group of anonymous global users were observed who voluntarily installed the Wysa app, engaged in text-based messaging, and self-reported symptoms of depression using the Patient Health Questionnaire-9. On the basis of the extent of app usage on and between 2 consecutive screening time points, 2 distinct groups of users (high users and low users) emerged. The study used mixed-methods approach to evaluate the impact and engagement levels among these users. The quantitative analysis measured the app impact by comparing the average improvement in symptoms of depression between high and low users. The qualitative analysis measured the app engagement and experience by analyzing in-app user feedback and evaluated the performance of a machine learning classifier to detect user objections during conversations.\n## RESULTS\nThe average mood improvement (ie, difference in pre- and post-self-reported depression scores) between the groups (ie, high vs low users; n=108 and n=21, respectively) revealed that the high users group had significantly higher average improvement (mean 5.84 [SD 6.66]) compared with the low users group (mean 3.52 [SD 6.15]); Mann-Whitney P=.03 and with a moderate effect size of 0.63. Moreover, 67.7% of user-provided feedback responses found the app experience helpful and encouraging.\n## CONCLUSIONS\nThe real-world data evaluation findings on the effectiveness and engagement levels of Wysa app on users with self-reported symptoms of depression show promise. However, further work is required to validate these initial findings in much larger samples and across longer periods.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A randomized controlled trial on a smartphone self-help application (Be Good to Yourself) to reduce depressive symptoms.",
        "key_reference_abstract": "Depressive symptoms are common, yet only a subgroup of individuals receive adequate treatment. To reduce the treatment gap, several online self-help programs have been developed, yielding small to moderate effects. We developed a smartphone self-help application addressing depressive symptoms. We sought to evaluate its feasibility and efficacy in participants reporting a subjective need for help (a diagnosis of depression was not mandatory). We conducted a randomized controlled trial (N\u202f=\u202f90). The primary outcome was a reduction of depressive symptoms measured with the Patient Health Questionnaire-9 (PHQ-9). Secondary outcomes included improved self-esteem (Rosenberg Self-Esteem Scale) and quality of life (WHOQOL-BREF). The intervention group obtained access to the application for four weeks, the wait-list group received access after the post assessment. No group differences emerged in either outcome in intention-to-treat analyses. Per protocol analyses with frequent users (i.e., several times a week or more) yielded a small effect size (\u03b7",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A Gamified Smartphone-Based Intervention for Depression: Randomized Controlled Pilot Trial.",
        "key_reference_abstract": "## BACKGROUND\nAvailable smartphone-based interventions for depression predominantly use evidence-based strategies from cognitive-behavioral therapy (CBT), but patient engagement and reported effect sizes are small. Recently, studies have demonstrated that smartphone-based interventions combining CBT with gamified approach-avoidance bias modification training (AAMT) can foster patient engagement and reduce symptoms of several mental health problems.\n## OBJECTIVE\nBased on these findings, we developed a gamified smartphone-based intervention, mentalis Phoenix (MT-Phoenix), and hypothesized the program would both engage patients and produce preliminary evidence for the reduction of depressive symptoms.\n## METHODS\nTo test this hypothesis, we evaluated MT-Phoenix in a randomized controlled pilot trial including 77 individuals with elevated depression scores (Patient Health Questionnaire-9 scores \u22655). Participants were either instructed to train for 14 days with MT-Phoenix or assigned to a waitlist control condition. Engagement with the intervention was measured by assessing usage data. The primary outcome was reduction in depressive symptom severity at postassessment.\n## RESULTS\nData from this pilot trial shows that participants in the intervention group used the smartphone-based intervention for 46% of all days (6.4/14) and reported a significantly greater reduction of depressive symptoms than did participants in the control condition (F\n## CONCLUSIONS\nA gamified smartphone-based intervention combining CBT with AAMT may foster patient engagement and effectively target depressive symptoms. Future studies should evaluate the effectiveness of this intervention in a phase 3 trial using clinical samples. Moreover, the intervention should be compared to active control conditions.\n## TRIAL REGISTRATION\nGerman Clinical Trial Registry DRKS00012769; https://tinyurl.com/47mw8du7.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Behavioural activation versus mindfulness-based guided self-help treatment administered through a smartphone application: a randomised controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nEvaluating and comparing the effectiveness of two smartphone-delivered treatments: one based on behavioural activation (BA) and other on mindfulness.\n## DESIGN\nParallel randomised controlled, open, trial. Participants were allocated using an online randomisation tool, handled by an independent person who was separate from the staff conducting the study.\n## SETTING\nGeneral community, with recruitment nationally through mass media and advertisements.\n## PARTICIPANTS\n40 participants diagnosed with major depressive disorder received a BA treatment, and 41 participants received a mindfulness treatment. 9 participants were lost at the post-treatment.\n## INTERVENTION BA\nAn 8-week long behaviour programme administered via a smartphone application. Mindfulness: An 8-week long mindfulness programme, administered via a smartphone application.\n## MAIN OUTCOME MEASURES\nThe Beck Depression Inventory-II (BDI-II) and the nine-item Patient Health Questionnaire Depression Scale (PHQ-9).\n## RESULTS\n81 participants were randomised (mean age 36.0 years (SD=10.8)) and analysed. Results showed no significant interaction effects of group and time on any of the outcome measures either from pretreatment to post-treatment or from pretreatment to the 6-month follow-up. Subgroup analyses showed that the BA treatment was more effective than the mindfulness treatment among participants with higher initial severity of depression from pretreatment to the 6-month follow-up (PHQ-9: F (1, 362.1)=5.2, p<0.05). In contrast, the mindfulness treatment worked better than the BA treatment among participants with lower initial severity from pretreatment to the 6-month follow-up (PHQ-9: F (1, 69.3)=7.7, p<0.01); BDI-II: (F(1, 53.60)=6.25, p<0.05).\n## CONCLUSIONS\nThe two interventions did not differ significantly from one another. For participants with higher severity of depression, the treatment based on BA was superior to the treatment based on mindfulness. For participants with lower initial severity, the treatment based on mindfulness worked significantly better than the treatment based on BA.\n## TRIAL REGISTRATION\nClinical Trials NCT01463020.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Development and Pilot Testing of an Internet-Based Self-Help Intervention for Depression for Indian Users.",
        "key_reference_abstract": "There is a dearth of published research on uptake and utility of mental health apps in India, despite a rising global trend in the application of technology in the field of mental health. We describe the development and pilot testing of a self-help intervention for depression, PUSH-D (Practice and Use Self-Help for Depression) for urban Indians. This guided self-help app, with essential and optional zone sections, was developed to provide a comprehensive coverage of therapeutic strategies drawn from cognitive behavior therapy, interpersonal therapy, supportive psychotherapy, and positive psychology. Pilot testing was carried out using a single group pre-, post- and follow-up design in 78 eligible participants. Participants were typically young adults with major depression or dysthymia and significant impairment in functioning. Almost two-thirds of the participants had never sought professional mental health help. Significant reductions in depression and improvement in the functioning and well-being were notedon standardized measures in participants completing all 10 essential zone sections. These gains were maintained at follow-up. The results were similar for partial completers, who completed fiveout of the 10 essential sections. PUSH-D is one of the first indigenously developed self-help apps for depression and it shows promise in reducing the treatment gap for depression in India.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Guided Self-Help Works: Randomized Waitlist Controlled Trial of Pacifica, a Mobile App Integrating Cognitive Behavioral Therapy and Mindfulness for Stress, Anxiety, and Depression.",
        "key_reference_abstract": "## BACKGROUND\nDespite substantial improvements in technology and the increased demand for technology-enabled behavioral health tools among consumers, little progress has been made in easing the burden of mental illness. This may be because of the inherent challenges of conducting traditional clinical trials in a rapidly evolving technology landscape.\n## OBJECTIVE\nThis study sought to validate the effectiveness of Pacifica, a popular commercially available app for the self-management of mild-to-moderate stress, anxiety, and depression.\n## METHODS\nA total of 500 adults with mild-to-moderate anxiety or depression were recruited from in-app onboarding to participate in a randomized waitlist controlled trial of Pacifica. We conducted an all-virtual study, recruiting, screening, and randomizing participants through a Web-based participant portal. Study participants used the app for 1 month, with no level of use required, closely mimicking real-world app usage. Participants in the waitlist group were given access to the app after 1 month. Measurements included self-reported symptoms of stress, anxiety, depression, and self-efficacy. We performed an intent-to-treat analysis to examine the interactive effects of time and condition.\n## RESULTS\nWe found significant interactions between time and group. Participants in the active condition demonstrated significantly greater decreases in depression, anxiety, and stress and increases in self-efficacy. Although we did not find a relationship between overall engagement with the app and symptom improvement, participants who completed relatively more thought record exercises sustained improvements in their symptoms through the 2-month follow-up to a greater degree than those who completed fewer. In addition, we found that participants who reported concomitantly taking psychiatric medications during the trial benefitted less from the app, as measured by the symptoms of anxiety and stress.\n## CONCLUSIONS\nThis study provides evidence that Pacifica, a popular commercially available self-help app, is effective in reducing self-reported symptoms of depression, anxiety, and stress, particularly among individuals who utilize thought records and are not taking psychiatric medication.\n## TRIAL REGISTRATION\nClinicalTrials.gov NCT03333707; https://clinicaltrials.gov/ct2/show/NCT03333707 (Archived by WebCite at http://www.webcitation.org/78YE07ADB).",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Comparison of the Effects of Coaching and Receipt of App Recommendations on Depression, Anxiety, and Engagement in the IntelliCare Platform: Factorial Randomized Controlled Trial.",
        "key_reference_abstract": "## BACKGROUND\nIntelliCare is a modular platform that includes 12 simple apps targeting specific psychological strategies for common mental health problems.\n## OBJECTIVE\nThis study aimed to examine the effect of 2 methods of maintaining engagement with the IntelliCare platform, coaching, and receipt of weekly recommendations to try different apps on depression, anxiety, and app use.\n## METHODS\nA total of 301 participants with depression or anxiety were randomized to 1 of 4 treatments lasting 8 weeks and were followed for 6 months posttreatment. The trial used a 2X2 factorial design (coached vs self-guided treatment and weekly app recommendations vs no recommendations) to compare engagement metrics.\n## RESULTS\nThe median time to last use of any app during treatment was 56 days (interquartile range 54-57), with 253 participants (84.0%, 253/301) continuing to use the apps over a median of 92 days posttreatment. Receipt of weekly recommendations resulted in a significantly higher number of app use sessions during treatment (overall median=216; P=.04) but only marginal effects for time to last use (P=.06) and number of app downloads (P=.08). Coaching resulted in significantly more app downloads (P<.001), but there were no significant effects for time to last download or number of app sessions (P=.36) or time to last download (P=.08). Participants showed significant reductions in the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) across all treatment arms (P s<.001). Coached treatment led to larger GAD-7 reductions than those observed for self-guided treatment (P=.03), but the effects for the PHQ-9 did not reach significance (P=.06). Significant interaction was observed between receiving recommendations and time for the PHQ-9 (P=.04), but there were no significant effects for GAD-7 (P=.58).\n## CONCLUSIONS\nIntelliCare produced strong engagement with apps across all treatment arms. Coaching was associated with stronger anxiety outcomes, and receipt of recommendations enhanced depression outcomes.\n## TRIAL REGISTRATION\nClinicalTrials.gov NCT02801877; https://clinicaltrials.gov/ct2/show/NCT02801877.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Using Mobile Apps to Assess and Treat Depression in Hispanic and Latino Populations: Fully Remote Randomized Clinical Trial.",
        "key_reference_abstract": "## BACKGROUND\nMost people with mental health disorders fail to receive timely access to adequate care. US Hispanic/Latino individuals are particularly underrepresented in mental health care and are historically a very difficult population to recruit into clinical trials; however, they have increasing access to mobile technology, with over 75% owning a smartphone. This technology has the potential to overcome known barriers to accessing and utilizing traditional assessment and treatment approaches.\n## OBJECTIVE\nThis study aimed to compare recruitment and engagement in a fully remote trial of individuals with depression who either self-identify as Hispanic/Latino or not. A secondary aim was to assess treatment outcomes in these individuals using three different self-guided mobile apps: iPST (based on evidence-based therapeutic principles from problem-solving therapy, PST), Project Evolution (EVO; a cognitive training app based on cognitive neuroscience principles), and health tips (a health information app that served as an information control).\n## METHODS\nWe recruited Spanish and English speaking participants through social media platforms, internet-based advertisements, and traditional fliers in select locations in each state across the United States. Assessment and self-guided treatment was conducted on each participant's smartphone or tablet. We enrolled 389 Hispanic/Latino and 637 non-Hispanic/Latino adults with mild to moderate depression as determined by Patient Health Questionnaire-9 (PHQ-9) score\u22655 or related functional impairment. Participants were first asked about their preferences among the three apps and then randomized to their top two choices. Outcomes were depressive symptom severity (measured using PHQ-9) and functional impairment (assessed with Sheehan Disability Scale), collected over 3 months. Engagement in the study was assessed based on the number of times participants completed active surveys.\n## RESULTS\nWe screened 4502 participants and enrolled 1040 participants from throughout the United States over 6 months, yielding a sample of 348 active users. Long-term engagement surfaced as a key issue among Hispanic/Latino participants, who dropped from the study 2 weeks earlier than their non-Hispanic/Latino counterparts (P<.02). No significant differences were observed for treatment outcomes between those identifying as Hispanic/Latino or not. Although depressive symptoms improved (beta=-2.66, P=.006) over the treatment course, outcomes did not vary by treatment app.\n## CONCLUSIONS\nFully remote mobile-based studies can attract a diverse participant pool including people from traditionally underserved communities in mental health care and research (here, Hispanic/Latino individuals). However, keeping participants engaged in this type of \"low-touch\" research study remains challenging. Hispanic/Latino populations may be less willing to use mobile apps for assessing and managing depression. Future research endeavors should use a user-centered design to determine the role of mobile apps in the assessment and treatment of depression for this population, app features they would be interested in using, and strategies for long-term engagement.\n## TRIAL REGISTRATION\nClinicaltrials.gov NCT01808976; https://clinicaltrials.gov/ct2/show/NCT01808976 (Archived by WebCite at http://www.webcitation.org/70xI3ILkz).",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Randomized Controlled Trial of SuperBetter, a Smartphone-Based/Internet-Based Self-Help Tool to Reduce Depressive Symptoms.",
        "key_reference_abstract": "## OBJECTIVE\nTechnological advances have sparked the development of computer- and smartphone-based self-help programs for depressed people, but these programs' efficacy is uncertain. This randomized controlled trial evaluated an intervention called SuperBetter (SB), which is accessed via smartphone and/or the SB Web site.\n## MATERIALS AND METHODS\nOnline, we recruited 283 adult iPhone(\u00ae) (Apple, Cupertino, CA) users with significant depression symptoms according to the Center for Epidemiological Studies Depression questionnaire (CES-D). They were randomly assigned to one of three conditions: (a) a version of SB using cognitive-behavioral therapy and positive psychotherapy strategies to target depression (CBT-PPT SB); (b) a general SB version focused on self-esteem and acceptance (General SB); or (c) a waiting list control group (WL). The two SB groups were instructed to use SB for 10 minutes daily for 1 month. All participants completed psychological distress and well-being measures online every 2 weeks through follow-up. An intent-to-treat analysis was conducted using hierarchical linear modeling.\n## RESULTS\nAs hypothesized, SB participants achieved greater reductions in CES-D scores than WL participants by posttest (Cohen's d=0.67) and by follow-up (d=1.05). Contrary to prediction, CBT-PPT SB did not perform better than General SB; both versions of SB were more effective than the WL control. Differences between SB versions favored General SB but were not statistically significant.\n## CONCLUSIONS\nThese large effect sizes should be interpreted cautiously in light of high attrition rates and the motivated, self-selected sample. Nonetheless, smartphone-based/Internet-based self-help may play an important role in treating depression.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Behavioral and cognitive intervention strategies delivered via coached apps for depression: Pilot trial.",
        "key_reference_abstract": "Depression is common in primary care settings, but barriers prevent many primary care patients from initiating treatment. Smartphone apps stand as a possible means to overcome such barriers. However, there is limited evidence to understand the use and efficacy of these apps. The purpose of the current study was to pilot an evaluation of the usage and efficacy of apps for depression based upon behavioral or cognitive intervention skills, compared to a wait-list control. Thirty adults with depression were randomized to the use of either a behavioral app (Boost Me) or a cognitive app (Thought Challenger) or to a wait-list control. Boost Me and Thought Challenger participants received 6 weeks of the respective intervention along with weekly coaching sessions, with a 4-week follow-up period; wait-list control participants received no interventions for 10 weeks. A repeated-measures analysis of variance was conducted to examine depression over time and across treatment groups; t tests compared app usage across groups. Depression scores changed significantly over time (p < .001), with group differences occurring between Thought Challenger and wait-list control participants (p = .03). Boost Me was used significantly more than was Thought Challenger (p = .02); however, there was no evidence to suggest correlations between usage and changes in depression (ps > .05). The present study provides initial support that intervention strategies for depression delivered via apps with human support can impact symptoms and may promote continued use over 6 weeks. This pilot also demonstrates the feasibility of future research regarding the delivery of behavioral and cognitive intervention strategies via apps. (PsycINFO Database Record (c) 2019 APA, all rights reserved).",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A mobile app for social anxiety disorder: A three-arm randomized controlled trial comparing mobile and PC-based guided self-help interventions.",
        "key_reference_abstract": "## OBJECTIVE\nInternet-based cognitive-behavioral treatments (ICBT) have shown promise for various mental disorders, including social anxiety disorder (SAD). Most of these treatments have been delivered on desktop computers. However, the use of smartphones is becoming ubiquitous and could extend the reach of ICBT into users' everyday life. Only a few studies have empirically examined the efficacy of ICBT delivered through a smartphone app and there is no published study on mobile app delivered ICBT for SAD. This three-arm randomized-controlled trial (RCT) is the first to compare the efficacy of guided ICBT for smartphones (app) and conventional computers (PC) with a wait list control group (WL).\n## METHOD\nA total of 150 individuals meeting the diagnostic criteria for SAD were randomly assigned to one of the three conditions. Primary endpoints were self-report measures and diagnostic status of SAD.\n## RESULTS\nAfter 12 weeks of treatment, both active conditions showed superior outcome on the composite of all SAD measures (PC vs. WL: d = 0.74; App vs. WL: d = 0.89) and promising diagnostic response rates (NNTPC = 3.33; NNTApp = 6.00) compared to the WL. No significant between-groups effects were found between the two active conditions on the composite score (Cohen's d = 0.07). Treatment gains were maintained at 3-month follow-up. Program use was more evenly spread throughout the day in the mobile condition, indicating an integration of the program into daily routines.\n## CONCLUSIONS\nICBT can be delivered effectively using smartphones. (PsycINFO Database Record",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Mobile Sensing and Support for People With Depression: A Pilot Trial in the Wild.",
        "key_reference_abstract": "## BACKGROUND\nDepression is a burdensome, recurring mental health disorder with high prevalence. Even in developed countries, patients have to wait for several months to receive treatment. In many parts of the world there is only one mental health professional for over 200 people. Smartphones are ubiquitous and have a large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms and providing context-sensitive intervention support.\n## OBJECTIVE\nThe objective of this study is 2-fold, first to explore the detection of daily-life behavior based on sensor information to identify subjects with a clinically meaningful depression level, second to explore the potential of context sensitive intervention delivery to provide in-situ support for people with depressive symptoms.\n## METHODS\nA total of 126 adults (age 20-57) were recruited to use the smartphone app Mobile Sensing and Support (MOSS), collecting context-sensitive sensor information and providing just-in-time interventions derived from cognitive behavior therapy. Real-time learning-systems were deployed to adapt to each subject's preferences to optimize recommendations with respect to time, location, and personal preference. Biweekly, participants were asked to complete a self-reported depression survey (PHQ-9) to track symptom progression. Wilcoxon tests were conducted to compare scores before and after intervention. Correlation analysis was used to test the relationship between adherence and change in PHQ-9. One hundred twenty features were constructed based on smartphone usage and sensors including accelerometer, Wifi, and global positioning systems (GPS). Machine-learning models used these features to infer behavior and context for PHQ-9 level prediction and tailored intervention delivery.\n## RESULTS\nA total of 36 subjects used MOSS for \u22652 weeks. For subjects with clinical depression (PHQ-9\u226511) at baseline and adherence \u22658 weeks (n=12), a significant drop in PHQ-9 was observed (P=.01). This group showed a negative trend between adherence and change in PHQ-9 scores (rho=-.498, P=.099). Binary classification performance for biweekly PHQ-9 samples (n=143), with a cutoff of PHQ-9\u226511, based on Random Forest and Support Vector Machine leave-one-out cross validation resulted in 60.1% and 59.1% accuracy, respectively.\n## CONCLUSIONS\nProxies for social and physical behavior derived from smartphone sensor data was successfully deployed to deliver context-sensitive and personalized interventions to people with depressive symptoms. Subjects who used the app for an extended period of time showed significant reduction in self-reported symptom severity. Nonlinear classification models trained on features extracted from smartphone sensor data including Wifi, accelerometer, GPS, and phone use, demonstrated a proof of concept for the detection of depression superior to random classification. While findings of effectiveness must be reproduced in a RCT to proof causation, they pave the way for a new generation of digital health interventions leveraging smartphone sensors to provide context sensitive information for in-situ support and unobtrusive monitoring of critical mental health states.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "CBT for depression: a pilot RCT comparing mobile phone vs. computer.",
        "key_reference_abstract": "## BACKGROUND\nThis paper reports the results of a pilot randomized controlled trial comparing the delivery modality (mobile phone/tablet or fixed computer) of a cognitive behavioural therapy intervention for the treatment of depression. The aim was to establish whether a previously validated computerized program (The Sadness Program) remained efficacious when delivered via a mobile application.\n## METHOD\n35 participants were recruited with Major Depression (80% female) and randomly allocated to access the program using a mobile app (on either a mobile phone or iPad) or a computer. Participants completed 6 lessons, weekly homework assignments, and received weekly email contact from a clinical psychologist or psychiatrist until completion of lesson 2. After lesson 2 email contact was only provided in response to participant request, or in response to a deterioration in psychological distress scores. The primary outcome measure was the Patient Health Questionnaire 9 (PHQ-9). Of the 35 participants recruited, 68.6% completed 6 lessons and 65.7% completed the 3-months follow up. Attrition was handled using mixed-model repeated-measures ANOVA.\n## RESULTS\nBoth the Mobile and Computer Groups were associated with statistically significantly benefits in the PHQ-9 at post-test. At 3\u2009months follow up, the reduction seen for both groups remained significant.\n## CONCLUSIONS\nThese results provide evidence to indicate that delivering a CBT program using a mobile application, can result in clinically significant improvements in outcomes for patients with depression.\n## TRIAL REGISTRATION\nAustralian New Zealand Clinical Trials Registry ACTRN 12611001257954.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A Pilot Digital Intervention Targeting Loneliness in Youth Mental Health.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "The effects of using pacifica on depressed patients.",
        "key_reference_abstract": "Depression is a psychiatric condition that affects millions of Americans each year. It is a concern in today\u2019s society that needs to be treated and addressed with more care. According to the World Health Organization, major depression is the second largest health care problem worldwide when it comes to disability. Cognitive behavioral therapy has demonstrated positive outcomes in patients with depression. With advanced technology, millions of people are using the Internet to find a solution to their depressive symptoms. Pacifica is a mobile application that offers relaxation activities such as deep breathing, calming strategies, positive visualization, mindfulness, muscle relaxation, visualization, calming sounds, guided meditation, support groups, and daily tracking (Pacifica, 2017). A research project was completed by asking 30 individuals to participate in the study. Twenty-four of the 30 participated, but only 19 completed the pretest and posttest. The Beck Depression Inventory was analyzed pre- and post-intervention, along with a paired samples t-test and descriptive statistics.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "The CALM project: teaching mindfulness meditation in primary care using computer-based application",
        "key_reference_abstract": "Mindfulness-based interventions (MBI) have been studied extensively and the evidence is now credible that even brief techniques, delivered electronically using web-based applications (apps), easily accessed by smart phone, computer, or tablet, are consistently effective at anxiety reduction as well demonstrating efficacy in other commonly occurring comorbidities such as depression, stress, and panic symptoms. The purpose of this DNP project was to examine feasibility and the effect of the app, Calm.com, on anxious adult patients in primary care, using the Recovery Alliance Theory as its theoretical foundation. This pilot study was longitudinal, using a pre-test/post-test measurement of the Generalized Anxiety Disorder Seven-Item Scale (GAD-7), electronic collection of time the app was used, and qualitative measures in a group of 15 adult primary care patient volunteers. The MBI consisted of 28-sessions, varying in length from 9-18 minutes consisting of education on mindfulness and guided meditation practice. Changes in the pre/post GAD-7 scores were significant (p= 0.01), with a trend toward improvement in symptoms with more use of the app, but the changes were statistically insignificant (p= 0.20). The qualitative data confirmed participants\u2019 belief that the app was beneficial in helping them learn to relax, using short educational sessions. This project adds to the evidence that a web-based app is an evidence-based option for management of anxiety in adult primary care patients.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Engagement with a cognitive behavioural therapy mobile phone app predicts changes in mental health and wellbeing: MoodMission.",
        "key_reference_abstract": "## Objective:\nThere is an abundance of evidence supporting the efficacy of computerised cognitive behavioural therapy (CBT), but few studies have evaluated mobile applications (apps) that provide CBT strategies. This study investigating the relationships between mental health outcomes and engagement with a mobile app that recommended short CBT strategies. ## Method:\nParticipants downloaded the MoodMission app from the iOS and Android app stores, completed in-app baseline assessments, and final assessments 30 days later. Participants reported their mood to MoodMission when they were feeling low or anxious and received a list of short CBT strategies to choose from and engage in. Data from 617 assessment completers (71% female; M age = 27 years) were analysed via hierarchical and mediated regressions. ## Results:\nApp engagement ratings predicted increases in mental wellbeing. Mediation analyses revealed that there were indirect effects of app engagement on depression, anxiety, and mental wellbeing via the mediator of coping self-efficacy. Subsample analyses found this only for participants who were experiencing a moderate level of depression or anxiety at the time of the baseline assessment. ## Conclusions:\nEngaging with an app that provides CBT strategies can increase mental wellbeing, and coping self-efficacy may mediate effects of the app in individuals experiencing moderate depression or anxiety.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "A feasibility study of a mental health mobile app in the Dominican Republic: The untold story.",
        "key_reference_abstract": "Mobile health (mHealth) interventions include mental health apps (MHapps). There are hundreds of MHapps, which have been touted as a means of revolutionizing mental health care delivery. In spite of the rosy outlook and promise of MHapps, there are challenges to implementation in Low and Middle Income Countries (LMICs). We report on several domains of implementation: acceptance, appropriateness, engagement, and work processes assessed in two samples of clinicians and patients designed to develop and test the feasibility of a Spanish language Cognitive Behavioral VoiceThreadVR app for Dominican primary care patients with depression. Results indicated that feasibility of our eMH intervention was compromised by appropriateness of the target audience and the eligibility criteria used, including language, age, access to phones, and access to the internet. Both participants and clinical providers had varying degrees of engagement in the MHapp. Clinical providers had a desire for increased knowledge and capacity building, but also unspoken expectations and misaligned incentives. For participants, there were logistical and emotional barriers to use, some of which could not be fully determined in this study due to a lack of feasibility in terms of a low retention rate. Corresponding to these issues, we identified four potential solutions: 1) understanding of characteristics of end-users; 2) engagement of key stakeholders; 3) working within the existing infrastructure; and 4) addressing the social determinants of health. Unforeseen strengths also emerged as a result of our investigations. The challenges encountered in this pilot study can be viewed as evidence of failure or part of the incremental steps necessary to build future success.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis of app efficacy comparing pre-intervention to post-intervention change on an anxiety or depression symptoms. - All",
        "key_reference_title": "Attention Bias Modification Training Via Smartphone to Reduce Social Anxiety: A Randomized, Controlled Multi-Session Experiment.",
        "key_reference_abstract": "Testing feasibility and efficacy of psychological treatment via mobile devices is important, given its potential benefits for high-dosage treatment delivery, widespread and inexpensive dissemination, and efficient research methods. We conducted the first randomized controlled trial of attention bias modification training delivered via smartphones, comparing this training to control training in a double-blind design, also including a waitlist condition. All participants performed a variant of dot-probe training involving faces with neutral and disgust (representative of social threat) expressions in brief sessions three times daily over 4 weeks on their own smartphones, at home or anywhere they chose. Attention bias modification, also known as cognitive bias modification of attention, training included a contingency to induce attentional deployment away from disgust faces, whereas the control training included no contingency. Participants completed weekly Internet-based self-report symptom assessments as well as smartphone-delivered dot-probe attention bias assessments, whose reliability findings supported the viability of using smartphones for reaction-time based assessments. The between-groups training effect on attention bias scores was small, showing statistical significance in some analyses and not in others. On measures of social anxiety, intention-to-treat analyses (n = 326) revealed significant pre\u2013post treatment declines with medium to large effect sizes in both training groups, whereas small declines in a waitlist group were nonsignificant. Both training groups showed greater reductions in social anxiety than did waitlist; however, the benefits under these two training conditions were statistically indistinguishable. Improvements in the two training conditions beyond those of waitlist could be attributable to any factors common to them, but not to the contingency training specific to active attention bias modification training.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Conducting a fully mobile and randomised clinical trial for depression: access, engagement and expense.",
        "key_reference_abstract": "## IMPORTANCE\nAdvances in mobile technology have resulted in federal and industry-level initiatives to facilitate large-scale clinical research using smart devices. Although the benefits of technology to expand data collection are obvious, assumptions about the reach of mobile research methods (\n## OBJECTIVE\nTo assess the feasibility of a fully mobile randomised controlled trial using assessments and treatments delivered entirely through mobile devices to depressed individuals.\n## DESIGN\nUsing a web-based research portal, adult participants with depression who also owned a smart device were screened, consented and randomised to 1 of 3 mental health apps for treatment. Assessments of self-reported mood and cognitive function were conducted at baseline, 4, 8 and 12\u2005weeks. Physical and social activity was monitored daily using passively collected phone use data. All treatment and assessment tools were housed on each participant's smart phone or tablet.\n## INTERVENTIONS\nA cognitive training application, an application based on problem-solving therapy, and a mobile-sensing application promoting daily activities.\n## RESULTS\nNone\n## CONCLUSIONS AND RELEVANCE\nThese findings suggest that mobile randomised control trials can recruit large numbers of participants in a short period of time and with minimal cost, but study engagement remains challenging.\n## TRIAL REGISTRATION NUMBER\nNCT00540865.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "mHealth for Schizophrenia: Patient Engagement With a Mobile Phone Intervention Following Hospital Discharge.",
        "key_reference_abstract": "## BACKGROUND\nmHealth interventions that use mobile phones as instruments for illness management are gaining popularity. Research examining mobile phone\u2012based mHealth programs for people with psychosis has shown that these approaches are feasible, acceptable, and clinically promising. However, most mHealth initiatives involving people with schizophrenia have spanned periods ranging from a few days to several weeks and have typically involved participants who were clinically stable.\n## OBJECTIVE\nOur aim was to evaluate the viability of extended mHealth interventions for people with schizophrenia-spectrum disorders following hospital discharge. Specifically, we set out to examine the following: (1) Can individuals be engaged with a mobile phone intervention program during this high-risk period?, (2) Are age, gender, racial background, or hospitalization history associated with their engagement or persistence in using a mobile phone intervention over time?, and (3) Does engagement differ by characteristics of the mHealth intervention itself (ie, pre-programmed vs on-demand functions)?\n## METHODS\nWe examined mHealth intervention use and demographic and clinical predictors of engagement in 342 individuals with schizophrenia-spectrum disorders who were given the FOCUS mobile phone intervention as part of a technology-assisted relapse prevention program during the 6-month high-risk period following hospitalization.\n## RESULTS\nOn average, participants engaged with FOCUS for 82% of the weeks they had the mobile phone. People who used FOCUS more often continued using it over longer periods: 44% used the intervention over 5-6 months, on average 4.3 days a week. Gender, race, age, and number of past psychiatric hospitalizations were associated with engagement. Females used FOCUS on average 0.4 more days a week than males. White participants engaged on average 0.7 days more a week than African-Americans and responded to prompts on 0.7 days more a week than Hispanic participants. Younger participants (age 18-29) had 0.4 fewer days of on-demand use a week than individuals who were 30-45 years old and 0.5 fewer days a week than older participants (age 46-60). Participants with fewer past hospitalizations (1-6) engaged on average 0.2 more days a week than those with seven or more. mHealth program functions were associated with engagement. Participants responded to prompts more often than they self-initiated on-demand tools, but both FOCUS functions were used regularly. Both types of intervention use declined over time (on-demand use had a steeper decline). Although mHealth use declined, the majority of individuals used both on-demand and system-prompted functions regularly throughout their participation. Therefore, neither function is extraneous.\n## CONCLUSIONS\nThe findings demonstrated that individuals with schizophrenia-spectrum disorders can actively engage with a clinically supported mobile phone intervention for up to 6 months following hospital discharge. mHealth may be useful in reaching a clinical population that is typically difficult to engage during high-risk periods.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A multi-faceted approach to characterizing user behavior and experience in a digital mental health intervention.",
        "key_reference_abstract": "Digital interventions offer great promise for supporting health-related behavior change. However, there is much that we have yet to learn about how people respond to them. In this study, we present a novel mixed-methods approach to analysis of the complex and rich data that digital interventions collect. We perform secondary analysis of IntelliCare, an intervention in which participants are able to try 14 different mental health apps over the course of eight weeks. The goal of our analysis is to characterize users' app use behavior and experiences, and is rooted in theoretical conceptualizations of engagement as both usage and user experience. In the first aim, we employ cluster analysis to identify subgroups of participants that share similarities in terms of the frequency of their usage of particular apps, and then employ other engagement measures to compare the clusters. We identified four clusters with different app usage patterns: Low Usage, High Usage, Daily Feats Users, and Day to Day users. Each cluster was distinguished by its overall frequency of app use, or the main app that participants used. In the second aim, we developed a computer-assisted text analysis and visualization method - message highlighting - to facilitate comparison of the clusters. Last, we performed a qualitative analysis using participant messages to better understand the mechanisms of change and usability of salient apps from the cluster analysis. Our novel approach, integrating text and visual analytics with more traditional qualitative analysis techniques, can be used to generate insights concerning the behavior and experience of users in digital health contexts, for subsequent personalization and to identify areas for improvement of intervention technologies.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Pilot Randomized Trial of a Self-Help Behavioral Activation Mobile App for Utilization in Primary Care.",
        "key_reference_abstract": "Mobile technologies can be leveraged to meet the need for evidence-based psychological depression treatment via primary care. The purpose of the present study was to preliminarily examine the feasibility and efficacy of a self-help brief behavioral activation mobile application (app; \"Moodivate\") for depressive symptoms among adults treated via primary care. Participants (N = 52) were recruited from primary care practices between January and December 2017 and were randomized 2:2:1 to receive (a) Moodivate, (b) an active control cognitive-behavioral therapy-based mobile app (\"MoodKit\"), or (c) treatment as usual (TAU; no app). Participants completed assessments of depressive symptoms weekly for 8 weeks. App analytics data were captured to examine Moodivate feasibility (analytics unavailable for control app). Moodivate participants on average had 46.76 (SD = 30.10) app sessions throughout the trial duration, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total throughout the trial. Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period. A generalized estimating equation model examining change in depressive symptoms over time by treatment condition indicated a significant interaction between time and treatment condition (\u03c7",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Pilot randomized controlled trial of a Spanish-language Behavioral Activation mobile app (\u00a1Apt\u00edvate!) for the treatment of depressive symptoms among united states Latinx adults with limited English proficiency.",
        "key_reference_abstract": "## BACKGROUND\nTo address the need for disseminable, evidence-based depression treatment options for Latinx adults with limited English proficiency (LEP), our team developed \u00a1Apt\u00edvate!, a Spanish-language Behavioral Activation self-help mobile application. Primary aims of this study were to: 1) examine feasibility and uptake of \u00a1Apt\u00edvate! among depressed Latinx adults with LEP and 2) preliminarily examine \u00a1Apt\u00edvate! efficacy for depression treatment.\n## METHODS\nParticipants (N\u202f=\u202f42) with elevated depressive symptoms were randomized 2:1:1 to: 1) \u00a1Apt\u00edvate! (n\u202f=\u202f22), 2) an active control Spanish-language app (\"iCouch CBT\"; n\u202f=\u202f9), or 3) Treatment As Usual (i.e., no app; n\u202f=\u202f11). Feasibility was assessed via self-reported app utilization and app analytics data. Depressive symptoms were assessed weekly for eight weeks via self report.\n## RESULTS\nAll \u00a1Apt\u00edvate! participants used the app at least once, 81.8% of participants used the app \u22658 times, and 36.4% of participants used the app \u226556 times. Weekly retention was strong: 72.7% and 50% of participants continued to use the app at one- and two-months post-enrollment, respectively. Generalized Estimating Equation models indicated a significant interaction between time and treatment, such that \u00a1Apt\u00edvate! participants reported significantly lower depressive symptoms over time than TAU. Depressive symptoms did not differ on average across time between the iCouch and TAU conditions, nor between iCouch and \u00a1Apt\u00edvate!.\n## LIMITATIONS\nLimitations include small sample size, limited follow-up, and lack of analytics data for the active control condition.\n## CONCLUSIONS\nWith further research, \u00a1Apt\u00edvate! may offer a feasible, efficacious approach to extend the reach of evidence-based depression treatment for Latinx adults with LEP.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A Scenario-Based Cognitive Behavioral Therapy Mobile App to Reduce Dysfunctional Beliefs in Individuals with Depression: A Randomized Controlled Trial.",
        "key_reference_abstract": "## INTRODUCTION\nWhile self-administered mobile app-based cognitive behavioral therapy (CBT) has shown efficiency and effectiveness over the past decade, attempts to address automatic and negative beliefs have been lacking. The purpose of this study was to introduce and verify a mobile app that directly intervenes in dysfunctional thoughts. This app-based treatment includes recognizing automatic and negative thoughts of the protagonist of scenarios, writing advice directly to the main character, and sharing advice provided by other participants.\n## MATERIALS AND METHODS\nThirty-four participants diagnosed with Other Specified Depressive Disorder were recruited and randomly allocated to a CBT-based mobile-app program, the Todac Todac (TT group), or a daily mood chart app program (control group). Participants were asked to use the software for 3 weeks. Assessments for autonomic thoughts and clinical symptoms were administered at baseline and at a follow-up evaluation.\n## RESULTS\nAfter completing the 3-week program, Dysfunctional Attitude Scale (DAS) scores in TT group were lower than they were in the control group. In clinical measures, both TT group and control group showed reduced Beck Depression Inventory-II (BDI-II) scores and situation-dependent trait version of State-Trait Anxiety Inventory (STAI-X2) at follow-up. However, TT group showed significantly reduced STAI-X2 scores compared to control group. For all participants, changes in DAS scores were correlated with BDI-II and STAI-X2 scores.\n## CONCLUSIONS\nOur preliminary findings provide promising evidence that scenario-based CBT mobile apps can be used to deliver feasible and efficacious cognitive therapy. Long-term research is needed to determine the impact and effectiveness of this new treatment format.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "An Empathy-Driven, Conversational Artificial Intelligence Agent (Wysa) for Digital Mental Well-Being: Real-World Data Evaluation Mixed-Methods Study.",
        "key_reference_abstract": "## BACKGROUND\nA World Health Organization 2017 report stated that major depression affects almost 5% of the human population. Major depression is associated with impaired psychosocial functioning and reduced quality of life. Challenges such as shortage of mental health personnel, long waiting times, perceived stigma, and lower government spends pose barriers to the alleviation of mental health problems. Face-to-face psychotherapy alone provides only point-in-time support and cannot scale quickly enough to address this growing global public health challenge. Artificial intelligence (AI)-enabled, empathetic, and evidence-driven conversational mobile app technologies could play an active role in filling this gap by increasing adoption and enabling reach. Although such a technology can help manage these barriers, they should never replace time with a health care professional for more severe mental health problems. However, app technologies could act as a supplementary or intermediate support system. Mobile mental well-being apps need to uphold privacy and foster both short- and long-term positive outcomes.\n## OBJECTIVE\nThis study aimed to present a preliminary real-world data evaluation of the effectiveness and engagement levels of an AI-enabled, empathetic, text-based conversational mobile mental well-being app, Wysa, on users with self-reported symptoms of depression.\n## METHODS\nIn the study, a group of anonymous global users were observed who voluntarily installed the Wysa app, engaged in text-based messaging, and self-reported symptoms of depression using the Patient Health Questionnaire-9. On the basis of the extent of app usage on and between 2 consecutive screening time points, 2 distinct groups of users (high users and low users) emerged. The study used mixed-methods approach to evaluate the impact and engagement levels among these users. The quantitative analysis measured the app impact by comparing the average improvement in symptoms of depression between high and low users. The qualitative analysis measured the app engagement and experience by analyzing in-app user feedback and evaluated the performance of a machine learning classifier to detect user objections during conversations.\n## RESULTS\nThe average mood improvement (ie, difference in pre- and post-self-reported depression scores) between the groups (ie, high vs low users; n=108 and n=21, respectively) revealed that the high users group had significantly higher average improvement (mean 5.84 [SD 6.66]) compared with the low users group (mean 3.52 [SD 6.15]); Mann-Whitney P=.03 and with a moderate effect size of 0.63. Moreover, 67.7% of user-provided feedback responses found the app experience helpful and encouraging.\n## CONCLUSIONS\nThe real-world data evaluation findings on the effectiveness and engagement levels of Wysa app on users with self-reported symptoms of depression show promise. However, further work is required to validate these initial findings in much larger samples and across longer periods.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A randomized controlled trial on a smartphone self-help application (Be Good to Yourself) to reduce depressive symptoms.",
        "key_reference_abstract": "Depressive symptoms are common, yet only a subgroup of individuals receive adequate treatment. To reduce the treatment gap, several online self-help programs have been developed, yielding small to moderate effects. We developed a smartphone self-help application addressing depressive symptoms. We sought to evaluate its feasibility and efficacy in participants reporting a subjective need for help (a diagnosis of depression was not mandatory). We conducted a randomized controlled trial (N\u202f=\u202f90). The primary outcome was a reduction of depressive symptoms measured with the Patient Health Questionnaire-9 (PHQ-9). Secondary outcomes included improved self-esteem (Rosenberg Self-Esteem Scale) and quality of life (WHOQOL-BREF). The intervention group obtained access to the application for four weeks, the wait-list group received access after the post assessment. No group differences emerged in either outcome in intention-to-treat analyses. Per protocol analyses with frequent users (i.e., several times a week or more) yielded a small effect size (\u03b7",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A Gamified Smartphone-Based Intervention for Depression: Randomized Controlled Pilot Trial.",
        "key_reference_abstract": "## BACKGROUND\nAvailable smartphone-based interventions for depression predominantly use evidence-based strategies from cognitive-behavioral therapy (CBT), but patient engagement and reported effect sizes are small. Recently, studies have demonstrated that smartphone-based interventions combining CBT with gamified approach-avoidance bias modification training (AAMT) can foster patient engagement and reduce symptoms of several mental health problems.\n## OBJECTIVE\nBased on these findings, we developed a gamified smartphone-based intervention, mentalis Phoenix (MT-Phoenix), and hypothesized the program would both engage patients and produce preliminary evidence for the reduction of depressive symptoms.\n## METHODS\nTo test this hypothesis, we evaluated MT-Phoenix in a randomized controlled pilot trial including 77 individuals with elevated depression scores (Patient Health Questionnaire-9 scores \u22655). Participants were either instructed to train for 14 days with MT-Phoenix or assigned to a waitlist control condition. Engagement with the intervention was measured by assessing usage data. The primary outcome was reduction in depressive symptom severity at postassessment.\n## RESULTS\nData from this pilot trial shows that participants in the intervention group used the smartphone-based intervention for 46% of all days (6.4/14) and reported a significantly greater reduction of depressive symptoms than did participants in the control condition (F\n## CONCLUSIONS\nA gamified smartphone-based intervention combining CBT with AAMT may foster patient engagement and effectively target depressive symptoms. Future studies should evaluate the effectiveness of this intervention in a phase 3 trial using clinical samples. Moreover, the intervention should be compared to active control conditions.\n## TRIAL REGISTRATION\nGerman Clinical Trial Registry DRKS00012769; https://tinyurl.com/47mw8du7.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Behavioural activation versus mindfulness-based guided self-help treatment administered through a smartphone application: a randomised controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nEvaluating and comparing the effectiveness of two smartphone-delivered treatments: one based on behavioural activation (BA) and other on mindfulness.\n## DESIGN\nParallel randomised controlled, open, trial. Participants were allocated using an online randomisation tool, handled by an independent person who was separate from the staff conducting the study.\n## SETTING\nGeneral community, with recruitment nationally through mass media and advertisements.\n## PARTICIPANTS\n40 participants diagnosed with major depressive disorder received a BA treatment, and 41 participants received a mindfulness treatment. 9 participants were lost at the post-treatment.\n## INTERVENTION BA\nAn 8-week long behaviour programme administered via a smartphone application. Mindfulness: An 8-week long mindfulness programme, administered via a smartphone application.\n## MAIN OUTCOME MEASURES\nThe Beck Depression Inventory-II (BDI-II) and the nine-item Patient Health Questionnaire Depression Scale (PHQ-9).\n## RESULTS\n81 participants were randomised (mean age 36.0 years (SD=10.8)) and analysed. Results showed no significant interaction effects of group and time on any of the outcome measures either from pretreatment to post-treatment or from pretreatment to the 6-month follow-up. Subgroup analyses showed that the BA treatment was more effective than the mindfulness treatment among participants with higher initial severity of depression from pretreatment to the 6-month follow-up (PHQ-9: F (1, 362.1)=5.2, p<0.05). In contrast, the mindfulness treatment worked better than the BA treatment among participants with lower initial severity from pretreatment to the 6-month follow-up (PHQ-9: F (1, 69.3)=7.7, p<0.01); BDI-II: (F(1, 53.60)=6.25, p<0.05).\n## CONCLUSIONS\nThe two interventions did not differ significantly from one another. For participants with higher severity of depression, the treatment based on BA was superior to the treatment based on mindfulness. For participants with lower initial severity, the treatment based on mindfulness worked significantly better than the treatment based on BA.\n## TRIAL REGISTRATION\nClinical Trials NCT01463020.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Development and Pilot Testing of an Internet-Based Self-Help Intervention for Depression for Indian Users.",
        "key_reference_abstract": "There is a dearth of published research on uptake and utility of mental health apps in India, despite a rising global trend in the application of technology in the field of mental health. We describe the development and pilot testing of a self-help intervention for depression, PUSH-D (Practice and Use Self-Help for Depression) for urban Indians. This guided self-help app, with essential and optional zone sections, was developed to provide a comprehensive coverage of therapeutic strategies drawn from cognitive behavior therapy, interpersonal therapy, supportive psychotherapy, and positive psychology. Pilot testing was carried out using a single group pre-, post- and follow-up design in 78 eligible participants. Participants were typically young adults with major depression or dysthymia and significant impairment in functioning. Almost two-thirds of the participants had never sought professional mental health help. Significant reductions in depression and improvement in the functioning and well-being were notedon standardized measures in participants completing all 10 essential zone sections. These gains were maintained at follow-up. The results were similar for partial completers, who completed fiveout of the 10 essential sections. PUSH-D is one of the first indigenously developed self-help apps for depression and it shows promise in reducing the treatment gap for depression in India.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Guided Self-Help Works: Randomized Waitlist Controlled Trial of Pacifica, a Mobile App Integrating Cognitive Behavioral Therapy and Mindfulness for Stress, Anxiety, and Depression.",
        "key_reference_abstract": "## BACKGROUND\nDespite substantial improvements in technology and the increased demand for technology-enabled behavioral health tools among consumers, little progress has been made in easing the burden of mental illness. This may be because of the inherent challenges of conducting traditional clinical trials in a rapidly evolving technology landscape.\n## OBJECTIVE\nThis study sought to validate the effectiveness of Pacifica, a popular commercially available app for the self-management of mild-to-moderate stress, anxiety, and depression.\n## METHODS\nA total of 500 adults with mild-to-moderate anxiety or depression were recruited from in-app onboarding to participate in a randomized waitlist controlled trial of Pacifica. We conducted an all-virtual study, recruiting, screening, and randomizing participants through a Web-based participant portal. Study participants used the app for 1 month, with no level of use required, closely mimicking real-world app usage. Participants in the waitlist group were given access to the app after 1 month. Measurements included self-reported symptoms of stress, anxiety, depression, and self-efficacy. We performed an intent-to-treat analysis to examine the interactive effects of time and condition.\n## RESULTS\nWe found significant interactions between time and group. Participants in the active condition demonstrated significantly greater decreases in depression, anxiety, and stress and increases in self-efficacy. Although we did not find a relationship between overall engagement with the app and symptom improvement, participants who completed relatively more thought record exercises sustained improvements in their symptoms through the 2-month follow-up to a greater degree than those who completed fewer. In addition, we found that participants who reported concomitantly taking psychiatric medications during the trial benefitted less from the app, as measured by the symptoms of anxiety and stress.\n## CONCLUSIONS\nThis study provides evidence that Pacifica, a popular commercially available self-help app, is effective in reducing self-reported symptoms of depression, anxiety, and stress, particularly among individuals who utilize thought records and are not taking psychiatric medication.\n## TRIAL REGISTRATION\nClinicalTrials.gov NCT03333707; https://clinicaltrials.gov/ct2/show/NCT03333707 (Archived by WebCite at http://www.webcitation.org/78YE07ADB).",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Comparison of the Effects of Coaching and Receipt of App Recommendations on Depression, Anxiety, and Engagement in the IntelliCare Platform: Factorial Randomized Controlled Trial.",
        "key_reference_abstract": "## BACKGROUND\nIntelliCare is a modular platform that includes 12 simple apps targeting specific psychological strategies for common mental health problems.\n## OBJECTIVE\nThis study aimed to examine the effect of 2 methods of maintaining engagement with the IntelliCare platform, coaching, and receipt of weekly recommendations to try different apps on depression, anxiety, and app use.\n## METHODS\nA total of 301 participants with depression or anxiety were randomized to 1 of 4 treatments lasting 8 weeks and were followed for 6 months posttreatment. The trial used a 2X2 factorial design (coached vs self-guided treatment and weekly app recommendations vs no recommendations) to compare engagement metrics.\n## RESULTS\nThe median time to last use of any app during treatment was 56 days (interquartile range 54-57), with 253 participants (84.0%, 253/301) continuing to use the apps over a median of 92 days posttreatment. Receipt of weekly recommendations resulted in a significantly higher number of app use sessions during treatment (overall median=216; P=.04) but only marginal effects for time to last use (P=.06) and number of app downloads (P=.08). Coaching resulted in significantly more app downloads (P<.001), but there were no significant effects for time to last download or number of app sessions (P=.36) or time to last download (P=.08). Participants showed significant reductions in the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) across all treatment arms (P s<.001). Coached treatment led to larger GAD-7 reductions than those observed for self-guided treatment (P=.03), but the effects for the PHQ-9 did not reach significance (P=.06). Significant interaction was observed between receiving recommendations and time for the PHQ-9 (P=.04), but there were no significant effects for GAD-7 (P=.58).\n## CONCLUSIONS\nIntelliCare produced strong engagement with apps across all treatment arms. Coaching was associated with stronger anxiety outcomes, and receipt of recommendations enhanced depression outcomes.\n## TRIAL REGISTRATION\nClinicalTrials.gov NCT02801877; https://clinicaltrials.gov/ct2/show/NCT02801877.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Using Mobile Apps to Assess and Treat Depression in Hispanic and Latino Populations: Fully Remote Randomized Clinical Trial.",
        "key_reference_abstract": "## BACKGROUND\nMost people with mental health disorders fail to receive timely access to adequate care. US Hispanic/Latino individuals are particularly underrepresented in mental health care and are historically a very difficult population to recruit into clinical trials; however, they have increasing access to mobile technology, with over 75% owning a smartphone. This technology has the potential to overcome known barriers to accessing and utilizing traditional assessment and treatment approaches.\n## OBJECTIVE\nThis study aimed to compare recruitment and engagement in a fully remote trial of individuals with depression who either self-identify as Hispanic/Latino or not. A secondary aim was to assess treatment outcomes in these individuals using three different self-guided mobile apps: iPST (based on evidence-based therapeutic principles from problem-solving therapy, PST), Project Evolution (EVO; a cognitive training app based on cognitive neuroscience principles), and health tips (a health information app that served as an information control).\n## METHODS\nWe recruited Spanish and English speaking participants through social media platforms, internet-based advertisements, and traditional fliers in select locations in each state across the United States. Assessment and self-guided treatment was conducted on each participant's smartphone or tablet. We enrolled 389 Hispanic/Latino and 637 non-Hispanic/Latino adults with mild to moderate depression as determined by Patient Health Questionnaire-9 (PHQ-9) score\u22655 or related functional impairment. Participants were first asked about their preferences among the three apps and then randomized to their top two choices. Outcomes were depressive symptom severity (measured using PHQ-9) and functional impairment (assessed with Sheehan Disability Scale), collected over 3 months. Engagement in the study was assessed based on the number of times participants completed active surveys.\n## RESULTS\nWe screened 4502 participants and enrolled 1040 participants from throughout the United States over 6 months, yielding a sample of 348 active users. Long-term engagement surfaced as a key issue among Hispanic/Latino participants, who dropped from the study 2 weeks earlier than their non-Hispanic/Latino counterparts (P<.02). No significant differences were observed for treatment outcomes between those identifying as Hispanic/Latino or not. Although depressive symptoms improved (beta=-2.66, P=.006) over the treatment course, outcomes did not vary by treatment app.\n## CONCLUSIONS\nFully remote mobile-based studies can attract a diverse participant pool including people from traditionally underserved communities in mental health care and research (here, Hispanic/Latino individuals). However, keeping participants engaged in this type of \"low-touch\" research study remains challenging. Hispanic/Latino populations may be less willing to use mobile apps for assessing and managing depression. Future research endeavors should use a user-centered design to determine the role of mobile apps in the assessment and treatment of depression for this population, app features they would be interested in using, and strategies for long-term engagement.\n## TRIAL REGISTRATION\nClinicaltrials.gov NCT01808976; https://clinicaltrials.gov/ct2/show/NCT01808976 (Archived by WebCite at http://www.webcitation.org/70xI3ILkz).",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Randomized Controlled Trial of SuperBetter, a Smartphone-Based/Internet-Based Self-Help Tool to Reduce Depressive Symptoms.",
        "key_reference_abstract": "## OBJECTIVE\nTechnological advances have sparked the development of computer- and smartphone-based self-help programs for depressed people, but these programs' efficacy is uncertain. This randomized controlled trial evaluated an intervention called SuperBetter (SB), which is accessed via smartphone and/or the SB Web site.\n## MATERIALS AND METHODS\nOnline, we recruited 283 adult iPhone(\u00ae) (Apple, Cupertino, CA) users with significant depression symptoms according to the Center for Epidemiological Studies Depression questionnaire (CES-D). They were randomly assigned to one of three conditions: (a) a version of SB using cognitive-behavioral therapy and positive psychotherapy strategies to target depression (CBT-PPT SB); (b) a general SB version focused on self-esteem and acceptance (General SB); or (c) a waiting list control group (WL). The two SB groups were instructed to use SB for 10 minutes daily for 1 month. All participants completed psychological distress and well-being measures online every 2 weeks through follow-up. An intent-to-treat analysis was conducted using hierarchical linear modeling.\n## RESULTS\nAs hypothesized, SB participants achieved greater reductions in CES-D scores than WL participants by posttest (Cohen's d=0.67) and by follow-up (d=1.05). Contrary to prediction, CBT-PPT SB did not perform better than General SB; both versions of SB were more effective than the WL control. Differences between SB versions favored General SB but were not statistically significant.\n## CONCLUSIONS\nThese large effect sizes should be interpreted cautiously in light of high attrition rates and the motivated, self-selected sample. Nonetheless, smartphone-based/Internet-based self-help may play an important role in treating depression.",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Behavioral and cognitive intervention strategies delivered via coached apps for depression: Pilot trial.",
        "key_reference_abstract": "Depression is common in primary care settings, but barriers prevent many primary care patients from initiating treatment. Smartphone apps stand as a possible means to overcome such barriers. However, there is limited evidence to understand the use and efficacy of these apps. The purpose of the current study was to pilot an evaluation of the usage and efficacy of apps for depression based upon behavioral or cognitive intervention skills, compared to a wait-list control. Thirty adults with depression were randomized to the use of either a behavioral app (Boost Me) or a cognitive app (Thought Challenger) or to a wait-list control. Boost Me and Thought Challenger participants received 6 weeks of the respective intervention along with weekly coaching sessions, with a 4-week follow-up period; wait-list control participants received no interventions for 10 weeks. A repeated-measures analysis of variance was conducted to examine depression over time and across treatment groups; t tests compared app usage across groups. Depression scores changed significantly over time (p < .001), with group differences occurring between Thought Challenger and wait-list control participants (p = .03). Boost Me was used significantly more than was Thought Challenger (p = .02); however, there was no evidence to suggest correlations between usage and changes in depression (ps > .05). The present study provides initial support that intervention strategies for depression delivered via apps with human support can impact symptoms and may promote continued use over 6 weeks. This pilot also demonstrates the feasibility of future research regarding the delivery of behavioral and cognitive intervention strategies via apps. (PsycINFO Database Record (c) 2019 APA, all rights reserved).",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A mobile app for social anxiety disorder: A three-arm randomized controlled trial comparing mobile and PC-based guided self-help interventions.",
        "key_reference_abstract": "## OBJECTIVE\nInternet-based cognitive-behavioral treatments (ICBT) have shown promise for various mental disorders, including social anxiety disorder (SAD). Most of these treatments have been delivered on desktop computers. However, the use of smartphones is becoming ubiquitous and could extend the reach of ICBT into users' everyday life. Only a few studies have empirically examined the efficacy of ICBT delivered through a smartphone app and there is no published study on mobile app delivered ICBT for SAD. This three-arm randomized-controlled trial (RCT) is the first to compare the efficacy of guided ICBT for smartphones (app) and conventional computers (PC) with a wait list control group (WL).\n## METHOD\nA total of 150 individuals meeting the diagnostic criteria for SAD were randomly assigned to one of the three conditions. Primary endpoints were self-report measures and diagnostic status of SAD.\n## RESULTS\nAfter 12 weeks of treatment, both active conditions showed superior outcome on the composite of all SAD measures (PC vs. WL: d = 0.74; App vs. WL: d = 0.89) and promising diagnostic response rates (NNTPC = 3.33; NNTApp = 6.00) compared to the WL. No significant between-groups effects were found between the two active conditions on the composite score (Cohen's d = 0.07). Treatment gains were maintained at 3-month follow-up. Program use was more evenly spread throughout the day in the mobile condition, indicating an integration of the program into daily routines.\n## CONCLUSIONS\nICBT can be delivered effectively using smartphones. (PsycINFO Database Record",
        "truth": "True"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Mobile Sensing and Support for People With Depression: A Pilot Trial in the Wild.",
        "key_reference_abstract": "## BACKGROUND\nDepression is a burdensome, recurring mental health disorder with high prevalence. Even in developed countries, patients have to wait for several months to receive treatment. In many parts of the world there is only one mental health professional for over 200 people. Smartphones are ubiquitous and have a large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms and providing context-sensitive intervention support.\n## OBJECTIVE\nThe objective of this study is 2-fold, first to explore the detection of daily-life behavior based on sensor information to identify subjects with a clinically meaningful depression level, second to explore the potential of context sensitive intervention delivery to provide in-situ support for people with depressive symptoms.\n## METHODS\nA total of 126 adults (age 20-57) were recruited to use the smartphone app Mobile Sensing and Support (MOSS), collecting context-sensitive sensor information and providing just-in-time interventions derived from cognitive behavior therapy. Real-time learning-systems were deployed to adapt to each subject's preferences to optimize recommendations with respect to time, location, and personal preference. Biweekly, participants were asked to complete a self-reported depression survey (PHQ-9) to track symptom progression. Wilcoxon tests were conducted to compare scores before and after intervention. Correlation analysis was used to test the relationship between adherence and change in PHQ-9. One hundred twenty features were constructed based on smartphone usage and sensors including accelerometer, Wifi, and global positioning systems (GPS). Machine-learning models used these features to infer behavior and context for PHQ-9 level prediction and tailored intervention delivery.\n## RESULTS\nA total of 36 subjects used MOSS for \u22652 weeks. For subjects with clinical depression (PHQ-9\u226511) at baseline and adherence \u22658 weeks (n=12), a significant drop in PHQ-9 was observed (P=.01). This group showed a negative trend between adherence and change in PHQ-9 scores (rho=-.498, P=.099). Binary classification performance for biweekly PHQ-9 samples (n=143), with a cutoff of PHQ-9\u226511, based on Random Forest and Support Vector Machine leave-one-out cross validation resulted in 60.1% and 59.1% accuracy, respectively.\n## CONCLUSIONS\nProxies for social and physical behavior derived from smartphone sensor data was successfully deployed to deliver context-sensitive and personalized interventions to people with depressive symptoms. Subjects who used the app for an extended period of time showed significant reduction in self-reported symptom severity. Nonlinear classification models trained on features extracted from smartphone sensor data including Wifi, accelerometer, GPS, and phone use, demonstrated a proof of concept for the detection of depression superior to random classification. While findings of effectiveness must be reproduced in a RCT to proof causation, they pave the way for a new generation of digital health interventions leveraging smartphone sensors to provide context sensitive information for in-situ support and unobtrusive monitoring of critical mental health states.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "CBT for depression: a pilot RCT comparing mobile phone vs. computer.",
        "key_reference_abstract": "## BACKGROUND\nThis paper reports the results of a pilot randomized controlled trial comparing the delivery modality (mobile phone/tablet or fixed computer) of a cognitive behavioural therapy intervention for the treatment of depression. The aim was to establish whether a previously validated computerized program (The Sadness Program) remained efficacious when delivered via a mobile application.\n## METHOD\n35 participants were recruited with Major Depression (80% female) and randomly allocated to access the program using a mobile app (on either a mobile phone or iPad) or a computer. Participants completed 6 lessons, weekly homework assignments, and received weekly email contact from a clinical psychologist or psychiatrist until completion of lesson 2. After lesson 2 email contact was only provided in response to participant request, or in response to a deterioration in psychological distress scores. The primary outcome measure was the Patient Health Questionnaire 9 (PHQ-9). Of the 35 participants recruited, 68.6% completed 6 lessons and 65.7% completed the 3-months follow up. Attrition was handled using mixed-model repeated-measures ANOVA.\n## RESULTS\nBoth the Mobile and Computer Groups were associated with statistically significantly benefits in the PHQ-9 at post-test. At 3\u2009months follow up, the reduction seen for both groups remained significant.\n## CONCLUSIONS\nThese results provide evidence to indicate that delivering a CBT program using a mobile application, can result in clinically significant improvements in outcomes for patients with depression.\n## TRIAL REGISTRATION\nAustralian New Zealand Clinical Trials Registry ACTRN 12611001257954.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A Pilot Digital Intervention Targeting Loneliness in Youth Mental Health.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "The effects of using pacifica on depressed patients.",
        "key_reference_abstract": "Depression is a psychiatric condition that affects millions of Americans each year. It is a concern in today\u2019s society that needs to be treated and addressed with more care. According to the World Health Organization, major depression is the second largest health care problem worldwide when it comes to disability. Cognitive behavioral therapy has demonstrated positive outcomes in patients with depression. With advanced technology, millions of people are using the Internet to find a solution to their depressive symptoms. Pacifica is a mobile application that offers relaxation activities such as deep breathing, calming strategies, positive visualization, mindfulness, muscle relaxation, visualization, calming sounds, guided meditation, support groups, and daily tracking (Pacifica, 2017). A research project was completed by asking 30 individuals to participate in the study. Twenty-four of the 30 participated, but only 19 completed the pretest and posttest. The Beck Depression Inventory was analyzed pre- and post-intervention, along with a paired samples t-test and descriptive statistics.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "The CALM project: teaching mindfulness meditation in primary care using computer-based application",
        "key_reference_abstract": "Mindfulness-based interventions (MBI) have been studied extensively and the evidence is now credible that even brief techniques, delivered electronically using web-based applications (apps), easily accessed by smart phone, computer, or tablet, are consistently effective at anxiety reduction as well demonstrating efficacy in other commonly occurring comorbidities such as depression, stress, and panic symptoms. The purpose of this DNP project was to examine feasibility and the effect of the app, Calm.com, on anxious adult patients in primary care, using the Recovery Alliance Theory as its theoretical foundation. This pilot study was longitudinal, using a pre-test/post-test measurement of the Generalized Anxiety Disorder Seven-Item Scale (GAD-7), electronic collection of time the app was used, and qualitative measures in a group of 15 adult primary care patient volunteers. The MBI consisted of 28-sessions, varying in length from 9-18 minutes consisting of education on mindfulness and guided meditation practice. Changes in the pre/post GAD-7 scores were significant (p= 0.01), with a trend toward improvement in symptoms with more use of the app, but the changes were statistically insignificant (p= 0.20). The qualitative data confirmed participants\u2019 belief that the app was beneficial in helping them learn to relax, using short educational sessions. This project adds to the evidence that a web-based app is an evidence-based option for management of anxiety in adult primary care patients.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Engagement with a cognitive behavioural therapy mobile phone app predicts changes in mental health and wellbeing: MoodMission.",
        "key_reference_abstract": "## Objective:\nThere is an abundance of evidence supporting the efficacy of computerised cognitive behavioural therapy (CBT), but few studies have evaluated mobile applications (apps) that provide CBT strategies. This study investigating the relationships between mental health outcomes and engagement with a mobile app that recommended short CBT strategies. ## Method:\nParticipants downloaded the MoodMission app from the iOS and Android app stores, completed in-app baseline assessments, and final assessments 30 days later. Participants reported their mood to MoodMission when they were feeling low or anxious and received a list of short CBT strategies to choose from and engage in. Data from 617 assessment completers (71% female; M age = 27 years) were analysed via hierarchical and mediated regressions. ## Results:\nApp engagement ratings predicted increases in mental wellbeing. Mediation analyses revealed that there were indirect effects of app engagement on depression, anxiety, and mental wellbeing via the mediator of coping self-efficacy. Subsample analyses found this only for participants who were experiencing a moderate level of depression or anxiety at the time of the baseline assessment. ## Conclusions:\nEngaging with an app that provides CBT strategies can increase mental wellbeing, and coping self-efficacy may mediate effects of the app in individuals experiencing moderate depression or anxiety.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "A feasibility study of a mental health mobile app in the Dominican Republic: The untold story.",
        "key_reference_abstract": "Mobile health (mHealth) interventions include mental health apps (MHapps). There are hundreds of MHapps, which have been touted as a means of revolutionizing mental health care delivery. In spite of the rosy outlook and promise of MHapps, there are challenges to implementation in Low and Middle Income Countries (LMICs). We report on several domains of implementation: acceptance, appropriateness, engagement, and work processes assessed in two samples of clinicians and patients designed to develop and test the feasibility of a Spanish language Cognitive Behavioral VoiceThreadVR app for Dominican primary care patients with depression. Results indicated that feasibility of our eMH intervention was compromised by appropriateness of the target audience and the eligibility criteria used, including language, age, access to phones, and access to the internet. Both participants and clinical providers had varying degrees of engagement in the MHapp. Clinical providers had a desire for increased knowledge and capacity building, but also unspoken expectations and misaligned incentives. For participants, there were logistical and emotional barriers to use, some of which could not be fully determined in this study due to a lack of feasibility in terms of a low retention rate. Corresponding to these issues, we identified four potential solutions: 1) understanding of characteristics of end-users; 2) engagement of key stakeholders; 3) working within the existing infrastructure; and 4) addressing the social determinants of health. Unforeseen strengths also emerged as a result of our investigations. The challenges encountered in this pilot study can be viewed as evidence of failure or part of the incremental steps necessary to build future success.",
        "truth": "False"
    },
    {
        "pmid": "33574573",
        "meta_analysis_title": "Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.",
        "meta_analysis_question": "What features of smartphone apps for depression and anxiety are associated with increased engagement, and how does this engagement relate to the clinical efficacy of these apps?",
        "criteria": "Titles and abstracts were evaluated against the inclusion and exclusion criteria. Studies that were deemed potentially relevant were next evaluated by their full text. Reasons for exclusion were recorded. When more than one publication of a study was found, the study with the most information was used for data analysis.",
        "subgroup": "Random effects meta-analysis in RCTs of app efficacy comparing change in anxiety or depression symptoms in apps vs. control. - All",
        "key_reference_title": "Attention Bias Modification Training Via Smartphone to Reduce Social Anxiety: A Randomized, Controlled Multi-Session Experiment.",
        "key_reference_abstract": "Testing feasibility and efficacy of psychological treatment via mobile devices is important, given its potential benefits for high-dosage treatment delivery, widespread and inexpensive dissemination, and efficient research methods. We conducted the first randomized controlled trial of attention bias modification training delivered via smartphones, comparing this training to control training in a double-blind design, also including a waitlist condition. All participants performed a variant of dot-probe training involving faces with neutral and disgust (representative of social threat) expressions in brief sessions three times daily over 4 weeks on their own smartphones, at home or anywhere they chose. Attention bias modification, also known as cognitive bias modification of attention, training included a contingency to induce attentional deployment away from disgust faces, whereas the control training included no contingency. Participants completed weekly Internet-based self-report symptom assessments as well as smartphone-delivered dot-probe attention bias assessments, whose reliability findings supported the viability of using smartphones for reaction-time based assessments. The between-groups training effect on attention bias scores was small, showing statistical significance in some analyses and not in others. On measures of social anxiety, intention-to-treat analyses (n = 326) revealed significant pre\u2013post treatment declines with medium to large effect sizes in both training groups, whereas small declines in a waitlist group were nonsignificant. Both training groups showed greater reductions in social anxiety than did waitlist; however, the benefits under these two training conditions were statistically indistinguishable. Improvements in the two training conditions beyond those of waitlist could be attributable to any factors common to them, but not to the contingency training specific to active attention bias modification training.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report.",
        "key_reference_abstract": "## INTRODUCTION\nOsimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in\u00a0patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy.\n## METHODS\nPatients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or\u00a0without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.\n## RESULTS\nCAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade \u22653 in 6% of patients])\u00a0in the osimertinib arm and rash (67% [grade \u22653 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.\n## CONCLUSION\nLimited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nThere are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma.\n## METHODS\nWe did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients.\n## FINDINGS\nBetween Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8\u00b74 months (95% CI 6\u00b74-9\u00b74) with pembrolizumab and 6\u00b79 months (5\u00b79-8\u00b70) with standard of care (hazard ratio 0\u00b780, 0\u00b765-0\u00b798; nominal p=0\u00b70161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia).\n## INTERPRETATION\nThe clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nMicrosatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.\n## METHODS\nIMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs \u226518 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.\n## FINDINGS\nBetween July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7\u00b73 months (IQR 3\u00b77-13\u00b76). Median overall survival was 8\u00b787 months (95% CI 7\u00b700-10\u00b761) with atezolizumab plus cobimetinib, 7\u00b710 months (6\u00b705-10\u00b705) with atezolizumab, and 8\u00b751 months (6\u00b741-10\u00b771) with regorafenib; the hazard ratio was 1\u00b700 (95% CI 0\u00b773-1\u00b738; p=0\u00b799) for the combination versus regorafenib and 1\u00b719 (0\u00b783-1\u00b771; p=0\u00b734) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).\n## INTERPRETATION\nIMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.\n## FUNDING\nF Hoffmann-La Roche Ltd/Genentech Inc.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.\n## FINDINGS\nBetween Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8\u00b71 months (IQR 4\u00b75-10\u00b79). Median progression-free survival was 5\u00b76 months (95% CI 3\u00b77-7\u00b75) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8\u00b74 months (5\u00b79-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1\u00b753; 95% CI 1\u00b705-2\u00b722; p=0\u00b798). Median overall survival was not reached (95% CI 12\u00b79-not reached) versus 15\u00b72 months (12\u00b77-not reached; HR 1\u00b761; 95% CI 0\u00b791-2\u00b785; p=0\u00b795); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.\n## METHODS\nThis randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (\u226518 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (\u226550% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0\u00b70122, p=0\u00b70120, and p=0\u00b70124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.\n## FINDINGS\nFrom Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12\u00b78 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (\u226550% hazard ratio 0\u00b769, 95% CI 0\u00b756-0\u00b785, p=0\u00b70003; \u226520% 0\u00b777, 0\u00b764-0\u00b792, p=0\u00b70020, and \u22651% 0\u00b781, 0\u00b771-0\u00b793, p=0\u00b70018). The median surival values by TPS population were 20\u00b70 months (95% CI 15\u00b74-24\u00b79) for pembrolizumab versus 12\u00b72 months (10\u00b74-14\u00b72) for chemotherapy, 17\u00b77 months (15\u00b73-22\u00b71) versus 13\u00b70 months (11\u00b76-15\u00b73), and 16\u00b77 months (13\u00b79-19\u00b77) versus 12\u00b71 months (11\u00b73-13\u00b73), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.\n## INTERPRETATION\nThe benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.\n## FUNDING\nMerck Sharp & Dohme.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.\n## METHODS\nIn this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.\n## FINDINGS\nOf 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11\u00b72 months in the atezolizumab plus bevacizumab group versus 7\u00b77 months in the sunitinib group (hazard ratio [HR] 0\u00b774 [95% CI 0\u00b757-0\u00b796]; p=0\u00b70217). In the ITT population, median overall survival had an HR of 0\u00b793 (0\u00b776-1\u00b714) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.\n## INTERPRETATION\nAtezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.\n## FUNDING\nF Hoffmann-La Roche Ltd and Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nThe combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.\n## METHODS\nIn an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.\n## RESULTS\nAfter a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.\n## CONCLUSIONS\nAmong patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nLenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual.\n## FINDINGS\nBetween Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6\u00b76 months (IQR 3\u00b74-9\u00b76), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82\u00b70% (95% CI 73\u00b72-88\u00b71) versus 85\u00b70% (76\u00b78-90\u00b75; hazard ratio [HR] 1\u00b722; 95% CI 0\u00b767-2\u00b722; p=0\u00b775). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure).\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer.\n## METHODS\nIMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m\n## FINDINGS\nBetween April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18\u00b75 months [IQR 15\u00b72-23\u00b76] in the atezolizumab plus chemotherapy group and 19\u00b72 months [15\u00b74-23\u00b70] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18\u00b76 months [95% CI 16\u00b70-21\u00b72] in the atezolizumab plus chemotherapy group and 13\u00b79 months [12\u00b70-18\u00b77] in the chemotherapy group; stratified hazard ratio [HR] 0\u00b779 [95% CI 0\u00b764-0\u00b798]; p=0\u00b7033) and median progression-free survival (7\u00b70 months [95% CI 6\u00b72-7\u00b73] in the atezolizumab plus chemotherapy group and 5\u00b75 months [4\u00b74-5\u00b79] in the chemotherapy group; stratified HR 0\u00b764 [95% CI 0\u00b754-0\u00b777]; p<0\u00b70001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group.\n## INTERPRETATION\nIMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer.\n## FUNDING\nF. Hoffmann-La Roche.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.",
        "key_reference_abstract": "## BACKGROUND\nThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.\n## PATIENTS AND METHODS\nPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10\u2009mg/kg by intravenous infusion every 2\u2009weeks or physician's choice of chemotherapy (paclitaxel 80\u2009mg/m2 on days 1, 8, and 15 or irinotecan 150\u2009mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.\n## RESULTS\nA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0\u2009months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P\u2009=\u20090.81} or the secondary end points of PFS [median, 1.4 versus 2.7\u2009months; HR=1.73 (95% CI 1.4-2.2); P\u2009>\u20090.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade \u22653 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.\n## CONCLUSIONS\nTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.\n## TRIAL REGISTRATION\nClinicalTrials.gov: NCT02625623.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nAntibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy.\n## METHODS\nJAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m\n## FINDINGS\nBetween March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11\u00b74 months [95% CI 9\u00b74-13\u00b79] vs 10\u00b73 months [8\u00b75-13\u00b70]; hazard ratio 0\u00b790 [96% CI 0\u00b772-1\u00b712]; one-sided p=0\u00b716). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes.\n## INTERPRETATION\nCompared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile.\n## FUNDING\nMerck and Pfizer.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.",
        "key_reference_abstract": "## BACKGROUND\nThe programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.\n## METHODS\nPatients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.\n## RESULTS\nAt a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.\n## CONCLUSIONS\nAs adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.\n## RESULTS\nAfter a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.\n## CONCLUSIONS\nIn patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nEnhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.\n## METHODS\nWe conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.\n## RESULTS\nA total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.\n## CONCLUSIONS\nThe addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIn the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.\n## METHODS\nIn the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.\n## FINDINGS\nBetween Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32\u00b74 months [IQR 13\u00b74-36\u00b73]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35\u00b76-not estimable] vs 26\u00b76 months [22\u00b71-33\u00b74]; hazard ratio [HR] 0\u00b766 [95% CI 0\u00b754-0\u00b780], p<0\u00b70001), progression-free survival (median 8\u00b72 months [95% CI 6\u00b79-10\u00b70] vs 8\u00b73 months [7\u00b70-8\u00b78]; HR 0\u00b777 [95% CI 0\u00b765-0\u00b790], p=0\u00b70014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0\u00b70001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37\u00b79 months [32\u00b72-not estimable]; HR 0\u00b771 [95% CI 0\u00b759-0\u00b786], p=0\u00b70003), progression-free survival (median 9\u00b77 months [95% CI 8\u00b71-11\u00b71] vs 9\u00b77 months [8\u00b73-11\u00b71]; HR 0\u00b785 [95% CI 0\u00b773-0\u00b798], p=0\u00b7027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0\u00b7015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.\n## INTERPRETATION\nThe results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.\n## FUNDING\nBristol-Myers Squibb and ONO Pharmaceutical.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nStandard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on \u226550% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.\n## RESULTS\nAfter a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).\n## CONCLUSIONS\nIn patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nFew options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population.\n## METHODS\nWe conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged \u226518 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m\n## FINDINGS\nBetween Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11\u00b71 months [95% CI 8\u00b76-15\u00b75; n=116] vs 10\u00b76 months [8\u00b74-12\u00b72; n=118]; stratified hazard ratio [HR] 0\u00b787, 95% CI 0\u00b763-1\u00b721; p=0\u00b741), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15\u00b79 months [95% CI 10\u00b74 to not estimable] vs 8\u00b73 months [5\u00b76-13\u00b72]; HR 0\u00b757, 95% CI 0\u00b726-1\u00b726). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).\n## INTERPRETATION\nAtezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.\n## FUNDING\nF Hoffmann-La Roche, Genentech.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.\n## METHODS\nThis randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0\u00b70135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.\n## FINDINGS\nBetween June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9\u00b71 months (95% CI 6\u00b72-10\u00b77) with pembrolizumab and 8\u00b73 months (7\u00b76-9\u00b70) with paclitaxel (hazard ratio [HR] 0\u00b782, 95% CI 0\u00b766-1\u00b703; one-sided p=0\u00b70421). Median progression-free survival was 1\u00b75 months (95% CI 1\u00b74-2\u00b70) with pembrolizumab and 4\u00b71 months (3\u00b71-4\u00b72) with paclitaxel (HR 1\u00b727, 95% CI 1\u00b703-1\u00b757). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.\n## INTERPRETATION\nPembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.",
        "key_reference_abstract": "## BACKGROUND\nAn earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.\n## METHODS\nWe randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety.\n## RESULTS\nOf the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.\n## CONCLUSIONS\nDurvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer.",
        "key_reference_abstract": "Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI, 1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. \u00a92017 AACR.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.\n## METHODS\nIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4\u03ba isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.\n## RESULTS\nThe median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).\n## CONCLUSIONS\nPembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.\n## METHODS\nWe randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.\n## RESULTS\nAmong the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.\n## CONCLUSIONS\nNivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-na\u00efve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.",
        "key_reference_abstract": "## AIM\nTo evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.\n## METHODS\nIn this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor\u00a0or both, if BRAF\n## RESULTS\nA total of 180 patients were randomised to pembrolizumab 2\u00a0mg/kg, 181 to pembrolizumab 10\u00a0mg/kg\u00a0and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died\u00a0and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2\u00a0mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p\u00a0=\u00a00.117) and 10\u00a0mg/kg (0.74, 0.57-0.96, p\u00a0=\u00a00.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate\u00a0and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%)\u00a0and 45 (26.3%) patients, respectively.\n## CONCLUSION\nImprovement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.",
        "key_reference_abstract": "## BACKGROUND\nNew therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.\n## METHODS\nDETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.\n## FINDINGS\nBetween May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7\u00b77 months (95% CI 6\u00b78-8\u00b79) in the tremelimumab group and 7\u00b73 months (5\u00b79-8\u00b77) in the placebo group (hazard ratio 0\u00b792 [95% CI 0\u00b776-1\u00b712], p=0\u00b741). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.\n## INTERPRETATION\nTremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.\n## FUNDING\nAstraZeneca.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.\n## METHODS\nWe did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m\n## FINDINGS\nBetween March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13\u00b78 months [95% CI 11\u00b78-15\u00b77] vs 9\u00b76 months [8\u00b76-11\u00b72]; hazard ratio [HR] 0\u00b773 [95% CI 0\u00b762-0\u00b787], p=0\u00b70003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15\u00b77 months [95% CI 12\u00b76-18\u00b70] with atezolizumab vs 10\u00b73 months [8\u00b78-12\u00b70] with docetaxel; HR 0\u00b774 [95% CI 0\u00b758-0\u00b793]; p=0\u00b70102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12\u00b76 months vs 8\u00b79 months; HR 0\u00b775 [95% CI 0\u00b759-0\u00b796]). Overall survival improvement was similar in patients with squamous (HR 0\u00b773 [95% CI 0\u00b754-0\u00b798]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0\u00b773 [0\u00b760-0\u00b789]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.\n## INTERPRETATION\nTo our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.\n## FUNDING\nF. Hoffmann-La Roche Ltd, Genentech, Inc.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nOutcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.\n## METHODS\nIn this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3\u226550%, TC2\u22655% and <50%, TC1\u22651% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3\u226510%, IC2\u22655% and <10%, IC1\u22651% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.\n## FINDINGS\nPatients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12\u00b76 months (95% CI 9\u00b77-16\u00b74) for atezolizumab versus 9\u00b77 months (8\u00b76-12\u00b70) for docetaxel (hazard ratio [HR] 0\u00b773 [95% CI 0\u00b753-0\u00b799]; p=0\u00b704). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0\u00b749 [0\u00b722-1\u00b707; p=0\u00b7068], TC2/3 or IC2/3 HR 0\u00b754 [0\u00b733-0\u00b789; p=0\u00b7014], TC1/2/3 or IC1/2/3 HR 0\u00b759 [0\u00b740-0\u00b785; p=0\u00b7005], TC0 and IC0 HR 1\u00b704 [0\u00b762-1\u00b775; p=0\u00b7871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-\u03b3-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.\n## INTERPRETATION\nAtezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.\n## FUNDING\nF Hoffmann-La Roche/Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.",
        "key_reference_abstract": "## BACKGROUND\nPatients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.\n## METHODS\nIn this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.\n## RESULTS\nThe median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.\n## CONCLUSIONS\nAmong patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.\n## METHODS\nWe did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.\n## FINDINGS\nBetween Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).\n## INTERPRETATION\nPembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.\n## FUNDING\nMerck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.",
        "key_reference_abstract": "## BACKGROUND\nLimited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.\n## METHODS\nIn this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs \u22651%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m\n## FINDINGS\nBetween Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%]; p=0\u00b70016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.\n## INTERPRETATION\nCombination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.\n## FUNDING\nMerck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).\n## METHODS\nIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.\n## RESULTS\nMedian progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).\n## CONCLUSIONS\nIn patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.\n## METHODS\nIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.\n## RESULTS\nOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (\u22651%, \u22655%, and \u226510%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.\n## CONCLUSIONS\nAmong patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.\n## METHODS\nWe did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis \u22641 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.\n## FINDINGS\nBetween July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2\u00b774 years (IQR 2\u00b728-3\u00b722), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26\u00b71 months (95% CI 19\u00b73-39\u00b73) in the ipilimumab group versus 17\u00b71 months (95% CI 13\u00b74-21\u00b76) in the placebo group (hazard ratio 0\u00b775; 95% CI 0\u00b764-0\u00b790; p=0\u00b70013); 3-year recurrence-free survival was 46\u00b75% (95% CI 41\u00b75-51\u00b73) in the ipilimumab group versus 34\u00b78% (30\u00b71-39\u00b75) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barr\u00e9 syndrome.\n## INTERPRETATION\nAdjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.\n## METHODS\nA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.\n## RESULTS\nThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P\u22640.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).\n## CONCLUSIONS\nAmong patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.\n## METHODS\nWe did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.\n## FINDINGS\nFrom May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11\u00b72 months (95% CI 9\u00b75-12\u00b77) with ipilimumab and 10\u00b70 months (8\u00b73-11\u00b70) with placebo (hazard ratio [HR] 0\u00b785, 0\u00b772-1\u00b700; p=0\u00b7053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0\u00b70031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1\u00b746 (95% CI 1\u00b710-1\u00b795), for 5-12 months was 0\u00b765 (0\u00b750-0\u00b785), and beyond 12 months was 0\u00b760 (0\u00b743-0\u00b786). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.\n## INTERPRETATION\nAlthough there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).\n## DESIGN\nPatients (n=130) with chemotherapy-na\u00efve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin) or phased ipilimumab (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.\n## RESULTS\nPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64; P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.\n## CONCLUSION\nThese results suggest further investigation of ipilimumab in ED-SCLC.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.\n## METHODS\nWe randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.\n## RESULTS\nOverall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.\n## CONCLUSIONS\nIpilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Neurotoxicity Analysis of Checkpoint Inhibitors vs Control - Immunotherapy",
        "key_reference_title": "Improved survival with ipilimumab in patients with metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nAn improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.\n## METHODS\nA total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.\n## RESULTS\nThe median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.\n## CONCLUSIONS\nIpilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report.",
        "key_reference_abstract": "## INTRODUCTION\nOsimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in\u00a0patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy.\n## METHODS\nPatients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or\u00a0without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.\n## RESULTS\nCAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade \u22653 in 6% of patients])\u00a0in the osimertinib arm and rash (67% [grade \u22653 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.\n## CONCLUSION\nLimited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nThere are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma.\n## METHODS\nWe did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients.\n## FINDINGS\nBetween Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8\u00b74 months (95% CI 6\u00b74-9\u00b74) with pembrolizumab and 6\u00b79 months (5\u00b79-8\u00b70) with standard of care (hazard ratio 0\u00b780, 0\u00b765-0\u00b798; nominal p=0\u00b70161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia).\n## INTERPRETATION\nThe clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nMicrosatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.\n## METHODS\nIMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs \u226518 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.\n## FINDINGS\nBetween July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7\u00b73 months (IQR 3\u00b77-13\u00b76). Median overall survival was 8\u00b787 months (95% CI 7\u00b700-10\u00b761) with atezolizumab plus cobimetinib, 7\u00b710 months (6\u00b705-10\u00b705) with atezolizumab, and 8\u00b751 months (6\u00b741-10\u00b771) with regorafenib; the hazard ratio was 1\u00b700 (95% CI 0\u00b773-1\u00b738; p=0\u00b799) for the combination versus regorafenib and 1\u00b719 (0\u00b783-1\u00b771; p=0\u00b734) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).\n## INTERPRETATION\nIMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.\n## FUNDING\nF Hoffmann-La Roche Ltd/Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.\n## FINDINGS\nBetween Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8\u00b71 months (IQR 4\u00b75-10\u00b79). Median progression-free survival was 5\u00b76 months (95% CI 3\u00b77-7\u00b75) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8\u00b74 months (5\u00b79-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1\u00b753; 95% CI 1\u00b705-2\u00b722; p=0\u00b798). Median overall survival was not reached (95% CI 12\u00b79-not reached) versus 15\u00b72 months (12\u00b77-not reached; HR 1\u00b761; 95% CI 0\u00b791-2\u00b785; p=0\u00b795); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.\n## METHODS\nThis randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (\u226518 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (\u226550% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0\u00b70122, p=0\u00b70120, and p=0\u00b70124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.\n## FINDINGS\nFrom Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12\u00b78 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (\u226550% hazard ratio 0\u00b769, 95% CI 0\u00b756-0\u00b785, p=0\u00b70003; \u226520% 0\u00b777, 0\u00b764-0\u00b792, p=0\u00b70020, and \u22651% 0\u00b781, 0\u00b771-0\u00b793, p=0\u00b70018). The median surival values by TPS population were 20\u00b70 months (95% CI 15\u00b74-24\u00b79) for pembrolizumab versus 12\u00b72 months (10\u00b74-14\u00b72) for chemotherapy, 17\u00b77 months (15\u00b73-22\u00b71) versus 13\u00b70 months (11\u00b76-15\u00b73), and 16\u00b77 months (13\u00b79-19\u00b77) versus 12\u00b71 months (11\u00b73-13\u00b73), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.\n## INTERPRETATION\nThe benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.\n## FUNDING\nMerck Sharp & Dohme.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.\n## METHODS\nIn this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.\n## FINDINGS\nOf 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11\u00b72 months in the atezolizumab plus bevacizumab group versus 7\u00b77 months in the sunitinib group (hazard ratio [HR] 0\u00b774 [95% CI 0\u00b757-0\u00b796]; p=0\u00b70217). In the ITT population, median overall survival had an HR of 0\u00b793 (0\u00b776-1\u00b714) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.\n## INTERPRETATION\nAtezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.\n## FUNDING\nF Hoffmann-La Roche Ltd and Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nThe combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.\n## METHODS\nIn an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.\n## RESULTS\nAfter a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.\n## CONCLUSIONS\nAmong patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nLenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual.\n## FINDINGS\nBetween Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6\u00b76 months (IQR 3\u00b74-9\u00b76), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82\u00b70% (95% CI 73\u00b72-88\u00b71) versus 85\u00b70% (76\u00b78-90\u00b75; hazard ratio [HR] 1\u00b722; 95% CI 0\u00b767-2\u00b722; p=0\u00b775). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure).\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer.\n## METHODS\nIMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m\n## FINDINGS\nBetween April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18\u00b75 months [IQR 15\u00b72-23\u00b76] in the atezolizumab plus chemotherapy group and 19\u00b72 months [15\u00b74-23\u00b70] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18\u00b76 months [95% CI 16\u00b70-21\u00b72] in the atezolizumab plus chemotherapy group and 13\u00b79 months [12\u00b70-18\u00b77] in the chemotherapy group; stratified hazard ratio [HR] 0\u00b779 [95% CI 0\u00b764-0\u00b798]; p=0\u00b7033) and median progression-free survival (7\u00b70 months [95% CI 6\u00b72-7\u00b73] in the atezolizumab plus chemotherapy group and 5\u00b75 months [4\u00b74-5\u00b79] in the chemotherapy group; stratified HR 0\u00b764 [95% CI 0\u00b754-0\u00b777]; p<0\u00b70001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group.\n## INTERPRETATION\nIMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer.\n## FUNDING\nF. Hoffmann-La Roche.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.",
        "key_reference_abstract": "## BACKGROUND\nThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.\n## PATIENTS AND METHODS\nPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10\u2009mg/kg by intravenous infusion every 2\u2009weeks or physician's choice of chemotherapy (paclitaxel 80\u2009mg/m2 on days 1, 8, and 15 or irinotecan 150\u2009mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.\n## RESULTS\nA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0\u2009months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P\u2009=\u20090.81} or the secondary end points of PFS [median, 1.4 versus 2.7\u2009months; HR=1.73 (95% CI 1.4-2.2); P\u2009>\u20090.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade \u22653 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.\n## CONCLUSIONS\nTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.\n## TRIAL REGISTRATION\nClinicalTrials.gov: NCT02625623.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nAntibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy.\n## METHODS\nJAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m\n## FINDINGS\nBetween March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11\u00b74 months [95% CI 9\u00b74-13\u00b79] vs 10\u00b73 months [8\u00b75-13\u00b70]; hazard ratio 0\u00b790 [96% CI 0\u00b772-1\u00b712]; one-sided p=0\u00b716). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes.\n## INTERPRETATION\nCompared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile.\n## FUNDING\nMerck and Pfizer.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.",
        "key_reference_abstract": "## BACKGROUND\nThe programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.\n## METHODS\nPatients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.\n## RESULTS\nAt a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.\n## CONCLUSIONS\nAs adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.\n## RESULTS\nAfter a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.\n## CONCLUSIONS\nIn patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nEnhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.\n## METHODS\nWe conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.\n## RESULTS\nA total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.\n## CONCLUSIONS\nThe addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIn the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.\n## METHODS\nIn the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.\n## FINDINGS\nBetween Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32\u00b74 months [IQR 13\u00b74-36\u00b73]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35\u00b76-not estimable] vs 26\u00b76 months [22\u00b71-33\u00b74]; hazard ratio [HR] 0\u00b766 [95% CI 0\u00b754-0\u00b780], p<0\u00b70001), progression-free survival (median 8\u00b72 months [95% CI 6\u00b79-10\u00b70] vs 8\u00b73 months [7\u00b70-8\u00b78]; HR 0\u00b777 [95% CI 0\u00b765-0\u00b790], p=0\u00b70014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0\u00b70001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37\u00b79 months [32\u00b72-not estimable]; HR 0\u00b771 [95% CI 0\u00b759-0\u00b786], p=0\u00b70003), progression-free survival (median 9\u00b77 months [95% CI 8\u00b71-11\u00b71] vs 9\u00b77 months [8\u00b73-11\u00b71]; HR 0\u00b785 [95% CI 0\u00b773-0\u00b798], p=0\u00b7027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0\u00b7015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.\n## INTERPRETATION\nThe results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.\n## FUNDING\nBristol-Myers Squibb and ONO Pharmaceutical.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nStandard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on \u226550% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.\n## RESULTS\nAfter a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).\n## CONCLUSIONS\nIn patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nFew options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population.\n## METHODS\nWe conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged \u226518 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m\n## FINDINGS\nBetween Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11\u00b71 months [95% CI 8\u00b76-15\u00b75; n=116] vs 10\u00b76 months [8\u00b74-12\u00b72; n=118]; stratified hazard ratio [HR] 0\u00b787, 95% CI 0\u00b763-1\u00b721; p=0\u00b741), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15\u00b79 months [95% CI 10\u00b74 to not estimable] vs 8\u00b73 months [5\u00b76-13\u00b72]; HR 0\u00b757, 95% CI 0\u00b726-1\u00b726). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).\n## INTERPRETATION\nAtezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.\n## FUNDING\nF Hoffmann-La Roche, Genentech.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.\n## METHODS\nThis randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0\u00b70135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.\n## FINDINGS\nBetween June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9\u00b71 months (95% CI 6\u00b72-10\u00b77) with pembrolizumab and 8\u00b73 months (7\u00b76-9\u00b70) with paclitaxel (hazard ratio [HR] 0\u00b782, 95% CI 0\u00b766-1\u00b703; one-sided p=0\u00b70421). Median progression-free survival was 1\u00b75 months (95% CI 1\u00b74-2\u00b70) with pembrolizumab and 4\u00b71 months (3\u00b71-4\u00b72) with paclitaxel (HR 1\u00b727, 95% CI 1\u00b703-1\u00b757). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.\n## INTERPRETATION\nPembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.",
        "key_reference_abstract": "## BACKGROUND\nAn earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.\n## METHODS\nWe randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety.\n## RESULTS\nOf the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.\n## CONCLUSIONS\nDurvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer.",
        "key_reference_abstract": "Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI, 1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. \u00a92017 AACR.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.\n## METHODS\nIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4\u03ba isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.\n## RESULTS\nThe median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).\n## CONCLUSIONS\nPembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.\n## METHODS\nWe randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.\n## RESULTS\nAmong the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.\n## CONCLUSIONS\nNivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-na\u00efve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.",
        "key_reference_abstract": "## AIM\nTo evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.\n## METHODS\nIn this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor\u00a0or both, if BRAF\n## RESULTS\nA total of 180 patients were randomised to pembrolizumab 2\u00a0mg/kg, 181 to pembrolizumab 10\u00a0mg/kg\u00a0and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died\u00a0and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2\u00a0mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p\u00a0=\u00a00.117) and 10\u00a0mg/kg (0.74, 0.57-0.96, p\u00a0=\u00a00.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate\u00a0and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%)\u00a0and 45 (26.3%) patients, respectively.\n## CONCLUSION\nImprovement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.",
        "key_reference_abstract": "## BACKGROUND\nNew therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.\n## METHODS\nDETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.\n## FINDINGS\nBetween May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7\u00b77 months (95% CI 6\u00b78-8\u00b79) in the tremelimumab group and 7\u00b73 months (5\u00b79-8\u00b77) in the placebo group (hazard ratio 0\u00b792 [95% CI 0\u00b776-1\u00b712], p=0\u00b741). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.\n## INTERPRETATION\nTremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.\n## FUNDING\nAstraZeneca.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.\n## METHODS\nWe did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m\n## FINDINGS\nBetween March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13\u00b78 months [95% CI 11\u00b78-15\u00b77] vs 9\u00b76 months [8\u00b76-11\u00b72]; hazard ratio [HR] 0\u00b773 [95% CI 0\u00b762-0\u00b787], p=0\u00b70003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15\u00b77 months [95% CI 12\u00b76-18\u00b70] with atezolizumab vs 10\u00b73 months [8\u00b78-12\u00b70] with docetaxel; HR 0\u00b774 [95% CI 0\u00b758-0\u00b793]; p=0\u00b70102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12\u00b76 months vs 8\u00b79 months; HR 0\u00b775 [95% CI 0\u00b759-0\u00b796]). Overall survival improvement was similar in patients with squamous (HR 0\u00b773 [95% CI 0\u00b754-0\u00b798]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0\u00b773 [0\u00b760-0\u00b789]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.\n## INTERPRETATION\nTo our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.\n## FUNDING\nF. Hoffmann-La Roche Ltd, Genentech, Inc.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nOutcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.\n## METHODS\nIn this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3\u226550%, TC2\u22655% and <50%, TC1\u22651% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3\u226510%, IC2\u22655% and <10%, IC1\u22651% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.\n## FINDINGS\nPatients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12\u00b76 months (95% CI 9\u00b77-16\u00b74) for atezolizumab versus 9\u00b77 months (8\u00b76-12\u00b70) for docetaxel (hazard ratio [HR] 0\u00b773 [95% CI 0\u00b753-0\u00b799]; p=0\u00b704). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0\u00b749 [0\u00b722-1\u00b707; p=0\u00b7068], TC2/3 or IC2/3 HR 0\u00b754 [0\u00b733-0\u00b789; p=0\u00b7014], TC1/2/3 or IC1/2/3 HR 0\u00b759 [0\u00b740-0\u00b785; p=0\u00b7005], TC0 and IC0 HR 1\u00b704 [0\u00b762-1\u00b775; p=0\u00b7871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-\u03b3-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.\n## INTERPRETATION\nAtezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.\n## FUNDING\nF Hoffmann-La Roche/Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.",
        "key_reference_abstract": "## BACKGROUND\nPatients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.\n## METHODS\nIn this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.\n## RESULTS\nThe median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.\n## CONCLUSIONS\nAmong patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.\n## METHODS\nWe did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.\n## FINDINGS\nBetween Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).\n## INTERPRETATION\nPembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.\n## FUNDING\nMerck & Co.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.",
        "key_reference_abstract": "## BACKGROUND\nLimited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.\n## METHODS\nIn this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs \u22651%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m\n## FINDINGS\nBetween Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%]; p=0\u00b70016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.\n## INTERPRETATION\nCombination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.\n## FUNDING\nMerck & Co.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).\n## METHODS\nIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.\n## RESULTS\nMedian progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).\n## CONCLUSIONS\nIn patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.\n## METHODS\nIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.\n## RESULTS\nOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (\u22651%, \u22655%, and \u226510%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.\n## CONCLUSIONS\nAmong patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.\n## METHODS\nWe did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis \u22641 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.\n## FINDINGS\nBetween July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2\u00b774 years (IQR 2\u00b728-3\u00b722), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26\u00b71 months (95% CI 19\u00b73-39\u00b73) in the ipilimumab group versus 17\u00b71 months (95% CI 13\u00b74-21\u00b76) in the placebo group (hazard ratio 0\u00b775; 95% CI 0\u00b764-0\u00b790; p=0\u00b70013); 3-year recurrence-free survival was 46\u00b75% (95% CI 41\u00b75-51\u00b73) in the ipilimumab group versus 34\u00b78% (30\u00b71-39\u00b75) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barr\u00e9 syndrome.\n## INTERPRETATION\nAdjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.\n## METHODS\nA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.\n## RESULTS\nThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P\u22640.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).\n## CONCLUSIONS\nAmong patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.\n## METHODS\nWe did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.\n## FINDINGS\nFrom May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11\u00b72 months (95% CI 9\u00b75-12\u00b77) with ipilimumab and 10\u00b70 months (8\u00b73-11\u00b70) with placebo (hazard ratio [HR] 0\u00b785, 0\u00b772-1\u00b700; p=0\u00b7053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0\u00b70031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1\u00b746 (95% CI 1\u00b710-1\u00b795), for 5-12 months was 0\u00b765 (0\u00b750-0\u00b785), and beyond 12 months was 0\u00b760 (0\u00b743-0\u00b786). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.\n## INTERPRETATION\nAlthough there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).\n## DESIGN\nPatients (n=130) with chemotherapy-na\u00efve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin) or phased ipilimumab (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.\n## RESULTS\nPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64; P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.\n## CONCLUSION\nThese results suggest further investigation of ipilimumab in ED-SCLC.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.\n## METHODS\nWe randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.\n## RESULTS\nOverall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.\n## CONCLUSIONS\nIpilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Chemotherapy",
        "key_reference_title": "Improved survival with ipilimumab in patients with metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nAn improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.\n## METHODS\nA total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.\n## RESULTS\nThe median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.\n## CONCLUSIONS\nIpilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report.",
        "key_reference_abstract": "## INTRODUCTION\nOsimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in\u00a0patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy.\n## METHODS\nPatients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or\u00a0without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.\n## RESULTS\nCAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade \u22653 in 6% of patients])\u00a0in the osimertinib arm and rash (67% [grade \u22653 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.\n## CONCLUSION\nLimited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nThere are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma.\n## METHODS\nWe did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients.\n## FINDINGS\nBetween Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8\u00b74 months (95% CI 6\u00b74-9\u00b74) with pembrolizumab and 6\u00b79 months (5\u00b79-8\u00b70) with standard of care (hazard ratio 0\u00b780, 0\u00b765-0\u00b798; nominal p=0\u00b70161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia).\n## INTERPRETATION\nThe clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nMicrosatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.\n## METHODS\nIMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs \u226518 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.\n## FINDINGS\nBetween July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7\u00b73 months (IQR 3\u00b77-13\u00b76). Median overall survival was 8\u00b787 months (95% CI 7\u00b700-10\u00b761) with atezolizumab plus cobimetinib, 7\u00b710 months (6\u00b705-10\u00b705) with atezolizumab, and 8\u00b751 months (6\u00b741-10\u00b771) with regorafenib; the hazard ratio was 1\u00b700 (95% CI 0\u00b773-1\u00b738; p=0\u00b799) for the combination versus regorafenib and 1\u00b719 (0\u00b783-1\u00b771; p=0\u00b734) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).\n## INTERPRETATION\nIMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.\n## FUNDING\nF Hoffmann-La Roche Ltd/Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.\n## FINDINGS\nBetween Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8\u00b71 months (IQR 4\u00b75-10\u00b79). Median progression-free survival was 5\u00b76 months (95% CI 3\u00b77-7\u00b75) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8\u00b74 months (5\u00b79-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1\u00b753; 95% CI 1\u00b705-2\u00b722; p=0\u00b798). Median overall survival was not reached (95% CI 12\u00b79-not reached) versus 15\u00b72 months (12\u00b77-not reached; HR 1\u00b761; 95% CI 0\u00b791-2\u00b785; p=0\u00b795); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.\n## METHODS\nThis randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (\u226518 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (\u226550% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0\u00b70122, p=0\u00b70120, and p=0\u00b70124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.\n## FINDINGS\nFrom Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12\u00b78 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (\u226550% hazard ratio 0\u00b769, 95% CI 0\u00b756-0\u00b785, p=0\u00b70003; \u226520% 0\u00b777, 0\u00b764-0\u00b792, p=0\u00b70020, and \u22651% 0\u00b781, 0\u00b771-0\u00b793, p=0\u00b70018). The median surival values by TPS population were 20\u00b70 months (95% CI 15\u00b74-24\u00b79) for pembrolizumab versus 12\u00b72 months (10\u00b74-14\u00b72) for chemotherapy, 17\u00b77 months (15\u00b73-22\u00b71) versus 13\u00b70 months (11\u00b76-15\u00b73), and 16\u00b77 months (13\u00b79-19\u00b77) versus 12\u00b71 months (11\u00b73-13\u00b73), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.\n## INTERPRETATION\nThe benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.\n## FUNDING\nMerck Sharp & Dohme.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nA phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.\n## METHODS\nIn this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.\n## FINDINGS\nOf 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11\u00b72 months in the atezolizumab plus bevacizumab group versus 7\u00b77 months in the sunitinib group (hazard ratio [HR] 0\u00b774 [95% CI 0\u00b757-0\u00b796]; p=0\u00b70217). In the ITT population, median overall survival had an HR of 0\u00b793 (0\u00b776-1\u00b714) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.\n## INTERPRETATION\nAtezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.\n## FUNDING\nF Hoffmann-La Roche Ltd and Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nThe combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.\n## METHODS\nIn an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.\n## RESULTS\nAfter a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.\n## CONCLUSIONS\nAmong patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nLenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA).\n## METHODS\nKEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual.\n## FINDINGS\nBetween Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6\u00b76 months (IQR 3\u00b74-9\u00b76), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82\u00b70% (95% CI 73\u00b72-88\u00b71) versus 85\u00b70% (76\u00b78-90\u00b75; hazard ratio [HR] 1\u00b722; 95% CI 0\u00b767-2\u00b722; p=0\u00b775). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure).\n## INTERPRETATION\nThe results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer.\n## METHODS\nIMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m\n## FINDINGS\nBetween April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18\u00b75 months [IQR 15\u00b72-23\u00b76] in the atezolizumab plus chemotherapy group and 19\u00b72 months [15\u00b74-23\u00b70] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18\u00b76 months [95% CI 16\u00b70-21\u00b72] in the atezolizumab plus chemotherapy group and 13\u00b79 months [12\u00b70-18\u00b77] in the chemotherapy group; stratified hazard ratio [HR] 0\u00b779 [95% CI 0\u00b764-0\u00b798]; p=0\u00b7033) and median progression-free survival (7\u00b70 months [95% CI 6\u00b72-7\u00b73] in the atezolizumab plus chemotherapy group and 5\u00b75 months [4\u00b74-5\u00b79] in the chemotherapy group; stratified HR 0\u00b764 [95% CI 0\u00b754-0\u00b777]; p<0\u00b70001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group.\n## INTERPRETATION\nIMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer.\n## FUNDING\nF. Hoffmann-La Roche.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.",
        "key_reference_abstract": "## BACKGROUND\nThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.\n## PATIENTS AND METHODS\nPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10\u2009mg/kg by intravenous infusion every 2\u2009weeks or physician's choice of chemotherapy (paclitaxel 80\u2009mg/m2 on days 1, 8, and 15 or irinotecan 150\u2009mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.\n## RESULTS\nA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0\u2009months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P\u2009=\u20090.81} or the secondary end points of PFS [median, 1.4 versus 2.7\u2009months; HR=1.73 (95% CI 1.4-2.2); P\u2009>\u20090.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade \u22653 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.\n## CONCLUSIONS\nTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.\n## TRIAL REGISTRATION\nClinicalTrials.gov: NCT02625623.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.",
        "key_reference_abstract": "## BACKGROUND\nAntibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy.\n## METHODS\nJAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m\n## FINDINGS\nBetween March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11\u00b74 months [95% CI 9\u00b74-13\u00b79] vs 10\u00b73 months [8\u00b75-13\u00b70]; hazard ratio 0\u00b790 [96% CI 0\u00b772-1\u00b712]; one-sided p=0\u00b716). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes.\n## INTERPRETATION\nCompared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile.\n## FUNDING\nMerck and Pfizer.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.",
        "key_reference_abstract": "## BACKGROUND\nThe programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.\n## METHODS\nPatients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.\n## RESULTS\nAt a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.\n## CONCLUSIONS\nAs adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nFirst-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.\n## RESULTS\nAfter a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.\n## CONCLUSIONS\nIn patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nEnhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.\n## METHODS\nWe conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.\n## RESULTS\nA total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.\n## CONCLUSIONS\nThe addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIn the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.\n## METHODS\nIn the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.\n## FINDINGS\nBetween Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32\u00b74 months [IQR 13\u00b74-36\u00b73]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35\u00b76-not estimable] vs 26\u00b76 months [22\u00b71-33\u00b74]; hazard ratio [HR] 0\u00b766 [95% CI 0\u00b754-0\u00b780], p<0\u00b70001), progression-free survival (median 8\u00b72 months [95% CI 6\u00b79-10\u00b70] vs 8\u00b73 months [7\u00b70-8\u00b78]; HR 0\u00b777 [95% CI 0\u00b765-0\u00b790], p=0\u00b70014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0\u00b70001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37\u00b79 months [32\u00b72-not estimable]; HR 0\u00b771 [95% CI 0\u00b759-0\u00b786], p=0\u00b70003), progression-free survival (median 9\u00b77 months [95% CI 8\u00b71-11\u00b71] vs 9\u00b77 months [8\u00b73-11\u00b71]; HR 0\u00b785 [95% CI 0\u00b773-0\u00b798], p=0\u00b7027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0\u00b7015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.\n## INTERPRETATION\nThe results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.\n## FUNDING\nBristol-Myers Squibb and ONO Pharmaceutical.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nStandard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on \u226550% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.\n## METHODS\nIn this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.\n## RESULTS\nAfter a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).\n## CONCLUSIONS\nIn patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nFew options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population.\n## METHODS\nWe conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged \u226518 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m\n## FINDINGS\nBetween Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11\u00b71 months [95% CI 8\u00b76-15\u00b75; n=116] vs 10\u00b76 months [8\u00b74-12\u00b72; n=118]; stratified hazard ratio [HR] 0\u00b787, 95% CI 0\u00b763-1\u00b721; p=0\u00b741), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15\u00b79 months [95% CI 10\u00b74 to not estimable] vs 8\u00b73 months [5\u00b76-13\u00b72]; HR 0\u00b757, 95% CI 0\u00b726-1\u00b726). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).\n## INTERPRETATION\nAtezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.\n## FUNDING\nF Hoffmann-La Roche, Genentech.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.\n## METHODS\nThis randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0\u00b70135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.\n## FINDINGS\nBetween June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9\u00b71 months (95% CI 6\u00b72-10\u00b77) with pembrolizumab and 8\u00b73 months (7\u00b76-9\u00b70) with paclitaxel (hazard ratio [HR] 0\u00b782, 95% CI 0\u00b766-1\u00b703; one-sided p=0\u00b70421). Median progression-free survival was 1\u00b75 months (95% CI 1\u00b74-2\u00b70) with pembrolizumab and 4\u00b71 months (3\u00b71-4\u00b72) with paclitaxel (HR 1\u00b727, 95% CI 1\u00b703-1\u00b757). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.\n## INTERPRETATION\nPembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.\n## FUNDING\nMerck Sharp & Dohme, a subsidiary of Merck & Co.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.",
        "key_reference_abstract": "## BACKGROUND\nAn earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.\n## METHODS\nWe randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety.\n## RESULTS\nOf the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.\n## CONCLUSIONS\nDurvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer.",
        "key_reference_abstract": "Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI, 1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. \u00a92017 AACR.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.\n## METHODS\nIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4\u03ba isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.\n## RESULTS\nThe median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).\n## CONCLUSIONS\nPembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.\n## METHODS\nWe randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.\n## RESULTS\nAmong the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.\n## CONCLUSIONS\nNivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-na\u00efve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.",
        "key_reference_abstract": "## AIM\nTo evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.\n## METHODS\nIn this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor\u00a0or both, if BRAF\n## RESULTS\nA total of 180 patients were randomised to pembrolizumab 2\u00a0mg/kg, 181 to pembrolizumab 10\u00a0mg/kg\u00a0and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died\u00a0and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2\u00a0mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p\u00a0=\u00a00.117) and 10\u00a0mg/kg (0.74, 0.57-0.96, p\u00a0=\u00a00.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate\u00a0and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%)\u00a0and 45 (26.3%) patients, respectively.\n## CONCLUSION\nImprovement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.",
        "key_reference_abstract": "## BACKGROUND\nNew therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.\n## METHODS\nDETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.\n## FINDINGS\nBetween May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7\u00b77 months (95% CI 6\u00b78-8\u00b79) in the tremelimumab group and 7\u00b73 months (5\u00b79-8\u00b77) in the placebo group (hazard ratio 0\u00b792 [95% CI 0\u00b776-1\u00b712], p=0\u00b741). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.\n## INTERPRETATION\nTremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.\n## FUNDING\nAstraZeneca.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nAtezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.\n## METHODS\nWe did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m\n## FINDINGS\nBetween March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13\u00b78 months [95% CI 11\u00b78-15\u00b77] vs 9\u00b76 months [8\u00b76-11\u00b72]; hazard ratio [HR] 0\u00b773 [95% CI 0\u00b762-0\u00b787], p=0\u00b70003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15\u00b77 months [95% CI 12\u00b76-18\u00b70] with atezolizumab vs 10\u00b73 months [8\u00b78-12\u00b70] with docetaxel; HR 0\u00b774 [95% CI 0\u00b758-0\u00b793]; p=0\u00b70102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12\u00b76 months vs 8\u00b79 months; HR 0\u00b775 [95% CI 0\u00b759-0\u00b796]). Overall survival improvement was similar in patients with squamous (HR 0\u00b773 [95% CI 0\u00b754-0\u00b798]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0\u00b773 [0\u00b760-0\u00b789]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.\n## INTERPRETATION\nTo our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.\n## FUNDING\nF. Hoffmann-La Roche Ltd, Genentech, Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nOutcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.\n## METHODS\nIn this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3\u226550%, TC2\u22655% and <50%, TC1\u22651% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3\u226510%, IC2\u22655% and <10%, IC1\u22651% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.\n## FINDINGS\nPatients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12\u00b76 months (95% CI 9\u00b77-16\u00b74) for atezolizumab versus 9\u00b77 months (8\u00b76-12\u00b70) for docetaxel (hazard ratio [HR] 0\u00b773 [95% CI 0\u00b753-0\u00b799]; p=0\u00b704). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0\u00b749 [0\u00b722-1\u00b707; p=0\u00b7068], TC2/3 or IC2/3 HR 0\u00b754 [0\u00b733-0\u00b789; p=0\u00b7014], TC1/2/3 or IC1/2/3 HR 0\u00b759 [0\u00b740-0\u00b785; p=0\u00b7005], TC0 and IC0 HR 1\u00b704 [0\u00b762-1\u00b775; p=0\u00b7871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-\u03b3-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.\n## INTERPRETATION\nAtezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.\n## FUNDING\nF Hoffmann-La Roche/Genentech Inc.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.",
        "key_reference_abstract": "## BACKGROUND\nPatients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.\n## METHODS\nIn this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.\n## RESULTS\nThe median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.\n## CONCLUSIONS\nAmong patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nDespite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.\n## METHODS\nWe did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.\n## FINDINGS\nBetween Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).\n## INTERPRETATION\nPembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.\n## FUNDING\nMerck & Co.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.",
        "key_reference_abstract": "## BACKGROUND\nLimited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.\n## METHODS\nIn this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs \u22651%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m\n## FINDINGS\nBetween Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%]; p=0\u00b70016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.\n## INTERPRETATION\nCombination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.\n## FUNDING\nMerck & Co.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).\n## METHODS\nIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.\n## RESULTS\nMedian progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).\n## CONCLUSIONS\nIn patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.",
        "key_reference_abstract": "Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.\n## METHODS\nIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.\n## RESULTS\nOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (\u22651%, \u22655%, and \u226510%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.\n## CONCLUSIONS\nAmong patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.\n## METHODS\nWe did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis \u22641 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.\n## FINDINGS\nBetween July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2\u00b774 years (IQR 2\u00b728-3\u00b722), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26\u00b71 months (95% CI 19\u00b73-39\u00b73) in the ipilimumab group versus 17\u00b71 months (95% CI 13\u00b74-21\u00b76) in the placebo group (hazard ratio 0\u00b775; 95% CI 0\u00b764-0\u00b790; p=0\u00b70013); 3-year recurrence-free survival was 46\u00b75% (95% CI 41\u00b75-51\u00b73) in the ipilimumab group versus 34\u00b78% (30\u00b71-39\u00b75) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barr\u00e9 syndrome.\n## INTERPRETATION\nAdjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.",
        "key_reference_abstract": "## BACKGROUND\nNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.\n## METHODS\nA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.\n## RESULTS\nThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P\u22640.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).\n## CONCLUSIONS\nAmong patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.\n## METHODS\nWe did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.\n## FINDINGS\nFrom May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11\u00b72 months (95% CI 9\u00b75-12\u00b77) with ipilimumab and 10\u00b70 months (8\u00b73-11\u00b70) with placebo (hazard ratio [HR] 0\u00b785, 0\u00b772-1\u00b700; p=0\u00b7053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0\u00b70031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1\u00b746 (95% CI 1\u00b710-1\u00b795), for 5-12 months was 0\u00b765 (0\u00b750-0\u00b785), and beyond 12 months was 0\u00b760 (0\u00b743-0\u00b786). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.\n## INTERPRETATION\nAlthough there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.\n## FUNDING\nBristol-Myers Squibb.",
        "truth": "True"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).\n## DESIGN\nPatients (n=130) with chemotherapy-na\u00efve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin) or phased ipilimumab (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.\n## RESULTS\nPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64; P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.\n## CONCLUSION\nThese results suggest further investigation of ipilimumab in ED-SCLC.",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nIpilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.\n## METHODS\nWe randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.\n## RESULTS\nOverall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.\n## CONCLUSIONS\nIpilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).",
        "truth": "False"
    },
    {
        "pmid": "35438755",
        "meta_analysis_title": "Association of Immune Checkpoint Inhibitors With Neurologic Adverse Events: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "What is the association of the use of checkpoint inhibitors with the risk of neurological adverse events?",
        "criteria": "In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (Figure 1),8 2 authors (S.B.A. and P.L.) independently searched the bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and trial registries (ClinicalTrials.gov) from inception through March 1, 2020. Published trials fulfilling the PICO criteria (Participants, Intervention, Comparison, and Outcome) were included. Participants included adult patients with any cancer. The intervention included treatment with anti\u2013PD-1/PD-L1 and/or anti-CTLA4 drugs. The comparison included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat that cancer. Trials using placebo or supportive care were also included in the comparison arm. Outcomes included NAEs of any grade or type. Only phase II and III randomized control trials (RCTs) comparing single or dual ICI with the standard of care or placebo were selected. Only those studies where full-text articles were available were screened for the final analysis. In the event of multiple publications from the same trial, only those with the largest sample size were included in our analysis. Any trials whose results were not published in a peer-reviewed journal were excluded. All databases were searched for publications containing anti\u2013PD-1/PD-L1 or anti\u2013CTLA-4 checkpoint inhibitors by using the search string: ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR MED10680 OR AMP-224 OR pidilizumab OR atezolimab OR MED14736 OR avelumab OR BMS-936559 AND durvalumab OR MEDI4736. Two independent reviewers (P.F. and A.M.) examined all selected studies, and disagreements were resolved with mutual consensus or third-party review (M.Z.F.).",
        "subgroup": "Overall Neurotoxicity in the Subgroup Analysis (A) Immunotherapy vs Chemotherapy and (B) Immunotherapy vs Placebo - Immunotherapy vs Placebo",
        "key_reference_title": "Improved survival with ipilimumab in patients with metastatic melanoma.",
        "key_reference_abstract": "## BACKGROUND\nAn improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.\n## METHODS\nA total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.\n## RESULTS\nThe median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.\n## CONCLUSIONS\nIpilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)",
        "truth": "False"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Hand washing with soap and WASH educational intervention reduces under-five childhood diarrhoea incidence in Jigjiga District, Eastern Ethiopia: A community-based cluster randomized controlled trial.",
        "key_reference_abstract": "Despite the tremendous achievement in reducing child mortality and morbidity in the last two decades, diarrhoea is still a major cause of morbidity and mortality among children in many developing countries, including Ethiopia. Hand washing with soap promotion, water quality improvements and improvements in excreta disposal significantly reduces diarrhoeal diseases. The objective of this study was to evaluate the effect of hand washing with soap and water, sanitation and hygiene (WASH) educational Intervention on the incidence of under-five children diarrhoea. A community-based cluster randomized controlled trial was conducted in 24 clusters (sub-Kebelles) in Jigjiga district, Somali region, Eastern Ethiopia from February 1 to July 30, 2015. The trial compared incidence of diarrhoea among under-five children whose primary caretakers receive hand washing with soap and water, sanitation, hygiene educational messages with control households. Generalized estimating equation with a log link function Poisson distribution family was used to compute adjusted incidence rate ratio and the corresponding 95% confidence interval. The results of this study show that the longitudinal adjusted incidence rate ratio (IRR) of diarrhoeal diseases comparing interventional and control households was 0.65 (95% CI 0.57, 0.73) suggesting an overall diarrhoeal diseases reduction of 35%. The results are similar to other trials of WASH educational interventions and hand washing with soap. In conclusion, hand washing with soap practice during critical times and WASH educational messages reduces childhood diarrhoea in the rural pastoralist area.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Interim evaluation of a large scale sanitation, hygiene and water improvement programme on childhood diarrhea and respiratory disease in rural Bangladesh.",
        "key_reference_abstract": "Started in 2007, the Sanitation Hygiene Education and Water Supply in Bangladesh (SHEWA-B) project aims to improve the hygiene, sanitation and water supply for 20 million people in Bangladesh, and thus reduce disease among this population. This paper assesses the effectiveness of SHEWA-B on changing behaviors and reducing diarrhea and respiratory illness among children < 5 years of age. We assessed behaviors at baseline in 2007 and after 6 months and 18 months by conducting structured observation of handwashing behavior in 500 intervention and 500 control households. In addition we conducted spot checks of water and sanitation facilities in 850 intervention and 850 control households. We also collected monthly data on diarrhea and respiratory illness from 500 intervention and 500 control households from October 2007 to September 2009. Participants washed their hands with soap < 3% of the time around food related events in both intervention and control households at baseline and after 18 months. Washing both hands with soap or ash after cleaning a child's anus increased from 22% to 36%, and no access to a latrine decreased from 10% to 6.8% from baseline to 18 months. The prevalence of diarrhea and respiratory illness, among children <5 years of age were similar in intervention and control communities throughout the study. This large scale sanitation, hygiene and water improvement programme resulted in improvements in a few of its targeted behaviors, but these modest behavior changes have not yet resulted in a measurable reduction in childhood diarrhea and respiratory illness.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effect of community health clubs on child diarrhoea in western Rwanda: cluster-randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nCommunity health clubs are multi-session village-level gatherings led by trained facilitators and designed to promote healthy behaviours mainly related to water, sanitation, and hygiene. They have been implemented in several African and Asian countries but have never been evaluated rigorously. We aimed to evaluate the effect of two versions of the community health club model on child health and nutrition outcomes.\n## METHODS\nWe did a cluster-randomised trial in Rusizi district, western Rwanda. We defined villages as clusters. We assessed villages for eligibility then randomly selected 150 for the study using a simple random sampling routine in Stata. We stratified villages by wealth index and by the proportion of children younger than 2 years with caregiver-reported diarrhoea within the past 7 days. We randomly allocated these villages to three study groups: no intervention (control; n=50), eight community health club sessions (Lite intervention; n=50), or 20 community health club sessions (Classic intervention; n=50). Households in these villages were enrolled in 2013 for a baseline survey, then re-enrolled in 2015 for an endline survey. The primary outcome was caregiver-reported diarrhoea within the previous 7 days in children younger than 5 years. Analysis was by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT01836731.\n## FINDINGS\nAt the baseline survey undertaken between May, 2013, and August, 2013, 8734 households with children younger than 5 years of age were enrolled. At the endline survey undertaken between Sept 21, 2015, and Dec 22, 2015, 7934 (91%) of the households were re-enrolled. Among children younger than 5 years, the prevalence of caregiver-reported diarrhoea in the previous 7 days was 514 (14%) of 3616 assigned the control, 453 (14%) of 3196 allocated the Lite intervention (prevalence ratio compared with control 0\u00b797, 95% CI 0\u00b781-1\u00b716; p=0\u00b774), and 495 (14%) of 3464 assigned the Classic intervention (prevalence ratio compared with control 0\u00b799, 0\u00b785-1\u00b715; p=0\u00b787).\n## INTERPRETATION\nCommunity health clubs, in this setting in western Rwanda, had no effect on caregiver-reported diarrhoea among children younger than 5 years. Our results question the value of implementing this intervention at scale for the aim of achieving health gains.\n## FUNDING\nBill & Melinda Gates Foundation.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "A longitudinal study of the impact of behavioural change intervention on cleanliness, diarrhoeal morbidity and growth of children in rural Bangladesh.",
        "key_reference_abstract": "A community-based intervention was developed through direct participation of the target population in assessment and iterative trials to improve hygiene practices and to reduce childhood diarrhoea in lowland rural Bangladesh. A total of 185 (98%) households with children ages 0-18 months in five contiguous villages were targeted for the interventions. A comparison site was selected for a detailed observational study and for use as a control for the intervention. About 97% of all households with children ages 0-18 months were enrolled for study at the control site. Children in this age group were targeted because at this developmental stage they were most vulnerable to diarrhoeal morbidity and malnutrition (related to unhygienic practices). The intervention was implemented with the assistance of village leaders through a \"Clean Life\" campaign by local project workers and volunteer mothers who were chosen from the target households. The intervention activities started in January 1986 and lasted for 7 months. Higher adoption rates of the intervention were associated with better cleanliness status, which was related to lower diarrhoea and malnutrition rates in the intervention site. The results of between-site longitudinal analyses showed that after the intervention, the intervention site had substantially higher cleanliness scores, lower diarrhoeal morbidity, and better growth status compared to those of the control site, with differences increasing over time. The findings suggest that this type of community-based intervention can be very beneficial in modifying hygiene behaviours and lowering childhood diarrhoea and malnutrition.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effectiveness of a hand hygiene program to reduce acute gastroenteritis at child care centers: A cluster randomized trial.",
        "key_reference_abstract": "## UNLABELLED\nWe aimed to assess the effectiveness of an educational and hand hygiene program in daycare centers (DCCs) and homes on acute gastroenteritis (AGE) incidence in children attending DCCs.\n## METHODS\nA randomized, controlled, and open study of 911 children aged 0-3 years attending 24 DCCs in Almer\u00eda (Spain) with an 8-month follow-up was employed. Two intervention groups of DCCs families performed educational and hand hygiene measures, 1 with soap and water (soap and water group; n\u202f=\u202f274), another with hand sanitizer (hand sanitizer group [HSG]; n\u202f=\u202f339), and the control group (CG; n\u202f=\u202f298) followed usual handwashing procedures. We compared AGE episode rates with Poisson regression model.\n## RESULTS\nseven hundred fourteen AGE episodes were registered, significant differences between HSG and CG children were found during December and January. A multivariate model was applied and the adjusted incidence rate ratios by rotavirus vaccination found significant differences when children were previously vaccinated, the children in the soap and water group had a higher risk of AGE episodes (incidence rate ratio: 1.28, 95% confidence interval:1.0-1.64), compared with those in the HSG.\n## CONCLUSIONS\nThis study demonstrated that hand hygiene programs that included hand sanitizer were most effective in the winter months. Further, the largest reduction of AGE episodes occurred in the children that followed hand hygiene programs including hand sanitizer and educational measures for DCC staff, parents, and children, and were vaccinated for rotavirus.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effects of Multiple Cleaning and Disinfection Interventions on Infectious Diseases in Children: A Group Randomized Trial in China.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the effectiveness of multiple cleaning and disinfection interventions in the homes and kindergartens, in reducing gastrointestinal and respiratory illnesses of children.\n## METHODS\nFrom October 2010 to September 2011, we performed a prospective, controlled study in China. 408 children under 5 years old were recruited and group randomized into intervention and control groups. Families and kindergartens in the intervention group were provided with antibacterial products for hand hygiene and surface cleaning or disinfection for one year. Each child's illness symptoms and sick leave were recorded every day.\n## RESULTS\nA total of 393 children completed the study, with similar baseline demographics in each of the 2 groups. Except for abdominal pain, the odds of symptoms (fever, cough and expectoration, runny nose and nasal congestion, diarrhea), illness (acute respiratory illness and gastrointestinal illness), and sick leave per person each month were significantly reduced by interventions. The rates of fever, diarrhea, acute respiratory illness, gastrointestinal illness and sick leave per person per year were significantly decreased as well.\n## CONCLUSION\nNot only the acute respiratory and gastrointestinal illness but the sick leave rate in children were significantly reduced by multiple interventions.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Diarrheal illness among infants and toddlers in day care centers: effects of active surveillance and staff training without subsequent monitoring.",
        "key_reference_abstract": "From October 1981 to September 1984, the authors conducted a three-year longitudinal study of diarrhea among infants and toddlers attending day care centers in Maricopa County, Arizona. In the third year of study, they evaluated the effects on diarrhea rates of staff training without external monitoring and of active surveillance conducted throughout the study. From 21 study day care centers, they randomly selected 10 (\"intervention day care centers\") to receive staff training in procedures to reduce transmission of infectious diarrhea. Continuing active surveillance in the 10 intervention and 11 control day care centers found no difference between diarrhea rates in intervention day care centers in the pre- and posttraining years and no difference between diarrhea rates in the two groups of centers either before or after the training intervention. Biweekly family-based surveys during the two months after training also demonstrated no difference between infant-toddler diarrhea rates in intervention and control day care centers. These surveys found the 21 study day care centers to have significantly higher diarrhea rates than did day care homes or households not using day care, but significantly lower rates than day care centers not included in the active surveillance. Continuous surveillance without training was associated with a significant decrease in diarrheal illness during the course of longitudinal study. One-time staff training without subsequent monitoring did not result in additional decreases and did not lower day care center diarrhea rates to the levels observed in day care homes and households not using day care.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Handwashing to prevent diarrhea in day-care centers.",
        "key_reference_abstract": "Diarrhea has been recognized as a frequent health problem among children enrolled in day-care centers. Thus, we evaluated the effect of a handwashing program in two day-care centers (HWC) on the incidence of diarrhea among children when compared to children in two control centers (CC). After the program was begun, the incidence of diarrhea at the HWC began to fall and after the second month of the study was consistently lower than that at the CC. The incidence of diarrhea in the HWC was approximately half that of the CC for the entire 35-week study period. Adenoviruses, rotavirus, Giardia lamblia, and enteropathogenic Escherichia coli were found in the stools of a small number of ill children, but not pathogen was identified in the stools of most children with diarrhea. These results suggest that a handwashing program will probably prevent at least some of the diarrhea in day-care centers.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Occurrence of infectious symptoms in children in day care homes.",
        "key_reference_abstract": "Transmission of enteric pathogens is facilitated in child day care centers, including family day care homes, by frequent and intimate exposure among susceptible hosts, with diaper changing as the highest-risk procedure for such transmission. The objective of this study was to evaluate the effectiveness of an intervention program in decreasing the incidence of infectious disease symptoms in children attending family day care homes during a 12-month period. Each of 24 family day care homes was randomly assigned to an intervention or control group. The intervention included four components: (1) a handwashing educational program and (2) use of vinyl gloves, (3) use of disposable diaper changing pads, and (4) use of an alcohol-based hand rinse by the day care provider. Symptoms of enteric disease (diarrhea and vomiting) were significantly reduced in intervention family day care homes (p less than or equal to 0.05), whereas respiratory symptoms were not significantly different between intervention and control family day care homes (p = 0.35). Diarrhea was reported in 1 of every 100 child care days, representing one diarrhea episode per month in a typical family day care home.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effectiveness of a training program in reducing infections in toddlers attending day care centers.",
        "key_reference_abstract": "The objective of this study was to assess the effectiveness of a hygiene program in reducing the incidence of respiratory and diarrheal diseases in toddlers attending day care centers. A randomized field trial was conducted in 52 day care centers in Quebec, Canada, between September 1, 1996 and November 30, 1997. Absences for any reasons and the daily occurrence of colds and/or diarrhea in toddlers were recorded on calendars by the educators. The number of fecal coliforms on children's hands and on educators' hands was measured during three unannounced visits. Overall, 1,729 children were followed in 47 day care centers for a total of 153,643 child-days. The incidence rate of diarrhea was considerably reduced by the effect of monitoring (IRR = 0.73, 95% CI = 0.54,0.97), and the intervention reduced the incidence rate of upper respiratory tract infections (IRR = 0.80, 95% CI = 0.68,0.93). Monitoring alone also had an important effect in reducing the level of bacterial contamination on children's and educators' hands. The results indicate that both an intervention program and monitoring alone play a role in reducing infections in children attending day care centers.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Promoting Handwashing Behavior: The Effects of Large-scale Community and School-level Interventions.",
        "key_reference_abstract": "This paper analyzes a randomized experiment that uses novel strategies to promote handwashing with soap at critical points in time in Peru. It evaluates a large-scale comprehensive initiative that involved both community and school activities in addition to communication campaigns. The analysis indicates that the initiative was successful in reaching the target audience and in increasing the treated population's knowledge about appropriate handwashing behavior. These improvements translated into higher self-reported and observed handwashing with soap at critical junctures. However, no significant improvements in the health of children under the age of 5\u00a0years were observed. Copyright \u00a9 2015 John Wiley & Sons, Ltd.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Community-based hygiene education to reduce diarrhoeal disease in rural Zaire: impact of the intervention on diarrhoeal morbidity.",
        "key_reference_abstract": "## BACKGROUND\nDiarrhoeal disease is a leading cause of morbidity in young children in rural Zaire. Few diarrhoea prevention programmes have been implemented in Bandundu Province, where available data suggest an annual prevalence rate of 10%. The urgent need to reduce diarrhoeal morbidity in Zaire, together with the potential effectiveness and feasibility of hygiene education as a diarrhoea prevention strategy, led to the development of the present research project.\n## METHODS\nA randomized, controlled trial of an education intervention to reduce diarrhoea through improved personal and domestic hygiene behaviours was conducted in 18 geographically separate village clusters (sites) in rural Zaire. For 12 weeks baseline information on the diarrhoeal morbidity of 2082 children aged 3-35 months was collected at weekly home visits, and structured observations of hygiene practices related to diarrhoea were made on a subset of 300 families. Intervention messages addressed disposal of animal faeces from the yard, handwashing after defecation and before meal preparation and eating, and disposal of children's faeces. Three months after the start of the intervention and exactly 1 year after the baseline studies, a second diarrhoeal morbidity study and a second observational study were conducted in order to evaluate the intervention.\n## RESULTS\nChildren in intervention communities experienced an 11% reduction in the risk of reporting diarrhoea during the peak diarrhoeal season, compared to controls (P < 0.025). The largest differences were seen among children aged 24-35 months, with those from intervention communities reporting significantly fewer episodes, shorter mean durations and hence fewer days of diarrhoea. There was some evidence that greater reductions in diarrhoea occurred in sites where the quality of the intervention, a scored measure of volunteer efficacy and community participation, was highest.\n## CONCLUSIONS\nThe results of this study suggest that hygiene education may be an effective approach to reduce the incidence and duration of diarrhoeal episodes in rural Zaire. Children aged 2 years appear to benefit the most. A Hawthorne effect of the education may contribute to diarrhoeal reductions.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Prevention of diarrhoea and dysentery by hand washing.",
        "key_reference_abstract": "A 'non-blind' randomized hand washing intervention study was conducted in a low socioeconomic community in Rangoon to determine if hand washing by 494 children under 5 years old and their mothers could reduce the incidence of diarrhoea and dysentery in these children. Children and mothers in the intervention group were asked to wash their hands after defaecation and before preparing or eating their 3 main meals; 2 bars of plain soap were provided. The control group was left to follow customary practice. Diarrhoea and dysentery incidences in the 2 groups were monitored during 4 months by comparing the incidence density ratios (IDR). The diarrhoeal incidence among the children in the hand washing households was significantly lower than that among those in the control households (IDR = 0.70, 95% confidence interval (CI) = 0.54-0.92). For dysentery incidence, although there was a 40% reduction (IDR = 0.58, 95% CI = 0.22-1.55) in the children under 2 years, there seemed to be no impact in older children (IDR = 1.2, 95% CI = 0.52-2.80). The study indicates that hand washing is effective in reducing the morbidity from diarrhoea and dysentery.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Evaluation of an hygienic intervention in child day-care centers.",
        "key_reference_abstract": "The growing use of child day-care centers (CDCCs) has pro- duced a significant rise in morbidity due to infectious diseases which carry such consequences as discomfort, disability, and parental anxiety.\u20192 Haskins conservatively estimated the cost of day- care illnesses among children to be $1 .8 billion.3 To this must be added the cost of parents\u2019 and care givers\u2019 excess illness attribut- able to CDCCs. No published study describes a successful intervention to re- duce the risk of upper respiratory disease in CDCCs. Although many research groups have advocated hand washing and diapering hygiene as a means of reducing the spread of enteric disease in CDCCs,4\u201d there are only two controlled studies in the literature. In their pioneering work, Black et al showed the incidence of diarrhea in CDCCs following a rigorously monitored hand-washing program to be nearly twice that in intervention centers.\u20192 Bartlett et al monitored the impact of hand washing in randomly assigned CDCCs and found no intervention effect. However, rates of diarrhea were significantly lower among children in the actively monitored centers regardless of intervention status.\u20193 These studies share several limitations: the sources of incidence data were not blinded to center intervention status, the analyses did not statistically control for potential confounders, and nonindependence of multiple diarrhea episodes in the same child were not accounted for. The purposes of our study were to de- velop a feasible, multicomponent hygienic intervention and to carefully measure its impact while controlling for sources of bias. Use of trade names is for identification only and does not constitute endorsement by the Public Health Service, the Centers for Disease Control and Prevention, or any of the other co-spon- sors of this conference.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Hand-washing and diapering equipment reduces disease among children in out-of-home child care centers.",
        "key_reference_abstract": "## OBJECTIVE\nThe objective of this study was to determine whether the installation of equipment for diaper-changing, hand-washing, and food preparation that is specifically designed to reduce the transmission of infectious agents would result in a decrease in the rate of diarrheal illness among children and their teachers in child care centers.\n## METHODS\nTwenty-three pairs of child care centers were matched on size and star-rated license level. One member of each pair was randomly assigned to an intervention group and the other to a control group. Intervention centers received new diaper-changing, hand-washing, and food-preparation equipment, and both intervention and control centers received hygiene and sanitation training with reinforcement and follow-up as needed. Families with children in participating classrooms were called biweekly to ascertain the frequency and severity of any diarrheal illness episodes. Staff attendance was monitored, and staff hygiene and sanitation behaviors were observed and recorded monthly.\n## RESULTS\nAlthough hygiene and sanitation behaviors improved in both intervention and control centers, there was a significant difference favoring the intervention centers with respect to frequency of diarrheal illness (0.90 vs 1.58 illnesses per 100 child-days in control centers) and proportion of days ill as a result of diarrhea (4.0% vs 5.0% in control centers) among the children. Staff in those same classrooms were reported to have a significantly lower proportion of days absent as a result of any illness (0.77% in treatment centers versus 1.73% in control centers).\n## CONCLUSION\nDiapering, hand-washing, and food-preparation equipment that is specifically designed to reduce the spread of infectious agents significantly reduced diarrheal illness among the children and absence as a result of illness among staff in out-of-home child care centers.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Hand-washing, subclinical infections, and growth: a longitudinal evaluation of an intervention in Nepali slums.",
        "key_reference_abstract": "## OBJECTIVE\nWe conducted a longitudinal study to assess the impact of a hand-washing intervention on growth and biomarkers of child health in Nepali slums. This is the first study to evaluate the impact of hand-washing on markers of subclinical, asymptomatic infections associated with childhood growth faltering.\n## METHODS\nWe recruited a total sample of infants in the target age-range (3-12 months) living in the eight largest Kathmandu slums, allocating them to intervention (n = 45) and control (n = 43) groups. In intervention areas, a small-scale community-based hand-washing program was implemented for six months; in control areas, mothers continued their normal practices. Time series linear regression was used to assess the impact of the intervention on levels of morbidity, mucosal damage, immune stimulation and growth.\n## RESULTS\nAs expected, children with higher levels of mucosal damage exhibited worse growth over the period of the intervention (P = 0.01, <0.001 and 0.03 for height-for-age, weight-for-age, and weight-for-height z-scores, respectively). We observed a 41% reduction in diarrheal morbidity (P = 0.023) for the intervention group relative to control. However, the hand-washing intervention did not lower levels of mucosal damage or immune stimulation, nor slow growth faltering.\n## CONCLUSIONS\nReducing exposure to pathogens is an important global health priority. This study confirms the importance of hand-washing campaigns for reducing childhood morbidity. Yet our data suggest that promoting hand-washing is necessary but not sufficient to address chronic, subclinical infections. From a human biology standpoint, tackling the root causes of childhood infections is needed to address growth faltering in the context of highly contaminated slum environments.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "The impact of a community based health education program on the incidence of diarrheal disease in southern Thailand.",
        "key_reference_abstract": "This study has demonstrated that additional training of service providers [village health volunteers (VHVs), village health communicators (VHCs)] in combination with the mobilization of village leaders and influentials to promote selective preventive health behavior, can have a marked impact upon the effective practice of these behaviors and diarrheal incidence. Further, this impact can be achieved through the existing staff structure, ie, VHV/VHCs of the national health program. For example, increased contact between these service providers and mothers of children under 5 years through home visits and attendance at meetings held by the service providers, contributed positively to the practice of selected preventive behaviors. If the national program provided similar training inputs on the promotion of selected preventive behaviors and increased service provider contacts, the program's impact upon diarrheal disease would be enhanced.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Delayed effectiveness of home-based interventions in reducing childhood diarrhea, Karachi, Pakistan.",
        "key_reference_abstract": "We introduced home drinking water disinfection and handwashing with soap in Karachi squatter settlements to evaluate their effect on diarrhea. In April 2000, 150 households received soap, 76 received dilute bleach and a water storage vessel, and 76 were enrolled as controls. In 2000, among households wealthy enough to own a refrigerator, children in households that received bleach and a vessel had a 73% lower incidence of diarrhea than controls; those that received soap had a 56% lower incidence. There was no reduction in diarrhea in intervention households without a refrigerator. In 2001, households that received bleach and a vessel had a 71% lower incidence of diarrhea and children in households that received soap had a 35% lower incidence than controls. In 2001, the interventions were equally effective in households that had a refrigerator and those that did not. Both of these home-based interventions were ultimately effective in preventing diarrhea, but only households of slightly higher socioeconomic status changed their behavior quickly enough to benefit during the first summer.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nWashing hands with soap prevents diarrhea, but children at the highest risk of death from diarrhea are younger than 1 year, too young to wash their own hands. Previous studies lacked sufficient power to assess the impact of household handwashing on diarrhea in infants.\n## OBJECTIVE\nTo evaluate the effect of promoting household handwashing with soap among children at the highest risk of death from diarrhea.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cluster randomized controlled trial of 36 low-income neighborhoods in urban squatter settlements in Karachi, Pakistan. Field workers visited participating households at least weekly from April 15, 2002, to April 5, 2003. Eligible households located in the study area had at least 2 children younger than 15 years, at least 1 of whom was younger than 5 years.\n## INTERVENTIONS\nWeekly visits in 25 neighborhoods to promote handwashing with soap after defecation and before preparing food, eating, and feeding a child. Within intervention neighborhoods, 300 households (1523 children) received a regular supply of antibacterial soap and 300 households (1640 children) received plain soap. Eleven neighborhoods (306 households and 1528 children) comprised the control group.\n## MAIN OUTCOME MEASURE\nIncidence density of diarrhea among children, defined as the number of diarrheal episodes per 100 person-weeks of observation.\n## RESULTS\nChildren younger than 15 years living in households that received handwashing promotion and plain soap had a 53% lower incidence of diarrhea (95% confidence interval [CI], -65% to -41%) compared with children living in control neighborhoods. Infants living in households that received handwashing promotion and plain soap had 39% fewer days with diarrhea (95% CI, -61% to -16%) vs infants living in control neighborhoods. Severely malnourished children (weight for age z score, <-3.0) younger than 5 years living in households that received handwashing promotion and plain soap had 42% fewer days with diarrhea (95% CI, -69% to -16%) vs severely malnourished children in the control group. Similar reductions in diarrhea were observed among children living in households receiving antibacterial soap.\n## CONCLUSION\nIn a setting in which diarrhea is a leading cause of child death, improvement in handwashing in the household reduced the incidence of diarrhea among children at high risk of death from diarrhea.",
        "truth": "False"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Combining drinking water treatment and hand washing for diarrhoea prevention, a cluster randomised controlled trial.",
        "key_reference_abstract": "## OBJECTIVES\nTo evaluate the effectiveness of point of use water treatment with flocculent-disinfectant on reducing diarrhoea and the additional benefit of promoting hand washing with soap.\n## METHODS\nThe study was conducted in squatter settlements of Karachi, Pakistan, where diarrhoea is a leading cause of childhood death. Interventions were randomly assigned to 47 neighbourhoods. Households in 10 neighbourhoods received diluted bleach and a water vessel; nine neighbourhoods received soap and were encouraged to wash hands; nine neighbourhoods received flocculent-disinfectant water treatment and a water vessel; 10 neighbourhoods received disinfectant-disinfectant water treatment and soap and were encouraged to wash hands; and nine neighbourhoods were followed as controls. Field workers visited households at least once a week from April to December 2003 to promote use of the interventions and to collect data on diarrhoea.\n## RESULTS\nStudy participants in control neighbourhoods had diarrhoea on 5.2% of days. Compared to controls, participants living in intervention neighbourhoods had a lower prevalence of diarrhoea: 55% (95% CI 17%, 80%) lower in bleach and water vessel neighbourhoods, 51% (95% CI 12%, 76%) lower in hand washing promotion with soap neighbourhoods, 64% lower (95% CI 29%, 90%) in disinfectant-disinfectant neighbourhoods, and 55% (95% CI 18%, 80%) lower in disinfectant-disinfectant plus hand washing with soap neighbourhoods.\n## CONCLUSIONS\nWith an intense community-based intervention and supplies provided free of cost, each of the home-based interventions significantly reduced diarrhoea. There was no benefit by combining hand washing promotion with water treatment.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Bangladesh: a cluster randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nDiarrhoea and growth faltering in early childhood are associated with subsequent adverse outcomes. We aimed to assess whether water quality, sanitation, and handwashing interventions alone or combined with nutrition interventions reduced diarrhoea or growth faltering.\n## METHODS\nThe WASH Benefits Bangladesh cluster-randomised trial enrolled pregnant women from villages in rural Bangladesh and evaluated outcomes at 1-year and 2-years' follow-up. Pregnant women in geographically adjacent clusters were block-randomised to one of seven clusters: chlorinated drinking water (water); upgraded sanitation (sanitation); promotion of handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate child nutrition plus lipid-based nutrient supplements (nutrition); combined water, sanitation, handwashing, and nutrition; and control (data collection only). Primary outcomes were caregiver-reported diarrhoea in the past 7 days among children who were in utero or younger than 3 years at enrolment and length-for-age Z score among children born to enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCC01590095.\n## FINDINGS\nBetween May 31, 2012, and July 7, 2013, 5551 pregnant women in 720 clusters were randomly allocated to one of seven groups. 1382 women were assigned to the control group; 698 to water; 696 to sanitation; 688 to handwashing; 702 to water, sanitation, and handwashing; 699 to nutrition; and 686 to water, sanitation, handwashing, and nutrition. 331 (6%) women were lost to follow-up. Data on diarrhoea at year 1 or year 2 (combined) were available for 14\u2008425 children (7331 in year 1, 7094 in year 2) and data on length-for-age Z score in year 2 were available for 4584 children (92% of living children were measured at year 2). All interventions had high adherence. Compared with a prevalence of 5\u00b77% (200 of 3517 child weeks) in the control group, 7-day diarrhoea prevalence was lower among index children and children under 3 years at enrolment who received sanitation (61 [3\u00b75%] of 1760; prevalence ratio 0\u00b761, 95% CI 0\u00b746-0\u00b781), handwashing (62 [3\u00b75%] of 1795; 0\u00b760, 0\u00b745-0\u00b780), combined water, sanitation, and handwashing (74 [3\u00b79%] of 1902; 0\u00b769, 0\u00b753-0\u00b790), nutrition (62 [3\u00b75%] of 1766; 0\u00b764, 0\u00b749-0\u00b785), and combined water, sanitation, handwashing, and nutrition (66 [3\u00b75%] of 1861; 0\u00b762, 0\u00b747-0\u00b781); diarrhoea prevalence was not significantly lower in children receiving water treatment (90 [4\u00b79%] of 1824; 0\u00b789, 0\u00b770-1\u00b713). Compared with control (mean length-for-age Z score -1\u00b779), children were taller by year 2 in the nutrition group (mean difference 0\u00b725 [95% CI 0\u00b715-0\u00b736]) and in the combined water, sanitation, handwashing, and nutrition group (0\u00b713 [0\u00b702-0\u00b724]). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth.\n## INTERPRETATION\nNutrient supplementation and counselling modestly improved linear growth, but there was no benefit to the integration of water, sanitation, and handwashing with nutrition. Adherence was high in all groups and diarrhoea prevalence was reduced in all intervention groups except water treatment. Combined water, sanitation, and handwashing interventions provided no additive benefit over single interventions.\n## FUNDING\nBill & Melinda Gates Foundation.",
        "truth": "False"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Evaluating the impact of community health volunteer home visits on child diarrhea and fever in the Volta Region, Ghana: A cluster-randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nAlthough there is mounting evidence demonstrating beneficial effects of community health workers (CHWs), few studies have examined the impact of CHW programs focused on preventing infectious diseases in children through behavior changes. We assessed the preventive effects of community health volunteers (CHVs), who receive no financial incentive, on child diarrhea and fever prevalence in Ghana.\n## METHODS AND FINDINGS\nWe conducted a cluster-randomized controlled trial in 40 communities in the Volta Region, Ghana. Twenty communities were randomly allocated to the intervention arm, and 20 to the control arm, using a computer-generated block randomization list. In the intervention arm, CHVs were deployed in their own community with the key task of conducting home visits for health education and community mobilization. The primary outcomes of the trial were diarrhea and fever prevalence at 6 and 12 months among under-5 children based on caregivers' recall. Secondary outcomes included oral rehydration treatment and rapid diagnostic testing for malaria among under-5 children, and family planning practices of caregivers. Generalized estimating equations (GEEs) with a log link and exchangeable correlation matrix were used to determine the relative risk (RR) and 95% confidence intervals (CIs) for diarrhea, fever, and secondary outcomes adjusted for clustering and stratification. Between April 18 and May 4, 2015, 1,956 children were recruited and followed up until September 20, 2016. At 6 and 12 months post-randomization, 1,660 (85%) and 1,609 (82%) participants, respectively, had outcomes assessed. CHVs' home visits had no statistically significant effect on diarrhea or fever prevalence at either time point. After a follow-up of 12 months, the prevalence of diarrhea and fever was 7.0% (55/784) and 18.4% (144/784), respectively, in the control communities and 4.5% (37/825) and 14.7% (121/825), respectively, in the intervention communities (12-month RR adjusted for clustering and stratification: diarrhea, RR 0.73, 95% CI 0.37-1.45, p = 0.37; fever, RR 0.76, 95% CI 0.51-1.14, p = 0.20). However, the following were observed: improved hand hygiene practices, increased utilization of insecticide-treated bed nets, and greater participation in community outreach programs (p-values < 0.05) in the intervention group. In a post hoc subgroup analysis, the prevalence of diarrhea and fever at 6 months was 3.2% (2/62) and 17.7% (11/62), respectively, in the intervention communities with \u226570% coverage and a \u226530-minute visit duration, and 14.4% (116/806) and 30.2% (243/806) in the control communities (RR adjusted for clustering, stratification, baseline prevalence, and covariates: diarrhea, RR 0.23, 95% CI 0.09-0.60, p = 0.003; fever, RR 0.69, 95% CI 0.52-0.92, p = 0.01). The main limitations were the following: We were unable to investigate the longer-term effects of CHVs; the trial may have been underpowered to detect small to moderate effects due to the large decline in diarrheal and fever prevalence in both the intervention and control group; and caregivers' practices were based on self-report, and the possibility of caregivers providing socially desirable responses cannot be excluded.\n## CONCLUSIONS\nWe found no effect of CHVs' home visits on the prevalence of child diarrhea or fever. However, CHV programs with high community coverage and regular household contacts of effective duration may reduce childhood infectious disease prevalence.\n## TRIAL REGISTRATION\nInternational Standard Randomised Controlled Trial Registry, ISRCTN49236178.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effects on childhood infections of promoting safe and hygienic complementary-food handling practices through a community-based programme: A cluster randomised controlled trial in a rural area of The Gambia.",
        "key_reference_abstract": "## BACKGROUND\nThe Gambia has high rates of under-5 mortality from diarrhoea and pneumonia, peaking during complementary-feeding age. Community-based interventions may reduce complementary-food contamination and disease rates.\n## METHODS AND FINDINGS\nA public health intervention using critical control points and motivational drivers, delivered February-April 2015 in The Gambia, was evaluated in a cluster randomised controlled trial at 6- and 32-month follow-up in September-October 2015 and October-December 2017, respectively. After consent for trial participation and baseline data were collected, 30 villages (clusters) were randomly assigned to intervention or control, stratified by population size and geography. The intervention included a community-wide campaign on days 1, 2, 17, and 25, a reminder visit at 5 months, plus informal community-volunteer home visits. It promoted 5 key complementary-food and 1 key drinking-water safety and hygiene behaviours through performing arts, public meetings, and certifications delivered by a team from local health and village structures to all villagers who attended the activities, to which mothers of 6- to 24-month-old children were specifically invited. Control villages received a 1-day campaign on domestic-garden water use. The background characteristics of mother and clusters (villages) were balanced between the trial arms. Outcomes were measured at 6 and 32 months in a random sample of 21-26 mothers per cluster. There were no intervention or research team visits to villages between 6 and 32 months. The primary outcome was a composite outcome of the number of times key complementary-food behaviours were observed as a proportion of the number of opportunities to perform the behaviours during the observation period at 6 months. Secondary outcomes included the rate of each recommended behaviour; microbiological growth from complementary food and drinking water (6 months only); and reported acute respiratory infections, diarrhoea, and diarrhoea hospitalisation. Analysis was by intention-to-treat analysis adjusted by clustering. (Registration: PACTR201410000859336). We found that 394/571 (69%) of mothers with complementary-feeding children in the intervention villages were actively involved in the campaign. No villages withdrew, and there were no changes in the implementation of the intervention. The intervention improved behaviour adoption significantly. For the primary outcome, the rate was 662/4,351(incidence rate [IR] = 0.15) in control villages versus 2,861/4,378 (IR = 0.65) in intervention villages (adjusted incidence rate ratio [aIRR] = 4.44, 95% CI 3.62-5.44, p < 0.001), and at 32 months the aIRR was 1.17 (95% CI 1.07-1.29, p = 0.001). Secondary health outcomes also improved with the intervention: (1) mother-reported diarrhoea at 6 months, with adjusted relative risk (aRR) = 0.39 (95% CI 0.32-0.48, p < 0.001), and at 32 months, with aRR = 0.68 (95% CI 0.48-0.96, p = 0.027); (2) mother-reported diarrhoea hospitalisation at 6 months, with aRR = 0.35 (95% CI 0.19-0.66, p = 0.001), and at 32 months, with aRR = 0.38 (95% CI 0.18-0.80, p = 0.011); and (3) mother-reported acute respiratory tract infections at 6 months, with aRR = 0.67 (95% CI 0.53-0.86, p = 0.001), though at 32 months improvement was not significant (p = 0.200). No adverse events were reported. The main limitations were that only medium to small rural villages were involved. Obtaining laboratory cultures from food at 32 months was not possible, and no stool microorganisms were investigated.\n## CONCLUSIONS\nWe found that low-cost and culturally embedded behaviour change interventions were acceptable to communities and led to short- and long-term improvements in complementary-food safety and hygiene practices, and reported diarrhoea and acute respiratory tract infections.\n## TRIAL REGISTRATION\nThe trial was registered on the 17th October 2014 with the Pan African Clinical Trial Registry in South Africa with number (PACTR201410000859336) and 32-month follow-up as an amendment to the trial.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Health Outcomes of an Integrated Behaviour-Centred Water, Sanitation, Hygiene and Food Safety Intervention-A Randomised before and after Trial.",
        "key_reference_abstract": "Diarrhoeal disease in children under five in low income settings has been associated with multiple environmental exposure pathways, including complementary foods. Conducted from February to December 2018 in rural Malawi, this before and after trial with a control used diarrhoeal disease as a primary outcome, to measure the impact of a food hygiene intervention (food hygiene + handwashing) relative to a food hygiene and water, sanitation and hygiene (WASH) intervention (food hygiene + handwashing + faeces management + water management). The 31-week intervention was delivered by community-based coordinators through community events (",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "An investigation of the effects of a hand washing intervention on health outcomes and school absence using a randomised trial in Indian urban communities.",
        "key_reference_abstract": "## OBJECTIVES\nTo evaluate how an intervention, which combined hand washing promotion aimed at 5-year-olds with provision of free soap, affected illnesses among the children and their families and children's school absenteeism.\n## METHODS\nWe monitored illnesses, including diarrhoea and acute respiratory infections (ARIs), school absences and soap consumption for 41 weeks in 70 low-income communities in Mumbai, India (35 communities per arm).\n## RESULTS\nOutcomes from 847 intervention households (containing 847 5-year-olds and 4863 subjects in total) and 833 control households (containing 833 5-year-olds and 4812 subjects) were modelled using negative binomial regression. Intervention group 5-year-olds had fewer episodes of diarrhoea (-25%, 95% confidence intervals [CI] = -37%, -2%), ARIs (-15%, 95% CI = -30%, -8%), school absences due to illnesses (-27%, 95% CI = -41%, -18%) and eye infections (-46%, 95% CI = -58%, -31%). Further, there were fewer episodes of diarrhoea and ARIs in the intervention group for 'whole families' (-31%, 95% CI = -37%, -5%; and -14%, 95% CI = -23%, -6%, respectively), 6- to 15-year-olds (-30%, 95% CI = -39%, -7%; and -15%, 95% CI = -24%, -6%) and under 5 s (-32%, 95% CI = -41%, -4%; and -20%, 95% CI = -29%, -8%).\n## CONCLUSIONS\nDirect-contact hand washing interventions aimed at younger school-aged children can affect the health of the whole family. These may be scalable through public-private partnerships and classroom-based campaigns. Further work is required to understand the conditions under which health benefits are transferred and the mechanisms for transference.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Kenya: a cluster-randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nPoor nutrition and exposure to faecal contamination are associated with diarrhoea and growth faltering, both of which have long-term consequences for child health. We aimed to assess whether water, sanitation, handwashing, and nutrition interventions reduced diarrhoea or growth faltering.\n## METHODS\nThe WASH Benefits cluster-randomised trial enrolled pregnant women from villages in rural Kenya and evaluated outcomes at 1 year and 2 years of follow-up. Geographically-adjacent clusters were block-randomised to active control (household visits to measure mid-upper-arm circumference), passive control (data collection only), or compound-level interventions including household visits to promote target behaviours: drinking chlorinated water (water); safe sanitation consisting of disposing faeces in an improved latrine (sanitation); handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate maternal, infant, and young child feeding plus small-quantity lipid-based nutrient supplements from 6-24 months (nutrition); and combined water, sanitation, handwashing, and nutrition. Primary outcomes were caregiver-reported diarrhoea in the past 7 days and length-for-age Z score at year 2 in index children born to the enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704105.\n## FINDINGS\nBetween Nov 27, 2012, and May 21, 2014, 8246 women in 702 clusters were enrolled and randomly assigned an intervention or control group. 1919 women were assigned to the active control group; 938 to passive control; 904 to water; 892 to sanitation; 917 to handwashing; 912 to combined water, sanitation, and handwashing; 843 to nutrition; and 921 to combined water, sanitation, handwashing, and nutrition. Data on diarrhoea at year 1 or year 2 were available for 6494 children and data on length-for-age Z score in year 2 were available for 6583 children (86% of living children were measured at year 2). Adherence indicators for sanitation, handwashing, and nutrition were more than 70% at year 1, handwashing fell to less than 25% at year 2, and for water was less than 45% at year 1 and less than 25% at year 2; combined groups were comparable to single groups. None of the interventions reduced diarrhoea prevalence compared with the active control. Compared with active control (length-for-age Z score -1\u00b754) children in nutrition and combined water, sanitation, handwashing, and nutrition were taller by year 2 (mean difference 0\u00b713 [95% CI 0\u00b701-0\u00b725] in the nutrition group; 0\u00b716 [0\u00b705-0\u00b727] in the combined water, sanitation, handwashing, and nutrition group). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth.\n## INTERPRETATION\nBehaviour change messaging combined with technologically simple interventions such as water treatment, household sanitation upgrades from unimproved to improved latrines, and handwashing stations did not reduce childhood diarrhoea or improve growth, even when adherence was at least as high as has been achieved by other programmes. Counselling and supplementation in the nutrition group and combined water, sanitation, handwashing, and nutrition interventions led to small growth benefits, but there was no advantage to integrating water, sanitation, and handwashing with nutrition. The interventions might have been more efficacious with higher adherence or in an environment with lower baseline sanitation coverage, especially in this context of high diarrhoea prevalence.\n## FUNDING\nBill & Melinda Gates Foundation, United States Agency for International Development.",
        "truth": "False"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Water and hygiene interventions to reduce diarrhoea in rural Afghanistan: a randomized controlled study.",
        "key_reference_abstract": "A randomized controlled trial of four interventions was conducted using tubewells (n=2,486), liquid sodium hypochlorite ('Clorin') distributed with an improved water vessel (n=2,305), hygiene promotion (n=1,877), and a combination of the three (n=2,040) to create an evidence-base for water policy in Afghanistan. A fifth group served as a control (n=2,377). Interventions were randomized across 32 villages in Wardak province. Outcomes were measured through two household surveys separated by one year and twice-weekly household surveillance conducted over 16 months. The households receiving all three interventions showed reduction in diarrhoea compared with the control group, through both longitudinal surveillance data (IRR [95% CI]=0.61 [0.47-0.81]) and cross-sectional survey data (AOR [95% CI]=0.53 [0.30-0.93]). This reduction was significant when all household members were included, but did not reach significance when only children under five were considered. These results suggest multi-barrier methods are necessary where there are many opportunities for water contamination. Surveillance data suggested a greater impact of interventions on reducing diarrhoeal diseases than data from the surveys. Higher economic status as measured through household assets was associated with lower rates of diarrhoea and greater intervention uptake, excepting Clorin. Use of soap was also associated with lower prevalence of diarrhoea.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Impact of a hygiene curriculum and the installation of simple handwashing and drinking water stations in rural Kenyan primary schools on student health and hygiene practices.",
        "key_reference_abstract": "School-based hygiene and water treatment programs increase student knowledge, improve hygiene, and decrease absenteeism, however health impact studies of these programs are lacking. We collected baseline information from students in 42 schools in Kenya. We then instituted a curriculum on safe water and hand hygiene and installed water stations in half (\"intervention schools\"). One year later, we implemented the intervention in remaining schools. Through biweekly student household visits and two annual surveys, we compared the effect of the intervention on hygiene practices and reported student illness. We saw improvement in proper handwashing techniques after the school program was introduced. We observed a decrease in the median percentage of students with acute respiratory illness among those exposed to the program; no decrease in acute diarrhea was seen. Students in this school program exhibited sustained improvement in hygiene knowledge and a decreased risk of respiratory infections after the intervention.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Access to waterless hand sanitizer improves student hand hygiene behavior in primary schools in Nairobi, Kenya.",
        "key_reference_abstract": "Handwashing is difficult in settings with limited resources and water access. In primary schools within urban Kibera, Kenya, we investigated the impact of providing waterless hand sanitizer on student hand hygiene behavior. Two schools received a waterless hand sanitizer intervention, two schools received a handwashing with soap intervention, and two schools received no intervention. Hand cleaning behavior after toilet use was monitored for 2 months using structured observation. Hand cleaning after toileting was 82% at sanitizer schools (N = 2,507 toileting events), 38% at soap schools (N = 3,429), and 37% at control schools (N = 2,797). Students at sanitizer schools were 23% less likely to have observed rhinorrhea than control students (P = 0.02); reductions in student-reported gastrointestinal and respiratory illness symptoms were not statistically significant. Providing waterless hand sanitizer markedly increased student hand cleaning after toilet use, whereas the soap intervention did not. Waterless hand sanitizer may be a promising option to improve student hand cleansing behavior, particularly in schools with limited water access.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Measuring the effect of a hygiene behaviour intervention by indicators of behaviour and diarrhoeal disease.",
        "key_reference_abstract": "A social marketing approach used both qualitative and quantitative methods to develop a hygiene behaviour intervention in rural north-east Thailand. Behaviours were preselected from a previous study and the intervention was designed to promote hand washing, especially before feeding a baby, cooking, eating, and after defaecation or cleaning a baby's bottom, and dish washing immediately after eating. A bacteriological indicator (enumerating faecal streptococci using a finger impression technique) was developed to measure changes in hand washing behaviour and observation (spot checks) of dirty dishes to indicate dish washing practice. There was a significant improvement in both behaviours and a significant reduction in diarrhoeal disease as a result of the intervention. Furthermore, both indicators were retrospectively found to be positively related to diarrhoeal disease incidence. However, receiving and being able to recall the intervention messages was not necessarily sufficient to ensure behaviour change, as some adults found it difficult to change old habits. Villages showing the greatest improvement tended to have a stronger sense of community than others and to have more people actively involved in the intervention.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effect of infection control measures on the frequency of diarrheal episodes in child care: a randomized, controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nDiarrheal infections are common in children who attend child care, and preventing transmission of disease in this setting depends on actions by child care staff. We set out to discover whether transmission of gastrointestinal infections in child care could be reduced by improved infection control procedures.\n## METHODS\nWe performed a cluster randomized, controlled trial of an infection control intervention conducted in child care centers for 1 city in Australia. The intervention was training of child care staff about transmission of infection and handwashing and focused on both staff and child behavior. Implementation of the intervention was recorded by an observer. Illness was measured by parent report in telephone interviews every 2 weeks.\n## RESULTS\nThere were 311 child-years of surveillance for diarrheal episodes. The rate of episodes of diarrhea was 1.9 per child-year in intervention centers and 2.7 per child-year in control centers. Multivariable analysis showed that diarrheal episodes were significantly reduced in intervention center children by 50%. However, the impact of the intervention was confined to children over 24 months of age. For those centers in which children's compliance with handwashing was high, diarrheal episodes were reduced by 66%.\n## CONCLUSIONS\nThis trial supports education about infection control, for staff and children in child care, as a means of reducing transmission of diarrhea. Reduction in episodes of diarrhea in children in child care was limited to children over 24 months of age.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Hand washing with soap reduces diarrhoea and spread of bacterial pathogens in a Bangladesh village.",
        "key_reference_abstract": "Hand washing with soap and water can prevent the spread of diarrhoeal diseases in areas where comparatively costly interventions, such as supply of safe water and improved sanitation, are not possible. In this study, the practice of hand washing with soap and water was instituted in a periurban slum of Dhaka city, and the surveillance for diarrhoea sustained for a one-year period. Rates of primary and secondary attacks were compared to those of a non-intervention area similar in age structure, economic status, education, and other relevant variables. Rectal swabs of cases and contacts established aetiologies. There was a large (2.6 fold) reduction in diarrhoeal episodes in the intervention area during the observation period. Rates of bacterial pathogens were also lower in the intervention area. Significant reduction in diarrhoeal incidences was observed in all age groups for all pathogens except for rotavirus. These observations if implemented as health policy could reduce the spread of diarrhoeal diseases at low cost in high risk areas.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effect of handwashing on the incidence of diarrhoea in a Calcutta slum.",
        "key_reference_abstract": "Diarrheal diseases pose a major threat to the health of people living in developing countries, particularly where there is poverty and a poor environment. The effect of handwashing in reducing the incidence of diarrhea in day-care centers has been reported recently. The present study is a prospective community based study conducted to evaluate the effect of handwashing on the incidence of diarrheal disease in Calcutta slums. Handwashing was implemented in 1 slum and the other nearby slum, without handwashing program, served as control. The incidence of watery diarrhea during the 13 month period, between the study and control groups was not significantly different. However, the incidence of dysentery in individuals above 5 years of age in the control group was significantly higher as compared to those in the study group (p 0.05). The results of this study indicate that handwashing with soap may reduce the incidence of dysenteric cases in the community by interruption of transmission of the pathogens from 1 person to the other.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "An educational intervention for altering water-sanitation behaviors to reduce childhood diarrhea in urban Bangladesh. II. A randomized trial to assess the impact of the intervention on hygienic behaviors and rates of diarrhea.",
        "key_reference_abstract": "An educational intervention was designed to improve three water-sanitation behaviors empirically shown to be associated with high rates of childhood diarrhea in Dhaka, Bangladesh: lack of handwashing before preparing food, open defecation by children in the family compound, and inattention to proper disposal of garbage and feces, increasing the opportunity for young children to place waste products in their mouth. Fifty-one communities, each comprising 38 families, were randomized either to receive (n = 25) or not to receive (n = 26) the intervention. During the six months after the intervention, the rate of diarrhea (per 100 person-weeks) in children under six years of age was 4.3 in the intervention communities and 5.8 in the control communities (26% protective efficacy; p less than 0.0001). A corresponding improvement in handwashing practices before preparing food was noted, although no improvement was observed for defecation and waste disposal practices. These data suggest that educational interventions for water-sanitation practices can have an important beneficial effect upon childhood diarrhea in developing countries, particularly when the interventions are designed in a simple way to promote naturally occurring salutory behaviors that are empirically associated with lower rates of childhood diarrhea.",
        "truth": "False"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effects of hand hygiene campaigns on incidence of laboratory-confirmed influenza and absenteeism in schoolchildren, Cairo, Egypt.",
        "key_reference_abstract": "To evaluate the effectiveness of an intensive hand hygiene campaign on reducing absenteeism caused by influenza-like illness (ILI), diarrhea, conjunctivitis, and laboratory-confirmed influenza, we conducted a randomized control trial in 60 elementary schools in Cairo, Egypt. Children in the intervention schools were required to wash hands twice each day, and health messages were provided through entertainment activities. Data were collected on student absenteeism and reasons for illness. School nurses collected nasal swabs from students with ILI, which were tested by using a qualitative diagnostic test for influenza A and B. Compared with results for the control group, in the intervention group, overall absences caused by ILI, diarrhea, conjunctivitis, and laboratory-confirmed influenza were reduced by 40%, 30%, 67%, and 50%, respectively (p<0.0001 for each illness). An intensive hand hygiene campaign was effective in reducing absenteeism caused by these illnesses.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Hand-washing reduces diarrhoea episodes: a study in Lombok, Indonesia.",
        "key_reference_abstract": "Sixty-five mothers from Balai Lua, Central Lombok, Indonesia were given soap and an explanation of the faecal-oral route of diarrhoea transmission. This very simple health message was repeated and reinforced fortnightly when mothers were also asked whether any members of their family had suffered from diarrhoea over the previous 2 weeks. Children of these mothers experienced an 89% reduction in diarrhoea episodes compared to a control period before the intervention.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "A hand hygiene intervention to reduce infections in child daycare: a randomized controlled trial.",
        "key_reference_abstract": "Infections are common in children attending daycare centres (DCCs). We evaluated the effect of a hand hygiene (HH) intervention for caregivers on the incidence of gastrointestinal and respiratory infections in children. The intervention was evaluated in a two-arm cluster randomized controlled trial. Thirty-six DCCs received the intervention including HH products, training sessions, and posters/stickers. Thirty-five control DCCs continued usual practice. Incidence of episodes of diarrhoea and the common cold in children was monitored by parents during 6 months. Using multilevel Poisson regression, incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were obtained. Diarrhoeal incidence was monitored in 545 children for 91 937 days. During follow-up, the incidence was 3\u00b70 episodes per child-year in intervention DCCs vs. 3\u00b74 in control DCCs (IRR 0\u00b790, 95% CI 0\u00b773-1\u00b711). Incidence of the common cold was monitored in 541 children for 91 373 days. During follow-up, the incidence was 8\u00b72 episodes per child-year in intervention DCCs vs. 7\u00b74 in control DCCs (IRR 1\u00b707, 95% CI 0\u00b797-1\u00b719). In this study, no evidence for an effect of the intervention was demonstrated on the incidence of episodes of diarrhoea and the common cold.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Effectiveness of WASH Education to Prevent Diarrhea among Children under five in a Community of Patuakhali, Bangladesh",
        "key_reference_abstract": "Diarrhea is a leading cause of death among under five children in developing countries. The burden of child diarrhea in Bangladesh is still significant. Safe water, sanitation, and hygiene (WASH) can limit the events. This study aimed to assess the effectiveness of WASH education of mothers or caregivers on child diarrhea. A community-based randomized control trial was conducted in the selected households of a rural community in Dumki Upazila, Patuakhali from March\u2013June 2019. A total of 202 mothers/caregivers received intervention and 202 did not receive intervention. A pre-structured questionnaire was used to gather information on household WASH activities and diarrheal cases. Baseline data were collected first from the intervention group before providing education. WASH messages were given to the intervention group by face-to-face discussion. Both groups were followed up for diarrheal episodes for 3 months. Diarrheal prevalence of intervening group is compared with that of baseline and control. The results revealed that diarrheal prevalence was 11.4% (95% CI: 7.4\u201316.59%), 4.0% (95% CI: 1.7\u20137.65%), and 14.9% (95% CI: 10.25\u201320.52%) in baseline, intervention, and control group, respectively. Also, diarrhea was found lower in the intervention group than baseline (Z = \u2212 2.524; P value = 0.012) and control (Z = \u2212 1.85; P value = 0.04). WASH interventions were found effective to reduce the diarrheal episodes among under five children in rural community. Further investigation is necessary to assess the long-term effect of such intervention in other similar settings.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Promoting handwashing and sanitation: evidence from a large-scale randomized trial in rural Tanzania.",
        "key_reference_abstract": "The association between hygiene, sanitation, and health is well documented, yet thousands of children die each year from exposure to contaminated fecal matter. At the same time, evidence on the effectiveness of at-scale behavior change interventions to improve sanitation and hygiene practices is limited. This paper presents the results of two large-scale, government-led handwashing and sanitation promotion campaigns in rural Tanzania. For the campaign, 181 wards were randomly assigned to receive sanitation promotion, handwashing promotion, both interventions together, or neither. One year after the end of the program, sanitation wards increased latrine construction rates from 38.6 to 51 percent and reduced regular open defecation from 23.1 to 11.1 percent. Households in handwashing wards show marginal improvements in handwashing behavior related to food preparation, but not at other critical junctures. Limited interaction is observed between handwashing and sanitation on intermediate outcomes: wards that received both handwashing and sanitation promotion are less likely to have feces visible around their latrine and more likely to have a handwashing station close to their latrine facility relative to individual treatment groups. Final health effects on child health measured through diarrhea, anemia, stunting, and wasting are absent in the single-intervention groups. The combined-treatment group produces statistically detectable, but biologically insignificant and inconsistent, health impacts. The results highlight the importance of focusing on intermediate outcomes of take-up and behavior change as a critical first step in large-scale programs before realizing the changes in health that sanitation and hygiene interventions aim to deliver.",
        "truth": "True"
    },
    {
        "pmid": "35780792",
        "meta_analysis_title": "Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.",
        "meta_analysis_question": "What is the effectiveness of water, sanitation, and hygiene (WASH) interventions on reducing the risk of diarrhoeal disease in children in low-income and middle-income countries (LMICs)?",
        "criteria": "This systematic review and meta-analysis was conducted across multiple institutions, including WHO and the Institute for Health Metrics and Evaluation. On Sept 25, 2020, and again on June 23, 2021, we searched Ovid MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index (Web of Knowledge) using both key words and Medical Subject Headings terms. The search strategy and a full list of search terms are provided in appendix 1 (p 1). This search included literature published between Jan 1, 2016, and May 25, 2021. Including the results from two previous systematic reviews, this systematic review covered studies published from Jan 1, 1970.5, 18 Studies were included if they were published in a peer-reviewed scientific journal in English or French, or had been assessed according to transparent criteria for methodological quality in a previously conducted systematic review.",
        "subgroup": "Effects of hygiene interventions on risk of diarrhoea - All",
        "key_reference_title": "Handwashing behavior change at scale: evidence from a randomized evaluation in Vietnam.",
        "key_reference_abstract": "Handwashing with soap, which has been shown to reduce diarrhea in young children by as much as 48 percent, is frequently mentioned as one of the most effective and inexpensive ways to save children\u2019s lives. Yet rates of handwashing remain very low throughout the world. Handwashing with soap campaigns are de rigueur in developing countries, but little is known about their effectiveness. Few have been rigorously evaluated, and none on a large-scale. This paper evaluates a large-scale handwashing campaign in three provinces of Vietnam in 2010. Exposure to the campaign resulted in a slight increase in the availability of handwashing materials in the household, and caregivers in the treatment group were more likely to report washing hands at some of the times emphasized by the campaign. However, observed handwashing with soap at these times is low, and there isn\u2019t any difference between the treatment and control groups. As a result, no impact on health or productivity is found. These results suggest that even under seemingly optimal conditions, where knowledge and access to soap and water are not main constraints, behavior change campaigns that take place on a large scale face tradeoffs in terms of intensity and effectiveness.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study identified correlates of self-reports of being very depressed in the months after delivery in a population-based sample of women.\n## METHODS\nWe analyzed data on 14,609 recent mothers from the Centers for Disease Control and Prevention's (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS). The sample included mothers who delivered a live birth in Colorado, New York State, and North Carolina from 1996 (New York only) to 1999. We assessed risk factors for self-reports of being very depressed in the months after delivery using logistic regression.\n## RESULTS\nOverall, 5.9% (95% CI = 5.3, 6.4) of new mothers reported being very depressed in the months after delivery. Women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life\" had the highest prevalence of reporting being very depressed in the months after delivery (24.9%, 95% CI = 21.3, 28.5) and, when all risk factors were adjusted for simultaneously, were 4.6 times (95% CI = 3.1, 6.3) more likely to report being very depressed in the months after delivery than other women. Other significant risk factors for self-reports of being very depressed in the months after delivery included experiencing partner-associated stress (OR = 1.9, 95% CI = 1.5, 2.5), physical abuse during pregnancy (OR = 1.6, 95% CI = 1.1, 2.4), and not breast-feeding (OR = 1.4, 95% CI = 1.1, 1.8).\n## CONCLUSIONS\nThe highest prevalence for self-reports of being very depressed in the months after delivery was in women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life.\" Clinicians need to be aware of the needs of some women for mental health services both during and after pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Confinement and other psychosocial factors in perinatal depression: a transcultural study in Singapore.",
        "key_reference_abstract": "## BACKGROUND\nTo investigate the prevalence, socio-cultural and psychosocial risk factors for perinatal depression in Singaporean women.\n## METHOD\nA prospective cohort of 559 women was interviewed antenatally and at six weeks' postpartum at a tertiary hospital. Women were interviewed for diagnosis of depression using a two-stage design, with a screening questionnaire and diagnostic interview.\n## RESULTS\nPostnatally, a negative confinement experience was associated with depression. Other independent factors included poor emotional support, a past history of depression, unplanned pregnancy and perceived potential conflicts with relatives over childcare antenatally and dissatisfaction, poor instrumental support postnatally. The prevalence of depression antenatally and postnatally was 12.2% and 6.8%, respectively.\n## LIMITATIONS\nMeasures of satisfaction with social support were based on self-report; there were high dropout rates at six weeks' postpartum; and other modulating social factors such as pre-existing interpersonal conflicts were not studied.\n## CONCLUSIONS\nPerinatal depression in Singaporean women is common. Contrary to expectations, a negative 'confinement' experience is a significant risk factor for postnatal depression, and is not universally welcomed by women. Depression is modulated by dissimilar sets of psychosocial factors antenatally and postnatally.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice.",
        "key_reference_abstract": "## OBJECTIVE\nData are scarce regarding the sociodemographic predictors of antenatal and postpartum depression. This study investigated whether race/ethnicity, age, finances, and partnership status were associated with antenatal and postpartum depressive symptoms.\n## SETTING\n1662 participants in Project Viva, a US cohort study.\n## DESIGN\nMothers indicated mid-pregnancy and six month postpartum depressive symptoms on the Edinburgh postpartum depression scale (EPDS). Associations of sociodemographic factors with odds of scoring >12 on the EPDS were estimated.\n## MAIN RESULTS\nThe prevalence of depressive symptoms was 9% at mid-pregnancy and 8% postpartum. Black and Hispanic mothers had a higher prevalence of depressive symptoms compared with non-Hispanic white mothers. These associations were explained by lower income, financial hardship, and higher incidence of poor pregnancy outcome among minority women. Young maternal age was associated with greater risk of antenatal and postpartum depressive symptoms, largely attributable to the prevalence of financial hardship, unwanted pregnancy, and lack of a partner. The strongest risk factor for antenatal depressive symptoms was a history of depression (OR = 4.07; 95% CI 3.76, 4.40), and the strongest risk for postpartum depressive symptoms was depressive symptoms during pregnancy (6.78; 4.07, 11.31) or a history of depression before pregnancy (3.82; 2.31, 6.31).\n## CONCLUSIONS\nFinancial hardship and unwanted pregnancy are associated with antenatal and postpartum depressive symptoms. Women with a history of depression and those with poor pregnancy outcomes are especially vulnerable to depressive symptoms during the childbearing year. Once these factors are taken in account, minority mothers have the same risk of antenatal and postpartum depressive symptoms as white mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intentions and happiness among pregnant black women at high risk for adverse infant health outcomes.",
        "key_reference_abstract": "## CONTEXT\nUnintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman's feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.\n## METHODS\nA sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.\n## RESULTS\nPregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby's father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).\n## CONCLUSIONS\nAdditional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father's desire to have this child, may help improve prenatal care services and prevent adverse health outcomes.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Factors related to depression during pregnancy: are there gender differences?",
        "key_reference_abstract": "## OBJECTIVE\nTo determine gender differences between women and their partners in the effect of psychosocial and personal factors on depression during the third trimester of pregnancy.\n## METHOD\nA cross-sectional survey was carried out among 687 women and their partners (n = 669) attending the prenatal programme of Valencia province (Spain). Data collection was carried out by means of a self-reported questionnaire. The outcome variable was depression during the third trimester of pregnancy measured by the Edinburgh Postnatal Depression Scale. Predictor variables were psychosocial (marital dissatisfaction, confidant and affective social support) and personal (previous history of depression, partner depression and unplanned pregnancy) variables. The adjusted odds ratios (aOR) and their 95% confidence intervals were calculated by fitting a logistic regression model.\n## RESULTS\nThe prevalence of pregnancy depression was higher among women (10.3%) than men (6.5%). In both sexes, the probability of depression during pregnancy was higher in those with marital dissatisfaction (aOR 3.05, 95% CI 1.59 to 5.82 for women and 3.14, 95% CI 1.24 to 7.99 for men) and among those whose with a previous history of depression (aOR 2.18, 95% CI 1.22 to 3.89 for women and 5.22, 95% CI 2.05 to 13.34 for men). Unplanned pregnancy did not increase the risk of pregnancy depression either in women or men. Gender differences were found on the impact of social support and partner's depression. Whereas among men low affective social support and partner depression were associated with a higher probability of reporting depression, none of these variables were related to women's depression.\n## CONCLUSION\nMost predictor factors of depression during pregnancy are similar for both sexes but a gender-different impact of social support and partner depression on pregnancy depression was appreciated. Health professionals should be aware of potentially vulnerable groups for early diagnosis of pregnancy depression and to provide effective interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Psychosocial risk factors for depression during pregnancy.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the prevalence of antenatal depressive disorder in different trimesters and to evaluate the relation of psychosocial risk factors to antenatal depressive disorder.\n## DESIGN\nCohort follow-up.\n## SETTING\nUniversity Hospital, Kaunas, Lithuania.\n## SAMPLE\nTwo hundred and thirty pregnant women consecutively admitted.\n## METHODS\nAt 12-16 weeks, 22-26 weeks, and 32-36 weeks of pregnancy, participants were screened for depression using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). Women who gave at least one positive answer to the CIDI-SF depression-screening question were evaluated for depressive disorder using the non-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). Psychosocial stressors and two Big Five Personality dimensions, neuroticism and extraversion, were also evaluated.\n## MAIN OUTCOME MEASURES\nPrevalence of depressive disorder.\n## RESULTS\nThe prevalence of the antenatal depressive disorder at 12-16 weeks' gestation was 6.1%, at 22-26 weeks 3.5%, and at 32-36 weeks 4.4%. In the first trimester, a greater prevalence of current depressive disorder was independently associated with unplanned and unwanted pregnancy, high neuroticism, low education, and a previous history of depression; in the second trimester with unplanned and unwanted pregnancy and high neuroticism; in the third trimester with unplanned and unwanted pregnancy, high neuroticism, and the occurrence of psychosocial stressors during the last year.\n## CONCLUSIONS\nThe highest prevalence of depressive disorders was found in the first trimester, the lowest in mid-pregnancy. Several determinants (unwanted and unplanned pregnancy, high neuroticism) were independent predictors of antenatal depressive disorders throughout whole pregnancy, while other determinants (low education, previous history of depression, the occurrence of psychosocial stressors at the end of pregnancy) were trimester specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Unintended pregnancy and associated maternal preconception, prenatal and postpartum behaviors.",
        "key_reference_abstract": "## BACKGROUND\nThis study was conducted to determine the relationship between unintended pregnancy and maternal behaviors before, during and after pregnancy.\n## STUDY DESIGN\nData were analyzed from a stratified random sample of 9048 mothers who delivered live born infants between 2001 and 2006 and completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey 2 to 9 months after delivery. Binary and ordinal logistic regression methods with appropriate survey weights were used to control for socio-demographic factors.\n## RESULTS\nCompared to women with intended pregnancies, mothers with unwanted pregnancies were more likely to consume less than the recommended amount of preconception folic acid [adjusted odds ratio (OR) 2.39, 95% confidence interval (CI) 1.7-3.2], smoke prenatally (OR 2.03, 95% CI 1.5-2.9), smoke postpartum (OR 1.86, 95% CI 1.35-2.55) and report postpartum depression (OR 1.98, 95% CI 1.48-2.64); they were less likely to initiate prenatal care during the first trimester (OR 0.34, 95% CI 0.3-0.5) and breastfeed for 8 or more weeks (OR 0.74, 95% CI 0.57-0.97). Compared to women with intended pregnancies, women with mistimed pregnancies were also more likely to consume inadequate folic acid, delay prenatal care and report postpartum depression.\n## CONCLUSION\nEven after controlling for multiple socio-demographic factors, unwanted and mistimed pregnancies were associated with unhealthy perinatal behaviors.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Antenatal depression and male gender preference in Asian women in the UK.",
        "key_reference_abstract": "## OBJECTIVE\nto identify the prevalence of antenatal depression among Asian women living in the UK in one antenatal clinic, and to investigate the possible association with a desire for a male child and other risk factors.\n## DESIGN\ncross-sectional questionnaire-based study.\n## SETTING\ngeneral antenatal clinic in a hospital in Birmingham.\n## PARTICIPANTS\n300 Asian women, irrespective of place of birth.\n## METHODS\nconsecutive Asian women attending routine antenatal appointments during the study period self-completed a questionnaire. The first part investigated socio-demographic, cultural and other possible risk factors, including gender preference. The second part comprised the Edinburgh Postnatal Depression Scale (EPDS).\n## MEASUREMENTS\nEPDS score greater than or equal to 12 indicating probable depression.\n## FINDINGS\nthe prevalence of depression was 30.7% (92/300, 95% confidence interval 25.4-35.9%). Maternal male gender preference was not common and was not associated with antenatal depression. Family male gender preference, unplanned pregnancy, a history of depression and feeling anxious in pregnancy were independently associated with an increased likelihood of depression, whilst support from family and friends, being satisfied with pregnancy and being multiparous were associated with a reduced likelihood of depression.\n## CONCLUSION\nrates of antenatal depression were very high in Asian women with some associated risk factors. However, male gender preference was not associated with antenatal depression.\n## IMPLICATIONS FOR PRACTICE\ngiven the high prevalence, screening Asian women for depression may be indicated to allow treatment.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intention, demographic differences, and psychosocial health.",
        "key_reference_abstract": "## OBJECTIVES\nWe explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies.\n## METHODS\nData from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes.\n## RESULTS\nSixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups.\n## CONCLUSIONS\nFully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Obstetric and psychosocial risk factors for depressive symptoms during pregnancy.",
        "key_reference_abstract": "We aimed to determine the psychosocial and obstetric correlates of depressive symptomatology during pregnancy in South-Eastern Hungary. A total of 1719 women were screened for depression in four counties in 2006 and 2007, based on a Leverton Questionnaire (LQ) score of \u226512 at 14-24 weeks of gestation. The LQ scores indicated a probable depressive illness (PDI) in 17.2% of the study group. The best predictors in a multiple regression analysis were history of major depression (adjusted odds ratio [AOR]=3.23), and major life events (AOR=2.43). A perceived lack of social support from partner (AOR=1.79) and lack of support by family (AOR=1.23) were also significant determinants. Lack of planning of pregnancy (AOR=1.12) and a history of unfavourable obstetric outcome (AOR=1.42) also seem to predispose to PDI. Overall, psychosocial factors appeared important in the prediction of PDI, whereas economic features did not.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Unintended pregnancy and postpartum depression among first-time mothers.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is a mental disorder that occurs after birth and has negative consequences for the mother, infant, and family. The objective of this secondary analysis was to examine whether pregnancy intention was associated with postpartum depression among first-time mothers.\n## METHODS\nThe First Baby Study is a prospective cohort study of women aged 18-35 having a first singleton birth in Pennsylvania. Baseline data were collected during the third trimester. Postpartum depressive symptoms were measured at 1-month postpartum using the Edinburgh Postnatal Depression Scale. Logistic regression was performed to examine the association between unintended pregnancy and postpartum depression, controlling for prepregnancy anxiety/depression and sociodemographic data.\n## RESULTS\nOf 2972 first-time mothers, 83.4% were white, 70.7% were married, and 56.9% were college educated. Nine hundred fifty-two women (32.0%) reported their pregnancy was unintended and 151 (5.1%) met the threshold for postpartum depression. The prevalence of postpartum depression was higher in women with unintended pregnancies compared to women with intended pregnancies (6.7% vs. 4.3%, p<0.01). However, after controlling for confounders, unintended pregnancy was no longer associated with postpartum depression (adjusted OR 1.41; 95% CI 0.91-2.18). Variables independently associated with postpartum depression included prepregnancy anxiety/depression, Asian race, and Hispanic ethnicity.\n## CONCLUSION\nPregnancy intention was not independently associated with postpartum depression among first time mothers in Pennsylvania.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "The effect of pregnancy intention on maternal prenatal behaviours and parent and child health: results of an irish cohort study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors.\n## METHODS\nThis study uses data from the first wave of the 'Growing Up in Ireland Study', a large nationally representative cohort study of more than 11\u2009000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours.\n## RESULTS\nThe study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]).\n## CONCLUSIONS\nAscertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "From antenatal to postnatal depression: associated factors and mitigating influences.",
        "key_reference_abstract": "## INTRODUCTION\nPostnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression.\n## METHODS\nThe study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables.\n## RESULTS\nRisk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression.\n## CONCLUSION\nThis study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Intendedness of pregnancy and other predictive factors for symptoms of prenatal depression in a population-based study.",
        "key_reference_abstract": "Prenatal depression (PD) as a risk factor for adverse birth outcomes is well documented. Less is known about maternal risks for PD, which could inform preventive strategies for perinatal and interconceptional care. This exploratory study investigates associations between prenatal depression symptoms and unintended and mistimed pregnancies and other maternal risk factors for PD. A subset of birth records from the New York Statewide Perinatal Data System (n = 19,219) was used in this secondary analysis of cross-sectional data. Univariate and multivariate multinomial regression was used to identify factors that are independently associated with four self-reported levels of prenatal depression symptoms. Women with unintended pregnancies were more likely (AOR, 95 % CI) to report severe (3.6, 2.6-5.1) or moderate (2.0, 1.6-2.5) prenatal depression symptoms and less likely to report no symptoms, compared to women with intended pregnancies. Likewise, women with mistimed pregnancies were more likely to report severe (2.7, 2.2-3.5) or moderate (1.7, 1.5-2.1) prenatal depression symptoms than no symptoms, compared to women with intended pregnancies. Low education, drug use, smoking, minority race, being unmarried and having Medicaid insurance were also significant, independent predictors of PD symptoms. Results suggest that routine screening for depression, intendedness of pregnancy and other associated risk factors such as smoking and drug use during prenatal and interconceptional care visits may enable coordinated interventions that can reduce prenatal depression and unintended and mistimed pregnancies and improve pregnancy outcomes.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Impact of unintended pregnancy on maternal mental health: a causal analysis using follow up data of the Panel Study on Korean Children (PSKC).",
        "key_reference_abstract": "## BACKGROUND\nPregnancy intention is important for maternal and child health outcomes. The purpose of this study was to examine the causal relation between pregnancy intention and maternal depression and parenting stress in Korean women who gave birth during 2008.\n## METHODS\nThis study is a retrospective evaluation of prospectively collected data from the Panel Study on Korean Children from 2008 to 2010. Causal analyses were conducted using propensity score matching and inverse probability of treatment weighted methods. In addition, mediation analyses were performed to test mitigating effects of marital conflict, fathers' participation in childcare, and mothers' knowledge of infant development on the relation between unintended pregnancy and adverse maternal mental health.\n## RESULTS\nResults showed that the overall effect of an unintended pregnancy on maternal depression and parenting stress was statistically significant. An unintended pregnancy was associated with 20-22% greater odds of maternal depression, 0.28-0.39 greater depression score, and 0.85-1.16 greater parenting stress score. Relations between pregnancy intention and maternal depression, maternal depression score and parenting stress score were moderately explained by marital conflict and fathers' participation in childcare.\n## CONCLUSIONS\nUnintended pregnancy contributed to increased risks of maternal depression and parenting stress. Efforts to increase fathers' participation in childcare and decrease marital conflict might be helpful to mitigate adverse impacts of unintended pregnancy on perinatal maternal mental health.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Risk factors of transient and persistent anxiety during pregnancy.",
        "key_reference_abstract": "## PURPOSE\nchronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada.\n## METHODS\nwomen with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup.\n## FINDINGS\nwomen with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85-13.39) were unique predictors of chronic depressive symptoms.\n## CONCLUSIONS\nknowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Are pregnancy planning and pregnancy timing associated with maternal psychiatric illness, psychological distress and support during pregnancy?",
        "key_reference_abstract": "## BACKGROUND\nPregnancy planning and timing may be associated with psychiatric illness, psychological distress and support during pregnancy.\n## METHODS\nWe performed secondary analyses of a prospective cohort of 2654 pregnant women evaluating the impact of depression on preterm birth. We used multivariable logistic regression to test associations between pregnancy planning (\"Was this pregnancy planned? Yes/No\") and/or timing (\"Do you think this is a good time for you to be pregnant?\") with Composite International Diagnostic Interview generated psychiatric diagnoses and measures of psychological distress and support.\n## RESULTS\n37% and 13% of participants reported an unplanned or poorly timed pregnancy, respectively. Unplanned pregnancies were associated with a Major Depressive Episode (MDE) (adjusted odds ratio (aOR) 1.69, 95%CI 1.23-2.32) and the Cohen Perceived Stress Scale's (CPSS) highest quartile (aOR 1.74, 95%CI 1.40-2.16). Poorly timed pregnancies were associated with a MDE (aOR 3.47, 95%CI 2.46-4.91) and the CPSS's highest quartile (aOR 5.20, 95%CI 3.93-6.87). Poorly timed pregnancies were also associated with General Anxiety Disorder (GAD; aOR 1.60, 95%CI 1.07-2.40), and the modified Kendler Social Support Inventory's (MKSSI) lowest quartile (aOR 1.64, 95%CI 1.25-2.16). Psychiatric conditions were strongly associated with planned pregnancies that were subsequently deemed poorly timed (MDE=aOR 5.08, 95%CI 2.52-10.25; GAD=aOR 2.28, 95%CI 1.04-5.03); high CPSS=aOR 6.48, 95%CI 3.59-11.69; and low MKSSI=aOR 3.19, 95%CI 1.81-5.62.\n## LIMITATIONS\nParticipant characteristics may limit generalizability of findings.\n## CONCLUSIONS\nPregnancy timing was a stronger predictor of maternal psychiatric illness, psychological distress and low social support than pregnancy planning in our cohort.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs).\n## METHODS\nUsing Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross-sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design.\n## RESULTS\nIn multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23-2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs.\n## CONCLUSIONS\nThis study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "The association between pregnancy intendedness and experiencing symptoms of postpartum depression among new mothers in the United States, 2009 to 2011: A secondary analysis of PRAMS data.",
        "key_reference_abstract": "Postpartum depression (PPD) is a form of major depressive disorder affecting approximately 13% of women worldwide. Unintended pregnancies, reaching close to 50% of the pregnancies in the United States, have become a major health concern. While many physiologic and psychosocial causes have been analyzed, few studies have examined the relationship between unintended pregnancy and symptoms of PPD.A cross-sectional study was conducted using surveillance data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2009 to 2011. The PRAMS population-based random sample included women who have had recent live births and is representative of 78% of the United States population. The chi-squared test was used to examine bivariate associations. Binary logistic regression was utilized to study unadjusted and adjusted associations between PPD and pregnancy intendedness, as well as other demographic and clinical characteristics of mothers in the sample. Multicollinearity in the adjusted model was evaluated using variance inflation factors. Sampling weights were used to account for PRAMS' complex sampling design.Of the 110,231 mothers included in the sample, only 32.3% reported desiring the pregnancy at the time of conception. Women with pregnancies categorized as mistimed: desired sooner, mistimed: desired later, or unwanted were 20% (adjusted odds ratio [AOR]\u200a=\u200a1.2; 95% confidence interval [CI]: 1.1-1.3), 30% (AOR\u200a=\u200a1.3; 95% CI: 1.2-1.4), and 50% (AOR\u200a=\u200a1.5; 95% CI: 1.3-1.7) more likely to experience symptoms of PPD, respectively, compared to women with desired pregnancies. Other factors found to be associated with experiencing symptoms of PPD were a gestational age of <27 weeks (AOR\u200a=\u200a3.1; 95% CI: 2.5-4.0), having a previous history of depression (AOR\u200a=\u200a1.8; 95% CI: 1.6-2.0), and being abused during or before pregnancy (AOR\u200a=\u200a1.6; 95% CI: 1.4-2.0).We found that women with mistimed or unwanted pregnancies were more likely to experience symptoms of PPD. Our findings support the current US Preventive Services Task Force and American Academy of Pediatrics recommendations for an integrated approach to screening for depression, aiding in the maximization of intervention and early referral for women at risk for PPD.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Psychosocial status and prenatal care of unintended pregnancies among low-income women.",
        "key_reference_abstract": "## BACKGROUND\nNearly half of all pregnancies in the United States are reported as unintended and rates are highest among women of low socioeconomic status. The purpose of this study was to examine the associations between unintended pregnancies and maternal mental health and timing of prenatal care among low-income women.\n## METHODS\nIn this cross-sectional study, 870 women, whom were participating in the First 1000\u2009Days program in three community health centers in the Boston area, were enrolled at their first prenatal visit from August 2016 - September 2017. We assessed pregnancy intention by self-report using the Pregnancy Risk Assessment Monitoring System. We used self-reported survey information and electronic health record data to assess the following outcomes: current stress, current depression, and timing of initial prenatal visit. We used multivariable logistic regression models to examine associations and adjusted for sociodemographic factors.\n## RESULTS\nWomen were a mean (SD) age of 29.3 (6.1), and 39.2% reported that their pregnancy was unintended. 50.6% of women were Hispanic, 28.4% were White, 10.1% were Black, and 10.9% were other races. 78.9% of women reported an annual household income <$50,000. Overall, 26.7% of women reported current stress, 8.2% reported current depression, and 18.3% of women initiated prenatal care after their first trimester. In multivariable analyses, women with unintended pregnancies had higher odds of experiencing current stress (OR: 1.72; 95% CI: 1.22, 2.41), current depression (OR: 1.83; 95% CI: 1.04, 3.20), and initiation of prenatal care post-first trimester (OR: 1.84; 95% CI: 1.23, 2.74).\n## CONCLUSIONS\nUnintended pregnancies were associated with current stress and depression, and delayed prenatal care in this sample of low-income women suggesting the importance of identifying high-risk women and tailoring interventions to support women's needs.\n## TRIAL REGISTRATION\nClinicalTrials.gov (NCT03191591; Retrospectively registered on June 19, 2017).",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "The Role of Father Involvement and Intimate Partner Violence on Postnatal Depression Among Women With Unintended Pregnancy.",
        "key_reference_abstract": "This study set out to fill the research gap by including various aspects of father involvement and intimate partner violence (IPV) in the examination of the association between unintended pregnancy and maternal postnatal depression (PND). This study aimed to examine the effect of father involvement and IPV on the association between unintended pregnancy and PND. A sample of 1,083 pregnant women who attended antenatal clinic at selected hospitals in Hong Kong completed two surveys to report on their pregnancy intention, antenatal depression, PND, IPV during pregnancy, their partner's (i.e., father's) involvement during pregnancy and after childbirth, and perceived social support. Comparisons were made between women with unintended pregnancy and those with intended pregnancy, and the effects of unintended pregnancy, father involvement, IPV, and other factors on maternal PND were examined. Results show that women with unintended pregnancy were more likely to report PND, IPV, fear, postnatal stress, lower degree of father involvement, and lower level of social support. Unintended pregnancy independently increased the risk of PND by 1.95 times (95% confidence interval [CI] = [1.15, 3.28]), after adjustment for all other variables. When father involvement was included in the regression model, the negative effects of IPV and the related fear on PND became nonsignificant. The positive association between unintended pregnancy and PND was robust. Father involvement might help promote maternal health by reducing the negative effects of IPV on PND.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Do Pregnancy Intentions Matter? A Research Note Revisiting Relationships Among Pregnancy, Birth, and Maternal Outcomes.",
        "key_reference_abstract": "The prevention of unplanned or unintended pregnancies continues to be a cornerstone of U.S. reproductive health policy, but the evidence that such pregnancies cause adverse maternal and child outcomes is limited. In this research note, we examine these relationships using recent large-scale data and inverse propensity weights estimated from generalized boosted models. We find that pregnancy timing is related to maternal experience during pregnancy, but not to infant outcomes at birth-both of which are consistent with prior research. In an addition to the literature, we show that pregnancy timing is relevant for a number of maternal outcomes, such as the onset of depression and intimate partner violence, changes in smoking behavior, and receipt of medical care. These findings suggest that policy intended to improve infant welfare by preventing unintended pregnancies has little empirical support, but that policy focused on increasing reproductive autonomy and maternal well-being has the potential to improve outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy planning and acceptance and maternal psychological distress during pregnancy: results from the National Perinatal Survey, France, 2016.",
        "key_reference_abstract": "## BACKGROUND\nStudies report heightened risks of mental health problems among women who experience an unintended pregnancy, but few consider the complexity of pregnancy intentions. In this study, we evaluate how different dimensions of pregnancy intentions (pregnancy planning and pregnancy acceptance) relate to two maternal depressive symptoms and perceived psychological distress.\n## METHODS\nThis study draws from a cross-sectional national survey conducted in all maternities in France over a one-week period in 2016. All mothers 18\u2009years and older who had a live birth during the study period were invited to participate. After excluding women who underwent infertility treatment, our analytical sample included 10,339 women. We first described levels and correlates of pregnancy planning and acceptance, defined in four categories; planned/welcomed, unplanned/welcomed, planned/unwelcomed, unplanned/unwelcomed. We then assessed the bivariate and multivariate associations between pregnancy planning and acceptance and two outcomes: women's self-perceived psychological health and the presence of two depressive symptoms during pregnancy. We used multivariate logistic regressions to evaluate these associations, after adjusting for socio-demographic and medical factors.\n## RESULTS\nAltogether 7.5 to 24.1% of mothers perceived their psychological health during pregnancy was poor, according to pregnancy planning and acceptance categories and 10.3 to 22.4% indicated feelings of sadness and loss of interest during pregnancy, according to pregnancy planning and acceptance categories. As compared to women with planned/welcomed pregnancies, the odds of perceived poor psychological health and depressive symptoms were 2.55 times (CI 2.20-2.95) and 1.75 times higher (CI 1.51-2.02), respectively, among unplanned/unwelcomed pregnancies and 2.02 (CI 1.61-2.53) and 2.07 (CI 1.7-2.5) higher, among planned/unwelcomed pregnancies. Among women with unplanned pregnancies, we also found higher odds of perceived poor psychological health among women whose pregnancy was unwelcomed while the odds of depressive symptoms were not different by pregnancy planning status among women with unwelcomed pregnancies.\n## CONCLUSIONS\nThese findings consolidate previous reports of the association between pregnancy intentions and maternal psychological distress, while further specifying the relationship, which mostly depends on the acceptance of pregnancy timing rather than on pregnancy planning. Identifying women with low pregnancy acceptance can potentially enhance current medical practice by improving early detection of maternal depression.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors.\n## METHODS\nIn 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy.\n## RESULTS\nWomen who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester.\n## CONCLUSIONS\nWomen with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Unintended pregnancy and intimate partner violence before and during pregnancy among Latina women in Los Angeles, California.",
        "key_reference_abstract": "The purpose of this paper was to examine the relationship between unintended pregnancy and intimate partner violence (IPV) before and during pregnancy among Latinas. A cross-sectional interview measuring pregnancy intent, IPV, and acculturation, using the Acculturation Rating Scale for Mexican Americans (ARSMA-II), was conducted among Latina women in their 2(nd) or 3(rd) trimester of pregnancy at clinics in Los Angeles (n = 313). Overall, 44% of women reported an unintended pregnancy. The prevalence of physical (any) and emotional (only) abuse 12 months before pregnancy was 11% and 22%, respectively. Although both types of IPV decreased during pregnancy (10% and 19%, respectively), most reports of physical IPV during pregnancy (53%) were among women who did not report physical abuse before pregnancy. After adjusting for other factors, physical IPV before pregnancy was not associated with unintended pregnancy (adjusted OR = 0.92; 95% CI = 0.40, 2.16). The prevalence of unintended pregnancy was highest (76%) among highly acculturated Latinas. However, when an unintended pregnancy occurred among less acculturated Latinas, who comprised the majority of the sample (n = 270), it was associated with greater risk of physical IPV during pregnancy (unadjusted OR = 2.57; 95% CI = 1.06, 6.23); although the confidence interval included one after adjusting for other factors (adjusted OR = 2.79; 95% CI = 0.98, 7.92). An unintended pregnancy may have a unique impact on relationships in the context of Latino culture, where family and pregnancy are highly valued. Pregnancy often creates an opportunity for providers to discuss issues related to abuse and family planning with women who do not regularly access care. The results from this study may be used to increase the cultural sensitivity with which violence and reproductive health are addressed among the diverse population of Latinas when they connect with prenatal services.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Severity of intimate partner abuse indicators as perceived by women in Mexico and the United States.",
        "key_reference_abstract": "## OBJECTIVE\nWomen in Cuernavaca, Mexico and Los Angeles, California were surveyed to examine differences in their perceptions of the severity of domestic violence indicators.\n## METHODS\nOne hundred twenty women in each country rated the severity of 26 domestic violence indicators which were part of an abuse screen used for an ongoing study of the prevalence of abuse. Rasch analysis was conducted to determine the linear relationship in the perceptions of the severity of each event between the two countries.\n## RESULTS\nThe Rasch calibrated logit values show that women in the US rated 24 of the 26 events as more severe than women in Mexico. However, items were ranked in similar order and a clear linear pattern was established. In both countries, being shot with a gun was the most severe event and a partner becoming jealous was the least severe.\n## CONCLUSION\nThe country of origin did not dictate which events were most severe but did influence how severe these events were perceived.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse.\n## METHODS\nA prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used.\n## RESULTS\nApproximately one-fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68).\n## CONCLUSION\nWomen who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Early Childhood Victimization and Physical Intimate Partner Violence During Pregnancy: A Developmental and Person-Oriented Approach.",
        "key_reference_abstract": "Intimate partner violence (IPV) victimization during pregnancy is a major public health concern, yet little is known about how risk factors for IPV during pregnancy may depend on whether women have histories of victimization dating back to early childhood (ages 0-5 years). This study examined whether risk factors for physical IPV victimization during pregnancy (a pregnancy that was not planned and prenatal substance use) differed for women with versus without early childhood victimization. Participants were 236 ethnically diverse, low-income biological mothers ( M = 30.94 years; 50.0% Latina, 16.9% Caucasian, 13.1% African American, and 16.9% multiracial) of children aged 0 to 6 years. Mothers were classified into four groups based on whether they had experienced early childhood victimization and physical IPV victimization during pregnancy with the target child. Multinomial logistic regressions, controlling for demographic characteristics, examined whether a pregnancy not planned and prenatal substance use predicted group membership. Compared to mothers with early victimization only, mothers with both early childhood victimization and physical IPV during pregnancy were more than 3 times as likely to report that their pregnancy with the target child was not planned. In follow-up analyses, mothers with early victimization and physical IPV during pregnancy also reported higher lifetime parity than mothers with physical IPV during pregnancy but no early victimization. Early childhood victimization may place women on a risk pathway to physical IPV during pregnancy, particularly if the pregnancy is not planned. Prevention and policy efforts should screen women for early childhood victimization to understand risks for physical IPV during pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "The effect of pregnancy intention on child development.",
        "key_reference_abstract": "In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Unintended pregnancy and preterm birth.",
        "key_reference_abstract": "About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intention and its relationship to birth and maternal outcomes.",
        "key_reference_abstract": "## OBJECTIVE\nTo examine whether there are associations between pregnancy intention (intended, unwanted, mistimed, or ambivalent) and negative birth and maternal outcomes: low birth weight (less than 2,500 g), preterm delivery (fewer than 37 weeks), small for gestational age, premature labor, hypertension, and other maternal outcomes.\n## METHODS\nWe analyzed data from the population-based Pregnancy Risk Assessment Monitoring System, including 87,087 women who gave birth between 1996 and 1999 in 18 states. Information on pregnancy outcomes was derived from birth certificate data and a self-administered questionnaire completed postpartum. We employed SUDAAN (RTI International, Research Triangle Park, NC) for univariable and logistical regression analyses.\n## RESULTS\nIn analyses controlling for demographic and behavioral factors, women with unwanted pregnancies had an increased likelihood of preterm delivery (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33) and premature rupture of membranes (adjusted OR 1.37, 95% CI 1.01-1.85) compared with women with intended pregnancies. Women who were ambivalent toward their pregnancies had increased odds of delivering a low birth weight infant (adjusted OR 1.15, 95% CI 1.02-1.29); in contrast, women with mistimed pregnancies had a lower likelihood (adjusted OR 0.92, 95% CI 0.86-0.97).\n## CONCLUSION\nPregnancy intention, specifically unwanted and ambivalent, may be an indicator of increased risk for some poor birth and maternal outcomes and should be considered in interventions aimed at improving the health of the mother and child.\n## LEVEL OF EVIDENCE\nIII.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intention and preterm birth: differential associations among a diverse population of women.",
        "key_reference_abstract": "## CONTEXT\nStudies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups.\n## METHODS\nData from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics.\n## RESULTS\nIn unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites.\n## CONCLUSIONS\nWomen's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "The couple context of pregnancy and its effects on prenatal care and birth outcomes.",
        "key_reference_abstract": "The couple context of pregnancy and newborn health is gaining importance with the increase in births to unmarried couples, a disproportionate number of which were not intended. This study investigates the association of early prenatal care, preterm birth, and low birth weight with the couple relationship context, including partners' joint intentions for the pregnancy, their marital status at conception, and the presence of relationship problems during pregnancy. Data are drawn from the first wave of the Early Childhood Longitudinal Study--Birth Cohort, a representative study of births in 2001. The sample is composed of parents residing together with their biological child at the time the child is 9 months old, where both the mother and father completed the self-report interview (N = 5,788). Couple-level multivariate logistic regression models, weighted to account for the complex sampling design, were used in the analysis. Risk of inadequate prenatal care and preterm birth was increased when partners did not share intentions or when neither partner intended the pregnancy. Couples were at additional risk of inadequate prenatal care when the pregnancy was conceived nonmaritally and when the mother did not tell the father about the pregnancy, particularly when neither partner intended the pregnancy. The risk of premature birth was particularly high when the partners were unmarried and either or both did not intend the pregnancy. The couple context of pregnancy is important for a healthy pregnancy and birth. When the partner is present, practitioners and programs should maintain a focus on the couple, and researchers should make every effort to include the father's own perspective.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Assessing pregnancy intention and associated risks in pregnant adolescents.",
        "key_reference_abstract": "Unintended pregnancy and associated behaviors may play a substantial role in the increased risk of adverse maternal and neonatal outcomes associated with teen pregnancy. We evaluate a multi-dimensional measure of pregnancy intention among pregnant adolescents and quantify the association between intention dimensions and adverse outcomes and risk behaviors. Pregnancy intention measures were examined in a cohort of 300 pregnant adolescent women. We considered 18 items assessing elements of pregnancy intention including pregnancy planning, timing, emotional response, and readiness. Latent class analysis was performed to identify dimensions of pregnancy intention. Parsimonious scores were created by minimizing the number of covariates while maintaining substantial agreement with the latent class. Associations between intention measures and prenatal care, risk behaviors, and pregnancy outcomes were quantified using multivariable logistic regression. Two constructs of pregnancy intention were identified: planning and emotional readiness. Compared with emotionally ready adolescents, adolescents categorized as not emotionally ready had an increased odds of inadequate prenatal care (OR = 2.70, 95% CI:1.27-5.72), delayed prenatal care (OR = 2.54, 95% CI:1.27-5.09), and self-reported depression at the time of the first prenatal visit (OR = 2.21, 95% CI:1.03-4.77). Pregnancy planning was not associated with adverse pregnancy risk factors or outcomes. Among pregnant adolescents, emotional readiness for pregnancy and parenting was inversely associated with known risk factors for adverse pregnancy outcomes, suggesting that emotional readiness rather than pregnancy planning may be the more pertinent intention construct for adolescents.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy planning, smoking behaviour during pregnancy, and neonatal outcome: UK Millennium Cohort Study.",
        "key_reference_abstract": "## BACKGROUND\nPre-pregnancy health and care are important for the health of the future generations. Smoking during pregnancy has been well-researched and there is clear evidence of harm. But there has been little research on the health impact of planning for pregnancy. This study aims to investigate the independent effects of pregnancy planning and smoking during pregnancy on neonatal outcome.\n## METHODS\nThis analysis made use of data from the UK Millennium Cohort Study. The study sample consisted of 18,178 singleton babies born in UK between 2000 and 2001. The neonatal outcomes of interest were low birthweight (<2.5 Kg) and pre-term birth (<37 completed weeks gestation). Logistic regression was used to estimate the association between pregnancy planning and/or smoking and neonatal outcome. Adjusted odds ratios were used to calculate population attributable risk fractions (PAFs).\n## RESULTS\n43% of mothers did not plan their pregnancy and 34% were smoking just before and/or during pregnancy. Planners were half as likely to be smokers just before pregnancy, and more likely to give up or reduce the amount smoked if smokers. Unplanned pregnancies had 24% increased odds of low birth weight and prematurity compared to planned pregnancies (AORLBW1.24, 95% CI 1.04-1.48; AORPREM1.24, 95% CI 1.05-1.45), independent of smoking status. The odds of low birth weight for babies of mothers who were smoking just before pregnancy was 91% higher than that of mothers who were not (AORLBW1.91, 95% CI 1.56-2.34). Women who quit or reduced the amount smoked during pregnancy lowered the risk of a low birth weight baby by one third (AORLBW0.66, 95% CI 0.51-0.85) compared with women whose smoking level did not change. Smaller effects were found for prematurity. If all women planned their pregnancy and did not smoke before or during pregnancy, 30% of low birthweight and 14% of prematurity could, in theory, be avoided.\n## CONCLUSIONS\nPlanning a pregnancy and avoiding smoking during pregnancy has clear, independent, health benefits for babies. Quitting or reducing the amount smoked during pregnancy can reduce the risk of low birthweight.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Are pregnancy planning and timing associated with preterm or small for gestational age births?",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births.\n## DESIGN\nProspective cohort study.\n## SETTING\nNot applicable.\n## PATIENT(S)\nTwo thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy.\n## INTERVENTION(S)\nNone.\n## MAIN OUTCOME MEASURE(S)\nPreterm and small for gestational age births.\n## RESULT(S)\nIn adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age.\n## CONCLUSION(S)\nIn a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Prenatal depression",
        "key_reference_title": "Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma.",
        "key_reference_abstract": "Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed \u22652 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study identified correlates of self-reports of being very depressed in the months after delivery in a population-based sample of women.\n## METHODS\nWe analyzed data on 14,609 recent mothers from the Centers for Disease Control and Prevention's (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS). The sample included mothers who delivered a live birth in Colorado, New York State, and North Carolina from 1996 (New York only) to 1999. We assessed risk factors for self-reports of being very depressed in the months after delivery using logistic regression.\n## RESULTS\nOverall, 5.9% (95% CI = 5.3, 6.4) of new mothers reported being very depressed in the months after delivery. Women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life\" had the highest prevalence of reporting being very depressed in the months after delivery (24.9%, 95% CI = 21.3, 28.5) and, when all risk factors were adjusted for simultaneously, were 4.6 times (95% CI = 3.1, 6.3) more likely to report being very depressed in the months after delivery than other women. Other significant risk factors for self-reports of being very depressed in the months after delivery included experiencing partner-associated stress (OR = 1.9, 95% CI = 1.5, 2.5), physical abuse during pregnancy (OR = 1.6, 95% CI = 1.1, 2.4), and not breast-feeding (OR = 1.4, 95% CI = 1.1, 1.8).\n## CONCLUSIONS\nThe highest prevalence for self-reports of being very depressed in the months after delivery was in women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life.\" Clinicians need to be aware of the needs of some women for mental health services both during and after pregnancy.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Confinement and other psychosocial factors in perinatal depression: a transcultural study in Singapore.",
        "key_reference_abstract": "## BACKGROUND\nTo investigate the prevalence, socio-cultural and psychosocial risk factors for perinatal depression in Singaporean women.\n## METHOD\nA prospective cohort of 559 women was interviewed antenatally and at six weeks' postpartum at a tertiary hospital. Women were interviewed for diagnosis of depression using a two-stage design, with a screening questionnaire and diagnostic interview.\n## RESULTS\nPostnatally, a negative confinement experience was associated with depression. Other independent factors included poor emotional support, a past history of depression, unplanned pregnancy and perceived potential conflicts with relatives over childcare antenatally and dissatisfaction, poor instrumental support postnatally. The prevalence of depression antenatally and postnatally was 12.2% and 6.8%, respectively.\n## LIMITATIONS\nMeasures of satisfaction with social support were based on self-report; there were high dropout rates at six weeks' postpartum; and other modulating social factors such as pre-existing interpersonal conflicts were not studied.\n## CONCLUSIONS\nPerinatal depression in Singaporean women is common. Contrary to expectations, a negative 'confinement' experience is a significant risk factor for postnatal depression, and is not universally welcomed by women. Depression is modulated by dissimilar sets of psychosocial factors antenatally and postnatally.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice.",
        "key_reference_abstract": "## OBJECTIVE\nData are scarce regarding the sociodemographic predictors of antenatal and postpartum depression. This study investigated whether race/ethnicity, age, finances, and partnership status were associated with antenatal and postpartum depressive symptoms.\n## SETTING\n1662 participants in Project Viva, a US cohort study.\n## DESIGN\nMothers indicated mid-pregnancy and six month postpartum depressive symptoms on the Edinburgh postpartum depression scale (EPDS). Associations of sociodemographic factors with odds of scoring >12 on the EPDS were estimated.\n## MAIN RESULTS\nThe prevalence of depressive symptoms was 9% at mid-pregnancy and 8% postpartum. Black and Hispanic mothers had a higher prevalence of depressive symptoms compared with non-Hispanic white mothers. These associations were explained by lower income, financial hardship, and higher incidence of poor pregnancy outcome among minority women. Young maternal age was associated with greater risk of antenatal and postpartum depressive symptoms, largely attributable to the prevalence of financial hardship, unwanted pregnancy, and lack of a partner. The strongest risk factor for antenatal depressive symptoms was a history of depression (OR = 4.07; 95% CI 3.76, 4.40), and the strongest risk for postpartum depressive symptoms was depressive symptoms during pregnancy (6.78; 4.07, 11.31) or a history of depression before pregnancy (3.82; 2.31, 6.31).\n## CONCLUSIONS\nFinancial hardship and unwanted pregnancy are associated with antenatal and postpartum depressive symptoms. Women with a history of depression and those with poor pregnancy outcomes are especially vulnerable to depressive symptoms during the childbearing year. Once these factors are taken in account, minority mothers have the same risk of antenatal and postpartum depressive symptoms as white mothers.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intentions and happiness among pregnant black women at high risk for adverse infant health outcomes.",
        "key_reference_abstract": "## CONTEXT\nUnintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman's feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.\n## METHODS\nA sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.\n## RESULTS\nPregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby's father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).\n## CONCLUSIONS\nAdditional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father's desire to have this child, may help improve prenatal care services and prevent adverse health outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Factors related to depression during pregnancy: are there gender differences?",
        "key_reference_abstract": "## OBJECTIVE\nTo determine gender differences between women and their partners in the effect of psychosocial and personal factors on depression during the third trimester of pregnancy.\n## METHOD\nA cross-sectional survey was carried out among 687 women and their partners (n = 669) attending the prenatal programme of Valencia province (Spain). Data collection was carried out by means of a self-reported questionnaire. The outcome variable was depression during the third trimester of pregnancy measured by the Edinburgh Postnatal Depression Scale. Predictor variables were psychosocial (marital dissatisfaction, confidant and affective social support) and personal (previous history of depression, partner depression and unplanned pregnancy) variables. The adjusted odds ratios (aOR) and their 95% confidence intervals were calculated by fitting a logistic regression model.\n## RESULTS\nThe prevalence of pregnancy depression was higher among women (10.3%) than men (6.5%). In both sexes, the probability of depression during pregnancy was higher in those with marital dissatisfaction (aOR 3.05, 95% CI 1.59 to 5.82 for women and 3.14, 95% CI 1.24 to 7.99 for men) and among those whose with a previous history of depression (aOR 2.18, 95% CI 1.22 to 3.89 for women and 5.22, 95% CI 2.05 to 13.34 for men). Unplanned pregnancy did not increase the risk of pregnancy depression either in women or men. Gender differences were found on the impact of social support and partner's depression. Whereas among men low affective social support and partner depression were associated with a higher probability of reporting depression, none of these variables were related to women's depression.\n## CONCLUSION\nMost predictor factors of depression during pregnancy are similar for both sexes but a gender-different impact of social support and partner depression on pregnancy depression was appreciated. Health professionals should be aware of potentially vulnerable groups for early diagnosis of pregnancy depression and to provide effective interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Psychosocial risk factors for depression during pregnancy.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the prevalence of antenatal depressive disorder in different trimesters and to evaluate the relation of psychosocial risk factors to antenatal depressive disorder.\n## DESIGN\nCohort follow-up.\n## SETTING\nUniversity Hospital, Kaunas, Lithuania.\n## SAMPLE\nTwo hundred and thirty pregnant women consecutively admitted.\n## METHODS\nAt 12-16 weeks, 22-26 weeks, and 32-36 weeks of pregnancy, participants were screened for depression using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). Women who gave at least one positive answer to the CIDI-SF depression-screening question were evaluated for depressive disorder using the non-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). Psychosocial stressors and two Big Five Personality dimensions, neuroticism and extraversion, were also evaluated.\n## MAIN OUTCOME MEASURES\nPrevalence of depressive disorder.\n## RESULTS\nThe prevalence of the antenatal depressive disorder at 12-16 weeks' gestation was 6.1%, at 22-26 weeks 3.5%, and at 32-36 weeks 4.4%. In the first trimester, a greater prevalence of current depressive disorder was independently associated with unplanned and unwanted pregnancy, high neuroticism, low education, and a previous history of depression; in the second trimester with unplanned and unwanted pregnancy and high neuroticism; in the third trimester with unplanned and unwanted pregnancy, high neuroticism, and the occurrence of psychosocial stressors during the last year.\n## CONCLUSIONS\nThe highest prevalence of depressive disorders was found in the first trimester, the lowest in mid-pregnancy. Several determinants (unwanted and unplanned pregnancy, high neuroticism) were independent predictors of antenatal depressive disorders throughout whole pregnancy, while other determinants (low education, previous history of depression, the occurrence of psychosocial stressors at the end of pregnancy) were trimester specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Unintended pregnancy and associated maternal preconception, prenatal and postpartum behaviors.",
        "key_reference_abstract": "## BACKGROUND\nThis study was conducted to determine the relationship between unintended pregnancy and maternal behaviors before, during and after pregnancy.\n## STUDY DESIGN\nData were analyzed from a stratified random sample of 9048 mothers who delivered live born infants between 2001 and 2006 and completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey 2 to 9 months after delivery. Binary and ordinal logistic regression methods with appropriate survey weights were used to control for socio-demographic factors.\n## RESULTS\nCompared to women with intended pregnancies, mothers with unwanted pregnancies were more likely to consume less than the recommended amount of preconception folic acid [adjusted odds ratio (OR) 2.39, 95% confidence interval (CI) 1.7-3.2], smoke prenatally (OR 2.03, 95% CI 1.5-2.9), smoke postpartum (OR 1.86, 95% CI 1.35-2.55) and report postpartum depression (OR 1.98, 95% CI 1.48-2.64); they were less likely to initiate prenatal care during the first trimester (OR 0.34, 95% CI 0.3-0.5) and breastfeed for 8 or more weeks (OR 0.74, 95% CI 0.57-0.97). Compared to women with intended pregnancies, women with mistimed pregnancies were also more likely to consume inadequate folic acid, delay prenatal care and report postpartum depression.\n## CONCLUSION\nEven after controlling for multiple socio-demographic factors, unwanted and mistimed pregnancies were associated with unhealthy perinatal behaviors.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Antenatal depression and male gender preference in Asian women in the UK.",
        "key_reference_abstract": "## OBJECTIVE\nto identify the prevalence of antenatal depression among Asian women living in the UK in one antenatal clinic, and to investigate the possible association with a desire for a male child and other risk factors.\n## DESIGN\ncross-sectional questionnaire-based study.\n## SETTING\ngeneral antenatal clinic in a hospital in Birmingham.\n## PARTICIPANTS\n300 Asian women, irrespective of place of birth.\n## METHODS\nconsecutive Asian women attending routine antenatal appointments during the study period self-completed a questionnaire. The first part investigated socio-demographic, cultural and other possible risk factors, including gender preference. The second part comprised the Edinburgh Postnatal Depression Scale (EPDS).\n## MEASUREMENTS\nEPDS score greater than or equal to 12 indicating probable depression.\n## FINDINGS\nthe prevalence of depression was 30.7% (92/300, 95% confidence interval 25.4-35.9%). Maternal male gender preference was not common and was not associated with antenatal depression. Family male gender preference, unplanned pregnancy, a history of depression and feeling anxious in pregnancy were independently associated with an increased likelihood of depression, whilst support from family and friends, being satisfied with pregnancy and being multiparous were associated with a reduced likelihood of depression.\n## CONCLUSION\nrates of antenatal depression were very high in Asian women with some associated risk factors. However, male gender preference was not associated with antenatal depression.\n## IMPLICATIONS FOR PRACTICE\ngiven the high prevalence, screening Asian women for depression may be indicated to allow treatment.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intention, demographic differences, and psychosocial health.",
        "key_reference_abstract": "## OBJECTIVES\nWe explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies.\n## METHODS\nData from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes.\n## RESULTS\nSixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups.\n## CONCLUSIONS\nFully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Obstetric and psychosocial risk factors for depressive symptoms during pregnancy.",
        "key_reference_abstract": "We aimed to determine the psychosocial and obstetric correlates of depressive symptomatology during pregnancy in South-Eastern Hungary. A total of 1719 women were screened for depression in four counties in 2006 and 2007, based on a Leverton Questionnaire (LQ) score of \u226512 at 14-24 weeks of gestation. The LQ scores indicated a probable depressive illness (PDI) in 17.2% of the study group. The best predictors in a multiple regression analysis were history of major depression (adjusted odds ratio [AOR]=3.23), and major life events (AOR=2.43). A perceived lack of social support from partner (AOR=1.79) and lack of support by family (AOR=1.23) were also significant determinants. Lack of planning of pregnancy (AOR=1.12) and a history of unfavourable obstetric outcome (AOR=1.42) also seem to predispose to PDI. Overall, psychosocial factors appeared important in the prediction of PDI, whereas economic features did not.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Unintended pregnancy and postpartum depression among first-time mothers.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is a mental disorder that occurs after birth and has negative consequences for the mother, infant, and family. The objective of this secondary analysis was to examine whether pregnancy intention was associated with postpartum depression among first-time mothers.\n## METHODS\nThe First Baby Study is a prospective cohort study of women aged 18-35 having a first singleton birth in Pennsylvania. Baseline data were collected during the third trimester. Postpartum depressive symptoms were measured at 1-month postpartum using the Edinburgh Postnatal Depression Scale. Logistic regression was performed to examine the association between unintended pregnancy and postpartum depression, controlling for prepregnancy anxiety/depression and sociodemographic data.\n## RESULTS\nOf 2972 first-time mothers, 83.4% were white, 70.7% were married, and 56.9% were college educated. Nine hundred fifty-two women (32.0%) reported their pregnancy was unintended and 151 (5.1%) met the threshold for postpartum depression. The prevalence of postpartum depression was higher in women with unintended pregnancies compared to women with intended pregnancies (6.7% vs. 4.3%, p<0.01). However, after controlling for confounders, unintended pregnancy was no longer associated with postpartum depression (adjusted OR 1.41; 95% CI 0.91-2.18). Variables independently associated with postpartum depression included prepregnancy anxiety/depression, Asian race, and Hispanic ethnicity.\n## CONCLUSION\nPregnancy intention was not independently associated with postpartum depression among first time mothers in Pennsylvania.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "The effect of pregnancy intention on maternal prenatal behaviours and parent and child health: results of an irish cohort study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors.\n## METHODS\nThis study uses data from the first wave of the 'Growing Up in Ireland Study', a large nationally representative cohort study of more than 11\u2009000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours.\n## RESULTS\nThe study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]).\n## CONCLUSIONS\nAscertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "From antenatal to postnatal depression: associated factors and mitigating influences.",
        "key_reference_abstract": "## INTRODUCTION\nPostnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression.\n## METHODS\nThe study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables.\n## RESULTS\nRisk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression.\n## CONCLUSION\nThis study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Intendedness of pregnancy and other predictive factors for symptoms of prenatal depression in a population-based study.",
        "key_reference_abstract": "Prenatal depression (PD) as a risk factor for adverse birth outcomes is well documented. Less is known about maternal risks for PD, which could inform preventive strategies for perinatal and interconceptional care. This exploratory study investigates associations between prenatal depression symptoms and unintended and mistimed pregnancies and other maternal risk factors for PD. A subset of birth records from the New York Statewide Perinatal Data System (n = 19,219) was used in this secondary analysis of cross-sectional data. Univariate and multivariate multinomial regression was used to identify factors that are independently associated with four self-reported levels of prenatal depression symptoms. Women with unintended pregnancies were more likely (AOR, 95 % CI) to report severe (3.6, 2.6-5.1) or moderate (2.0, 1.6-2.5) prenatal depression symptoms and less likely to report no symptoms, compared to women with intended pregnancies. Likewise, women with mistimed pregnancies were more likely to report severe (2.7, 2.2-3.5) or moderate (1.7, 1.5-2.1) prenatal depression symptoms than no symptoms, compared to women with intended pregnancies. Low education, drug use, smoking, minority race, being unmarried and having Medicaid insurance were also significant, independent predictors of PD symptoms. Results suggest that routine screening for depression, intendedness of pregnancy and other associated risk factors such as smoking and drug use during prenatal and interconceptional care visits may enable coordinated interventions that can reduce prenatal depression and unintended and mistimed pregnancies and improve pregnancy outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Impact of unintended pregnancy on maternal mental health: a causal analysis using follow up data of the Panel Study on Korean Children (PSKC).",
        "key_reference_abstract": "## BACKGROUND\nPregnancy intention is important for maternal and child health outcomes. The purpose of this study was to examine the causal relation between pregnancy intention and maternal depression and parenting stress in Korean women who gave birth during 2008.\n## METHODS\nThis study is a retrospective evaluation of prospectively collected data from the Panel Study on Korean Children from 2008 to 2010. Causal analyses were conducted using propensity score matching and inverse probability of treatment weighted methods. In addition, mediation analyses were performed to test mitigating effects of marital conflict, fathers' participation in childcare, and mothers' knowledge of infant development on the relation between unintended pregnancy and adverse maternal mental health.\n## RESULTS\nResults showed that the overall effect of an unintended pregnancy on maternal depression and parenting stress was statistically significant. An unintended pregnancy was associated with 20-22% greater odds of maternal depression, 0.28-0.39 greater depression score, and 0.85-1.16 greater parenting stress score. Relations between pregnancy intention and maternal depression, maternal depression score and parenting stress score were moderately explained by marital conflict and fathers' participation in childcare.\n## CONCLUSIONS\nUnintended pregnancy contributed to increased risks of maternal depression and parenting stress. Efforts to increase fathers' participation in childcare and decrease marital conflict might be helpful to mitigate adverse impacts of unintended pregnancy on perinatal maternal mental health.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Risk factors of transient and persistent anxiety during pregnancy.",
        "key_reference_abstract": "## PURPOSE\nchronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada.\n## METHODS\nwomen with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup.\n## FINDINGS\nwomen with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85-13.39) were unique predictors of chronic depressive symptoms.\n## CONCLUSIONS\nknowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Are pregnancy planning and pregnancy timing associated with maternal psychiatric illness, psychological distress and support during pregnancy?",
        "key_reference_abstract": "## BACKGROUND\nPregnancy planning and timing may be associated with psychiatric illness, psychological distress and support during pregnancy.\n## METHODS\nWe performed secondary analyses of a prospective cohort of 2654 pregnant women evaluating the impact of depression on preterm birth. We used multivariable logistic regression to test associations between pregnancy planning (\"Was this pregnancy planned? Yes/No\") and/or timing (\"Do you think this is a good time for you to be pregnant?\") with Composite International Diagnostic Interview generated psychiatric diagnoses and measures of psychological distress and support.\n## RESULTS\n37% and 13% of participants reported an unplanned or poorly timed pregnancy, respectively. Unplanned pregnancies were associated with a Major Depressive Episode (MDE) (adjusted odds ratio (aOR) 1.69, 95%CI 1.23-2.32) and the Cohen Perceived Stress Scale's (CPSS) highest quartile (aOR 1.74, 95%CI 1.40-2.16). Poorly timed pregnancies were associated with a MDE (aOR 3.47, 95%CI 2.46-4.91) and the CPSS's highest quartile (aOR 5.20, 95%CI 3.93-6.87). Poorly timed pregnancies were also associated with General Anxiety Disorder (GAD; aOR 1.60, 95%CI 1.07-2.40), and the modified Kendler Social Support Inventory's (MKSSI) lowest quartile (aOR 1.64, 95%CI 1.25-2.16). Psychiatric conditions were strongly associated with planned pregnancies that were subsequently deemed poorly timed (MDE=aOR 5.08, 95%CI 2.52-10.25; GAD=aOR 2.28, 95%CI 1.04-5.03); high CPSS=aOR 6.48, 95%CI 3.59-11.69; and low MKSSI=aOR 3.19, 95%CI 1.81-5.62.\n## LIMITATIONS\nParticipant characteristics may limit generalizability of findings.\n## CONCLUSIONS\nPregnancy timing was a stronger predictor of maternal psychiatric illness, psychological distress and low social support than pregnancy planning in our cohort.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs).\n## METHODS\nUsing Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross-sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design.\n## RESULTS\nIn multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23-2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs.\n## CONCLUSIONS\nThis study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "The association between pregnancy intendedness and experiencing symptoms of postpartum depression among new mothers in the United States, 2009 to 2011: A secondary analysis of PRAMS data.",
        "key_reference_abstract": "Postpartum depression (PPD) is a form of major depressive disorder affecting approximately 13% of women worldwide. Unintended pregnancies, reaching close to 50% of the pregnancies in the United States, have become a major health concern. While many physiologic and psychosocial causes have been analyzed, few studies have examined the relationship between unintended pregnancy and symptoms of PPD.A cross-sectional study was conducted using surveillance data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2009 to 2011. The PRAMS population-based random sample included women who have had recent live births and is representative of 78% of the United States population. The chi-squared test was used to examine bivariate associations. Binary logistic regression was utilized to study unadjusted and adjusted associations between PPD and pregnancy intendedness, as well as other demographic and clinical characteristics of mothers in the sample. Multicollinearity in the adjusted model was evaluated using variance inflation factors. Sampling weights were used to account for PRAMS' complex sampling design.Of the 110,231 mothers included in the sample, only 32.3% reported desiring the pregnancy at the time of conception. Women with pregnancies categorized as mistimed: desired sooner, mistimed: desired later, or unwanted were 20% (adjusted odds ratio [AOR]\u200a=\u200a1.2; 95% confidence interval [CI]: 1.1-1.3), 30% (AOR\u200a=\u200a1.3; 95% CI: 1.2-1.4), and 50% (AOR\u200a=\u200a1.5; 95% CI: 1.3-1.7) more likely to experience symptoms of PPD, respectively, compared to women with desired pregnancies. Other factors found to be associated with experiencing symptoms of PPD were a gestational age of <27 weeks (AOR\u200a=\u200a3.1; 95% CI: 2.5-4.0), having a previous history of depression (AOR\u200a=\u200a1.8; 95% CI: 1.6-2.0), and being abused during or before pregnancy (AOR\u200a=\u200a1.6; 95% CI: 1.4-2.0).We found that women with mistimed or unwanted pregnancies were more likely to experience symptoms of PPD. Our findings support the current US Preventive Services Task Force and American Academy of Pediatrics recommendations for an integrated approach to screening for depression, aiding in the maximization of intervention and early referral for women at risk for PPD.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Psychosocial status and prenatal care of unintended pregnancies among low-income women.",
        "key_reference_abstract": "## BACKGROUND\nNearly half of all pregnancies in the United States are reported as unintended and rates are highest among women of low socioeconomic status. The purpose of this study was to examine the associations between unintended pregnancies and maternal mental health and timing of prenatal care among low-income women.\n## METHODS\nIn this cross-sectional study, 870 women, whom were participating in the First 1000\u2009Days program in three community health centers in the Boston area, were enrolled at their first prenatal visit from August 2016 - September 2017. We assessed pregnancy intention by self-report using the Pregnancy Risk Assessment Monitoring System. We used self-reported survey information and electronic health record data to assess the following outcomes: current stress, current depression, and timing of initial prenatal visit. We used multivariable logistic regression models to examine associations and adjusted for sociodemographic factors.\n## RESULTS\nWomen were a mean (SD) age of 29.3 (6.1), and 39.2% reported that their pregnancy was unintended. 50.6% of women were Hispanic, 28.4% were White, 10.1% were Black, and 10.9% were other races. 78.9% of women reported an annual household income <$50,000. Overall, 26.7% of women reported current stress, 8.2% reported current depression, and 18.3% of women initiated prenatal care after their first trimester. In multivariable analyses, women with unintended pregnancies had higher odds of experiencing current stress (OR: 1.72; 95% CI: 1.22, 2.41), current depression (OR: 1.83; 95% CI: 1.04, 3.20), and initiation of prenatal care post-first trimester (OR: 1.84; 95% CI: 1.23, 2.74).\n## CONCLUSIONS\nUnintended pregnancies were associated with current stress and depression, and delayed prenatal care in this sample of low-income women suggesting the importance of identifying high-risk women and tailoring interventions to support women's needs.\n## TRIAL REGISTRATION\nClinicalTrials.gov (NCT03191591; Retrospectively registered on June 19, 2017).",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "The Role of Father Involvement and Intimate Partner Violence on Postnatal Depression Among Women With Unintended Pregnancy.",
        "key_reference_abstract": "This study set out to fill the research gap by including various aspects of father involvement and intimate partner violence (IPV) in the examination of the association between unintended pregnancy and maternal postnatal depression (PND). This study aimed to examine the effect of father involvement and IPV on the association between unintended pregnancy and PND. A sample of 1,083 pregnant women who attended antenatal clinic at selected hospitals in Hong Kong completed two surveys to report on their pregnancy intention, antenatal depression, PND, IPV during pregnancy, their partner's (i.e., father's) involvement during pregnancy and after childbirth, and perceived social support. Comparisons were made between women with unintended pregnancy and those with intended pregnancy, and the effects of unintended pregnancy, father involvement, IPV, and other factors on maternal PND were examined. Results show that women with unintended pregnancy were more likely to report PND, IPV, fear, postnatal stress, lower degree of father involvement, and lower level of social support. Unintended pregnancy independently increased the risk of PND by 1.95 times (95% confidence interval [CI] = [1.15, 3.28]), after adjustment for all other variables. When father involvement was included in the regression model, the negative effects of IPV and the related fear on PND became nonsignificant. The positive association between unintended pregnancy and PND was robust. Father involvement might help promote maternal health by reducing the negative effects of IPV on PND.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Do Pregnancy Intentions Matter? A Research Note Revisiting Relationships Among Pregnancy, Birth, and Maternal Outcomes.",
        "key_reference_abstract": "The prevention of unplanned or unintended pregnancies continues to be a cornerstone of U.S. reproductive health policy, but the evidence that such pregnancies cause adverse maternal and child outcomes is limited. In this research note, we examine these relationships using recent large-scale data and inverse propensity weights estimated from generalized boosted models. We find that pregnancy timing is related to maternal experience during pregnancy, but not to infant outcomes at birth-both of which are consistent with prior research. In an addition to the literature, we show that pregnancy timing is relevant for a number of maternal outcomes, such as the onset of depression and intimate partner violence, changes in smoking behavior, and receipt of medical care. These findings suggest that policy intended to improve infant welfare by preventing unintended pregnancies has little empirical support, but that policy focused on increasing reproductive autonomy and maternal well-being has the potential to improve outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy planning and acceptance and maternal psychological distress during pregnancy: results from the National Perinatal Survey, France, 2016.",
        "key_reference_abstract": "## BACKGROUND\nStudies report heightened risks of mental health problems among women who experience an unintended pregnancy, but few consider the complexity of pregnancy intentions. In this study, we evaluate how different dimensions of pregnancy intentions (pregnancy planning and pregnancy acceptance) relate to two maternal depressive symptoms and perceived psychological distress.\n## METHODS\nThis study draws from a cross-sectional national survey conducted in all maternities in France over a one-week period in 2016. All mothers 18\u2009years and older who had a live birth during the study period were invited to participate. After excluding women who underwent infertility treatment, our analytical sample included 10,339 women. We first described levels and correlates of pregnancy planning and acceptance, defined in four categories; planned/welcomed, unplanned/welcomed, planned/unwelcomed, unplanned/unwelcomed. We then assessed the bivariate and multivariate associations between pregnancy planning and acceptance and two outcomes: women's self-perceived psychological health and the presence of two depressive symptoms during pregnancy. We used multivariate logistic regressions to evaluate these associations, after adjusting for socio-demographic and medical factors.\n## RESULTS\nAltogether 7.5 to 24.1% of mothers perceived their psychological health during pregnancy was poor, according to pregnancy planning and acceptance categories and 10.3 to 22.4% indicated feelings of sadness and loss of interest during pregnancy, according to pregnancy planning and acceptance categories. As compared to women with planned/welcomed pregnancies, the odds of perceived poor psychological health and depressive symptoms were 2.55 times (CI 2.20-2.95) and 1.75 times higher (CI 1.51-2.02), respectively, among unplanned/unwelcomed pregnancies and 2.02 (CI 1.61-2.53) and 2.07 (CI 1.7-2.5) higher, among planned/unwelcomed pregnancies. Among women with unplanned pregnancies, we also found higher odds of perceived poor psychological health among women whose pregnancy was unwelcomed while the odds of depressive symptoms were not different by pregnancy planning status among women with unwelcomed pregnancies.\n## CONCLUSIONS\nThese findings consolidate previous reports of the association between pregnancy intentions and maternal psychological distress, while further specifying the relationship, which mostly depends on the acceptance of pregnancy timing rather than on pregnancy planning. Identifying women with low pregnancy acceptance can potentially enhance current medical practice by improving early detection of maternal depression.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors.\n## METHODS\nIn 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy.\n## RESULTS\nWomen who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester.\n## CONCLUSIONS\nWomen with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Unintended pregnancy and intimate partner violence before and during pregnancy among Latina women in Los Angeles, California.",
        "key_reference_abstract": "The purpose of this paper was to examine the relationship between unintended pregnancy and intimate partner violence (IPV) before and during pregnancy among Latinas. A cross-sectional interview measuring pregnancy intent, IPV, and acculturation, using the Acculturation Rating Scale for Mexican Americans (ARSMA-II), was conducted among Latina women in their 2(nd) or 3(rd) trimester of pregnancy at clinics in Los Angeles (n = 313). Overall, 44% of women reported an unintended pregnancy. The prevalence of physical (any) and emotional (only) abuse 12 months before pregnancy was 11% and 22%, respectively. Although both types of IPV decreased during pregnancy (10% and 19%, respectively), most reports of physical IPV during pregnancy (53%) were among women who did not report physical abuse before pregnancy. After adjusting for other factors, physical IPV before pregnancy was not associated with unintended pregnancy (adjusted OR = 0.92; 95% CI = 0.40, 2.16). The prevalence of unintended pregnancy was highest (76%) among highly acculturated Latinas. However, when an unintended pregnancy occurred among less acculturated Latinas, who comprised the majority of the sample (n = 270), it was associated with greater risk of physical IPV during pregnancy (unadjusted OR = 2.57; 95% CI = 1.06, 6.23); although the confidence interval included one after adjusting for other factors (adjusted OR = 2.79; 95% CI = 0.98, 7.92). An unintended pregnancy may have a unique impact on relationships in the context of Latino culture, where family and pregnancy are highly valued. Pregnancy often creates an opportunity for providers to discuss issues related to abuse and family planning with women who do not regularly access care. The results from this study may be used to increase the cultural sensitivity with which violence and reproductive health are addressed among the diverse population of Latinas when they connect with prenatal services.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Severity of intimate partner abuse indicators as perceived by women in Mexico and the United States.",
        "key_reference_abstract": "## OBJECTIVE\nWomen in Cuernavaca, Mexico and Los Angeles, California were surveyed to examine differences in their perceptions of the severity of domestic violence indicators.\n## METHODS\nOne hundred twenty women in each country rated the severity of 26 domestic violence indicators which were part of an abuse screen used for an ongoing study of the prevalence of abuse. Rasch analysis was conducted to determine the linear relationship in the perceptions of the severity of each event between the two countries.\n## RESULTS\nThe Rasch calibrated logit values show that women in the US rated 24 of the 26 events as more severe than women in Mexico. However, items were ranked in similar order and a clear linear pattern was established. In both countries, being shot with a gun was the most severe event and a partner becoming jealous was the least severe.\n## CONCLUSION\nThe country of origin did not dictate which events were most severe but did influence how severe these events were perceived.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse.\n## METHODS\nA prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used.\n## RESULTS\nApproximately one-fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68).\n## CONCLUSION\nWomen who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Early Childhood Victimization and Physical Intimate Partner Violence During Pregnancy: A Developmental and Person-Oriented Approach.",
        "key_reference_abstract": "Intimate partner violence (IPV) victimization during pregnancy is a major public health concern, yet little is known about how risk factors for IPV during pregnancy may depend on whether women have histories of victimization dating back to early childhood (ages 0-5 years). This study examined whether risk factors for physical IPV victimization during pregnancy (a pregnancy that was not planned and prenatal substance use) differed for women with versus without early childhood victimization. Participants were 236 ethnically diverse, low-income biological mothers ( M = 30.94 years; 50.0% Latina, 16.9% Caucasian, 13.1% African American, and 16.9% multiracial) of children aged 0 to 6 years. Mothers were classified into four groups based on whether they had experienced early childhood victimization and physical IPV victimization during pregnancy with the target child. Multinomial logistic regressions, controlling for demographic characteristics, examined whether a pregnancy not planned and prenatal substance use predicted group membership. Compared to mothers with early victimization only, mothers with both early childhood victimization and physical IPV during pregnancy were more than 3 times as likely to report that their pregnancy with the target child was not planned. In follow-up analyses, mothers with early victimization and physical IPV during pregnancy also reported higher lifetime parity than mothers with physical IPV during pregnancy but no early victimization. Early childhood victimization may place women on a risk pathway to physical IPV during pregnancy, particularly if the pregnancy is not planned. Prevention and policy efforts should screen women for early childhood victimization to understand risks for physical IPV during pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "The effect of pregnancy intention on child development.",
        "key_reference_abstract": "In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Unintended pregnancy and preterm birth.",
        "key_reference_abstract": "About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intention and its relationship to birth and maternal outcomes.",
        "key_reference_abstract": "## OBJECTIVE\nTo examine whether there are associations between pregnancy intention (intended, unwanted, mistimed, or ambivalent) and negative birth and maternal outcomes: low birth weight (less than 2,500 g), preterm delivery (fewer than 37 weeks), small for gestational age, premature labor, hypertension, and other maternal outcomes.\n## METHODS\nWe analyzed data from the population-based Pregnancy Risk Assessment Monitoring System, including 87,087 women who gave birth between 1996 and 1999 in 18 states. Information on pregnancy outcomes was derived from birth certificate data and a self-administered questionnaire completed postpartum. We employed SUDAAN (RTI International, Research Triangle Park, NC) for univariable and logistical regression analyses.\n## RESULTS\nIn analyses controlling for demographic and behavioral factors, women with unwanted pregnancies had an increased likelihood of preterm delivery (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33) and premature rupture of membranes (adjusted OR 1.37, 95% CI 1.01-1.85) compared with women with intended pregnancies. Women who were ambivalent toward their pregnancies had increased odds of delivering a low birth weight infant (adjusted OR 1.15, 95% CI 1.02-1.29); in contrast, women with mistimed pregnancies had a lower likelihood (adjusted OR 0.92, 95% CI 0.86-0.97).\n## CONCLUSION\nPregnancy intention, specifically unwanted and ambivalent, may be an indicator of increased risk for some poor birth and maternal outcomes and should be considered in interventions aimed at improving the health of the mother and child.\n## LEVEL OF EVIDENCE\nIII.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intention and preterm birth: differential associations among a diverse population of women.",
        "key_reference_abstract": "## CONTEXT\nStudies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups.\n## METHODS\nData from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics.\n## RESULTS\nIn unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites.\n## CONCLUSIONS\nWomen's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "The couple context of pregnancy and its effects on prenatal care and birth outcomes.",
        "key_reference_abstract": "The couple context of pregnancy and newborn health is gaining importance with the increase in births to unmarried couples, a disproportionate number of which were not intended. This study investigates the association of early prenatal care, preterm birth, and low birth weight with the couple relationship context, including partners' joint intentions for the pregnancy, their marital status at conception, and the presence of relationship problems during pregnancy. Data are drawn from the first wave of the Early Childhood Longitudinal Study--Birth Cohort, a representative study of births in 2001. The sample is composed of parents residing together with their biological child at the time the child is 9 months old, where both the mother and father completed the self-report interview (N = 5,788). Couple-level multivariate logistic regression models, weighted to account for the complex sampling design, were used in the analysis. Risk of inadequate prenatal care and preterm birth was increased when partners did not share intentions or when neither partner intended the pregnancy. Couples were at additional risk of inadequate prenatal care when the pregnancy was conceived nonmaritally and when the mother did not tell the father about the pregnancy, particularly when neither partner intended the pregnancy. The risk of premature birth was particularly high when the partners were unmarried and either or both did not intend the pregnancy. The couple context of pregnancy is important for a healthy pregnancy and birth. When the partner is present, practitioners and programs should maintain a focus on the couple, and researchers should make every effort to include the father's own perspective.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Assessing pregnancy intention and associated risks in pregnant adolescents.",
        "key_reference_abstract": "Unintended pregnancy and associated behaviors may play a substantial role in the increased risk of adverse maternal and neonatal outcomes associated with teen pregnancy. We evaluate a multi-dimensional measure of pregnancy intention among pregnant adolescents and quantify the association between intention dimensions and adverse outcomes and risk behaviors. Pregnancy intention measures were examined in a cohort of 300 pregnant adolescent women. We considered 18 items assessing elements of pregnancy intention including pregnancy planning, timing, emotional response, and readiness. Latent class analysis was performed to identify dimensions of pregnancy intention. Parsimonious scores were created by minimizing the number of covariates while maintaining substantial agreement with the latent class. Associations between intention measures and prenatal care, risk behaviors, and pregnancy outcomes were quantified using multivariable logistic regression. Two constructs of pregnancy intention were identified: planning and emotional readiness. Compared with emotionally ready adolescents, adolescents categorized as not emotionally ready had an increased odds of inadequate prenatal care (OR = 2.70, 95% CI:1.27-5.72), delayed prenatal care (OR = 2.54, 95% CI:1.27-5.09), and self-reported depression at the time of the first prenatal visit (OR = 2.21, 95% CI:1.03-4.77). Pregnancy planning was not associated with adverse pregnancy risk factors or outcomes. Among pregnant adolescents, emotional readiness for pregnancy and parenting was inversely associated with known risk factors for adverse pregnancy outcomes, suggesting that emotional readiness rather than pregnancy planning may be the more pertinent intention construct for adolescents.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy planning, smoking behaviour during pregnancy, and neonatal outcome: UK Millennium Cohort Study.",
        "key_reference_abstract": "## BACKGROUND\nPre-pregnancy health and care are important for the health of the future generations. Smoking during pregnancy has been well-researched and there is clear evidence of harm. But there has been little research on the health impact of planning for pregnancy. This study aims to investigate the independent effects of pregnancy planning and smoking during pregnancy on neonatal outcome.\n## METHODS\nThis analysis made use of data from the UK Millennium Cohort Study. The study sample consisted of 18,178 singleton babies born in UK between 2000 and 2001. The neonatal outcomes of interest were low birthweight (<2.5 Kg) and pre-term birth (<37 completed weeks gestation). Logistic regression was used to estimate the association between pregnancy planning and/or smoking and neonatal outcome. Adjusted odds ratios were used to calculate population attributable risk fractions (PAFs).\n## RESULTS\n43% of mothers did not plan their pregnancy and 34% were smoking just before and/or during pregnancy. Planners were half as likely to be smokers just before pregnancy, and more likely to give up or reduce the amount smoked if smokers. Unplanned pregnancies had 24% increased odds of low birth weight and prematurity compared to planned pregnancies (AORLBW1.24, 95% CI 1.04-1.48; AORPREM1.24, 95% CI 1.05-1.45), independent of smoking status. The odds of low birth weight for babies of mothers who were smoking just before pregnancy was 91% higher than that of mothers who were not (AORLBW1.91, 95% CI 1.56-2.34). Women who quit or reduced the amount smoked during pregnancy lowered the risk of a low birth weight baby by one third (AORLBW0.66, 95% CI 0.51-0.85) compared with women whose smoking level did not change. Smaller effects were found for prematurity. If all women planned their pregnancy and did not smoke before or during pregnancy, 30% of low birthweight and 14% of prematurity could, in theory, be avoided.\n## CONCLUSIONS\nPlanning a pregnancy and avoiding smoking during pregnancy has clear, independent, health benefits for babies. Quitting or reducing the amount smoked during pregnancy can reduce the risk of low birthweight.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Are pregnancy planning and timing associated with preterm or small for gestational age births?",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births.\n## DESIGN\nProspective cohort study.\n## SETTING\nNot applicable.\n## PATIENT(S)\nTwo thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy.\n## INTERVENTION(S)\nNone.\n## MAIN OUTCOME MEASURE(S)\nPreterm and small for gestational age births.\n## RESULT(S)\nIn adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age.\n## CONCLUSION(S)\nIn a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Postpartum depression",
        "key_reference_title": "Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma.",
        "key_reference_abstract": "Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed \u22652 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study identified correlates of self-reports of being very depressed in the months after delivery in a population-based sample of women.\n## METHODS\nWe analyzed data on 14,609 recent mothers from the Centers for Disease Control and Prevention's (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS). The sample included mothers who delivered a live birth in Colorado, New York State, and North Carolina from 1996 (New York only) to 1999. We assessed risk factors for self-reports of being very depressed in the months after delivery using logistic regression.\n## RESULTS\nOverall, 5.9% (95% CI = 5.3, 6.4) of new mothers reported being very depressed in the months after delivery. Women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life\" had the highest prevalence of reporting being very depressed in the months after delivery (24.9%, 95% CI = 21.3, 28.5) and, when all risk factors were adjusted for simultaneously, were 4.6 times (95% CI = 3.1, 6.3) more likely to report being very depressed in the months after delivery than other women. Other significant risk factors for self-reports of being very depressed in the months after delivery included experiencing partner-associated stress (OR = 1.9, 95% CI = 1.5, 2.5), physical abuse during pregnancy (OR = 1.6, 95% CI = 1.1, 2.4), and not breast-feeding (OR = 1.4, 95% CI = 1.1, 1.8).\n## CONCLUSIONS\nThe highest prevalence for self-reports of being very depressed in the months after delivery was in women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life.\" Clinicians need to be aware of the needs of some women for mental health services both during and after pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Confinement and other psychosocial factors in perinatal depression: a transcultural study in Singapore.",
        "key_reference_abstract": "## BACKGROUND\nTo investigate the prevalence, socio-cultural and psychosocial risk factors for perinatal depression in Singaporean women.\n## METHOD\nA prospective cohort of 559 women was interviewed antenatally and at six weeks' postpartum at a tertiary hospital. Women were interviewed for diagnosis of depression using a two-stage design, with a screening questionnaire and diagnostic interview.\n## RESULTS\nPostnatally, a negative confinement experience was associated with depression. Other independent factors included poor emotional support, a past history of depression, unplanned pregnancy and perceived potential conflicts with relatives over childcare antenatally and dissatisfaction, poor instrumental support postnatally. The prevalence of depression antenatally and postnatally was 12.2% and 6.8%, respectively.\n## LIMITATIONS\nMeasures of satisfaction with social support were based on self-report; there were high dropout rates at six weeks' postpartum; and other modulating social factors such as pre-existing interpersonal conflicts were not studied.\n## CONCLUSIONS\nPerinatal depression in Singaporean women is common. Contrary to expectations, a negative 'confinement' experience is a significant risk factor for postnatal depression, and is not universally welcomed by women. Depression is modulated by dissimilar sets of psychosocial factors antenatally and postnatally.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice.",
        "key_reference_abstract": "## OBJECTIVE\nData are scarce regarding the sociodemographic predictors of antenatal and postpartum depression. This study investigated whether race/ethnicity, age, finances, and partnership status were associated with antenatal and postpartum depressive symptoms.\n## SETTING\n1662 participants in Project Viva, a US cohort study.\n## DESIGN\nMothers indicated mid-pregnancy and six month postpartum depressive symptoms on the Edinburgh postpartum depression scale (EPDS). Associations of sociodemographic factors with odds of scoring >12 on the EPDS were estimated.\n## MAIN RESULTS\nThe prevalence of depressive symptoms was 9% at mid-pregnancy and 8% postpartum. Black and Hispanic mothers had a higher prevalence of depressive symptoms compared with non-Hispanic white mothers. These associations were explained by lower income, financial hardship, and higher incidence of poor pregnancy outcome among minority women. Young maternal age was associated with greater risk of antenatal and postpartum depressive symptoms, largely attributable to the prevalence of financial hardship, unwanted pregnancy, and lack of a partner. The strongest risk factor for antenatal depressive symptoms was a history of depression (OR = 4.07; 95% CI 3.76, 4.40), and the strongest risk for postpartum depressive symptoms was depressive symptoms during pregnancy (6.78; 4.07, 11.31) or a history of depression before pregnancy (3.82; 2.31, 6.31).\n## CONCLUSIONS\nFinancial hardship and unwanted pregnancy are associated with antenatal and postpartum depressive symptoms. Women with a history of depression and those with poor pregnancy outcomes are especially vulnerable to depressive symptoms during the childbearing year. Once these factors are taken in account, minority mothers have the same risk of antenatal and postpartum depressive symptoms as white mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intentions and happiness among pregnant black women at high risk for adverse infant health outcomes.",
        "key_reference_abstract": "## CONTEXT\nUnintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman's feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.\n## METHODS\nA sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.\n## RESULTS\nPregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby's father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).\n## CONCLUSIONS\nAdditional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father's desire to have this child, may help improve prenatal care services and prevent adverse health outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Factors related to depression during pregnancy: are there gender differences?",
        "key_reference_abstract": "## OBJECTIVE\nTo determine gender differences between women and their partners in the effect of psychosocial and personal factors on depression during the third trimester of pregnancy.\n## METHOD\nA cross-sectional survey was carried out among 687 women and their partners (n = 669) attending the prenatal programme of Valencia province (Spain). Data collection was carried out by means of a self-reported questionnaire. The outcome variable was depression during the third trimester of pregnancy measured by the Edinburgh Postnatal Depression Scale. Predictor variables were psychosocial (marital dissatisfaction, confidant and affective social support) and personal (previous history of depression, partner depression and unplanned pregnancy) variables. The adjusted odds ratios (aOR) and their 95% confidence intervals were calculated by fitting a logistic regression model.\n## RESULTS\nThe prevalence of pregnancy depression was higher among women (10.3%) than men (6.5%). In both sexes, the probability of depression during pregnancy was higher in those with marital dissatisfaction (aOR 3.05, 95% CI 1.59 to 5.82 for women and 3.14, 95% CI 1.24 to 7.99 for men) and among those whose with a previous history of depression (aOR 2.18, 95% CI 1.22 to 3.89 for women and 5.22, 95% CI 2.05 to 13.34 for men). Unplanned pregnancy did not increase the risk of pregnancy depression either in women or men. Gender differences were found on the impact of social support and partner's depression. Whereas among men low affective social support and partner depression were associated with a higher probability of reporting depression, none of these variables were related to women's depression.\n## CONCLUSION\nMost predictor factors of depression during pregnancy are similar for both sexes but a gender-different impact of social support and partner depression on pregnancy depression was appreciated. Health professionals should be aware of potentially vulnerable groups for early diagnosis of pregnancy depression and to provide effective interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Psychosocial risk factors for depression during pregnancy.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the prevalence of antenatal depressive disorder in different trimesters and to evaluate the relation of psychosocial risk factors to antenatal depressive disorder.\n## DESIGN\nCohort follow-up.\n## SETTING\nUniversity Hospital, Kaunas, Lithuania.\n## SAMPLE\nTwo hundred and thirty pregnant women consecutively admitted.\n## METHODS\nAt 12-16 weeks, 22-26 weeks, and 32-36 weeks of pregnancy, participants were screened for depression using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). Women who gave at least one positive answer to the CIDI-SF depression-screening question were evaluated for depressive disorder using the non-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). Psychosocial stressors and two Big Five Personality dimensions, neuroticism and extraversion, were also evaluated.\n## MAIN OUTCOME MEASURES\nPrevalence of depressive disorder.\n## RESULTS\nThe prevalence of the antenatal depressive disorder at 12-16 weeks' gestation was 6.1%, at 22-26 weeks 3.5%, and at 32-36 weeks 4.4%. In the first trimester, a greater prevalence of current depressive disorder was independently associated with unplanned and unwanted pregnancy, high neuroticism, low education, and a previous history of depression; in the second trimester with unplanned and unwanted pregnancy and high neuroticism; in the third trimester with unplanned and unwanted pregnancy, high neuroticism, and the occurrence of psychosocial stressors during the last year.\n## CONCLUSIONS\nThe highest prevalence of depressive disorders was found in the first trimester, the lowest in mid-pregnancy. Several determinants (unwanted and unplanned pregnancy, high neuroticism) were independent predictors of antenatal depressive disorders throughout whole pregnancy, while other determinants (low education, previous history of depression, the occurrence of psychosocial stressors at the end of pregnancy) were trimester specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Unintended pregnancy and associated maternal preconception, prenatal and postpartum behaviors.",
        "key_reference_abstract": "## BACKGROUND\nThis study was conducted to determine the relationship between unintended pregnancy and maternal behaviors before, during and after pregnancy.\n## STUDY DESIGN\nData were analyzed from a stratified random sample of 9048 mothers who delivered live born infants between 2001 and 2006 and completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey 2 to 9 months after delivery. Binary and ordinal logistic regression methods with appropriate survey weights were used to control for socio-demographic factors.\n## RESULTS\nCompared to women with intended pregnancies, mothers with unwanted pregnancies were more likely to consume less than the recommended amount of preconception folic acid [adjusted odds ratio (OR) 2.39, 95% confidence interval (CI) 1.7-3.2], smoke prenatally (OR 2.03, 95% CI 1.5-2.9), smoke postpartum (OR 1.86, 95% CI 1.35-2.55) and report postpartum depression (OR 1.98, 95% CI 1.48-2.64); they were less likely to initiate prenatal care during the first trimester (OR 0.34, 95% CI 0.3-0.5) and breastfeed for 8 or more weeks (OR 0.74, 95% CI 0.57-0.97). Compared to women with intended pregnancies, women with mistimed pregnancies were also more likely to consume inadequate folic acid, delay prenatal care and report postpartum depression.\n## CONCLUSION\nEven after controlling for multiple socio-demographic factors, unwanted and mistimed pregnancies were associated with unhealthy perinatal behaviors.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Antenatal depression and male gender preference in Asian women in the UK.",
        "key_reference_abstract": "## OBJECTIVE\nto identify the prevalence of antenatal depression among Asian women living in the UK in one antenatal clinic, and to investigate the possible association with a desire for a male child and other risk factors.\n## DESIGN\ncross-sectional questionnaire-based study.\n## SETTING\ngeneral antenatal clinic in a hospital in Birmingham.\n## PARTICIPANTS\n300 Asian women, irrespective of place of birth.\n## METHODS\nconsecutive Asian women attending routine antenatal appointments during the study period self-completed a questionnaire. The first part investigated socio-demographic, cultural and other possible risk factors, including gender preference. The second part comprised the Edinburgh Postnatal Depression Scale (EPDS).\n## MEASUREMENTS\nEPDS score greater than or equal to 12 indicating probable depression.\n## FINDINGS\nthe prevalence of depression was 30.7% (92/300, 95% confidence interval 25.4-35.9%). Maternal male gender preference was not common and was not associated with antenatal depression. Family male gender preference, unplanned pregnancy, a history of depression and feeling anxious in pregnancy were independently associated with an increased likelihood of depression, whilst support from family and friends, being satisfied with pregnancy and being multiparous were associated with a reduced likelihood of depression.\n## CONCLUSION\nrates of antenatal depression were very high in Asian women with some associated risk factors. However, male gender preference was not associated with antenatal depression.\n## IMPLICATIONS FOR PRACTICE\ngiven the high prevalence, screening Asian women for depression may be indicated to allow treatment.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intention, demographic differences, and psychosocial health.",
        "key_reference_abstract": "## OBJECTIVES\nWe explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies.\n## METHODS\nData from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes.\n## RESULTS\nSixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups.\n## CONCLUSIONS\nFully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Obstetric and psychosocial risk factors for depressive symptoms during pregnancy.",
        "key_reference_abstract": "We aimed to determine the psychosocial and obstetric correlates of depressive symptomatology during pregnancy in South-Eastern Hungary. A total of 1719 women were screened for depression in four counties in 2006 and 2007, based on a Leverton Questionnaire (LQ) score of \u226512 at 14-24 weeks of gestation. The LQ scores indicated a probable depressive illness (PDI) in 17.2% of the study group. The best predictors in a multiple regression analysis were history of major depression (adjusted odds ratio [AOR]=3.23), and major life events (AOR=2.43). A perceived lack of social support from partner (AOR=1.79) and lack of support by family (AOR=1.23) were also significant determinants. Lack of planning of pregnancy (AOR=1.12) and a history of unfavourable obstetric outcome (AOR=1.42) also seem to predispose to PDI. Overall, psychosocial factors appeared important in the prediction of PDI, whereas economic features did not.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Unintended pregnancy and postpartum depression among first-time mothers.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is a mental disorder that occurs after birth and has negative consequences for the mother, infant, and family. The objective of this secondary analysis was to examine whether pregnancy intention was associated with postpartum depression among first-time mothers.\n## METHODS\nThe First Baby Study is a prospective cohort study of women aged 18-35 having a first singleton birth in Pennsylvania. Baseline data were collected during the third trimester. Postpartum depressive symptoms were measured at 1-month postpartum using the Edinburgh Postnatal Depression Scale. Logistic regression was performed to examine the association between unintended pregnancy and postpartum depression, controlling for prepregnancy anxiety/depression and sociodemographic data.\n## RESULTS\nOf 2972 first-time mothers, 83.4% were white, 70.7% were married, and 56.9% were college educated. Nine hundred fifty-two women (32.0%) reported their pregnancy was unintended and 151 (5.1%) met the threshold for postpartum depression. The prevalence of postpartum depression was higher in women with unintended pregnancies compared to women with intended pregnancies (6.7% vs. 4.3%, p<0.01). However, after controlling for confounders, unintended pregnancy was no longer associated with postpartum depression (adjusted OR 1.41; 95% CI 0.91-2.18). Variables independently associated with postpartum depression included prepregnancy anxiety/depression, Asian race, and Hispanic ethnicity.\n## CONCLUSION\nPregnancy intention was not independently associated with postpartum depression among first time mothers in Pennsylvania.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "The effect of pregnancy intention on maternal prenatal behaviours and parent and child health: results of an irish cohort study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors.\n## METHODS\nThis study uses data from the first wave of the 'Growing Up in Ireland Study', a large nationally representative cohort study of more than 11\u2009000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours.\n## RESULTS\nThe study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]).\n## CONCLUSIONS\nAscertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "From antenatal to postnatal depression: associated factors and mitigating influences.",
        "key_reference_abstract": "## INTRODUCTION\nPostnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression.\n## METHODS\nThe study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables.\n## RESULTS\nRisk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression.\n## CONCLUSION\nThis study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Intendedness of pregnancy and other predictive factors for symptoms of prenatal depression in a population-based study.",
        "key_reference_abstract": "Prenatal depression (PD) as a risk factor for adverse birth outcomes is well documented. Less is known about maternal risks for PD, which could inform preventive strategies for perinatal and interconceptional care. This exploratory study investigates associations between prenatal depression symptoms and unintended and mistimed pregnancies and other maternal risk factors for PD. A subset of birth records from the New York Statewide Perinatal Data System (n = 19,219) was used in this secondary analysis of cross-sectional data. Univariate and multivariate multinomial regression was used to identify factors that are independently associated with four self-reported levels of prenatal depression symptoms. Women with unintended pregnancies were more likely (AOR, 95 % CI) to report severe (3.6, 2.6-5.1) or moderate (2.0, 1.6-2.5) prenatal depression symptoms and less likely to report no symptoms, compared to women with intended pregnancies. Likewise, women with mistimed pregnancies were more likely to report severe (2.7, 2.2-3.5) or moderate (1.7, 1.5-2.1) prenatal depression symptoms than no symptoms, compared to women with intended pregnancies. Low education, drug use, smoking, minority race, being unmarried and having Medicaid insurance were also significant, independent predictors of PD symptoms. Results suggest that routine screening for depression, intendedness of pregnancy and other associated risk factors such as smoking and drug use during prenatal and interconceptional care visits may enable coordinated interventions that can reduce prenatal depression and unintended and mistimed pregnancies and improve pregnancy outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Impact of unintended pregnancy on maternal mental health: a causal analysis using follow up data of the Panel Study on Korean Children (PSKC).",
        "key_reference_abstract": "## BACKGROUND\nPregnancy intention is important for maternal and child health outcomes. The purpose of this study was to examine the causal relation between pregnancy intention and maternal depression and parenting stress in Korean women who gave birth during 2008.\n## METHODS\nThis study is a retrospective evaluation of prospectively collected data from the Panel Study on Korean Children from 2008 to 2010. Causal analyses were conducted using propensity score matching and inverse probability of treatment weighted methods. In addition, mediation analyses were performed to test mitigating effects of marital conflict, fathers' participation in childcare, and mothers' knowledge of infant development on the relation between unintended pregnancy and adverse maternal mental health.\n## RESULTS\nResults showed that the overall effect of an unintended pregnancy on maternal depression and parenting stress was statistically significant. An unintended pregnancy was associated with 20-22% greater odds of maternal depression, 0.28-0.39 greater depression score, and 0.85-1.16 greater parenting stress score. Relations between pregnancy intention and maternal depression, maternal depression score and parenting stress score were moderately explained by marital conflict and fathers' participation in childcare.\n## CONCLUSIONS\nUnintended pregnancy contributed to increased risks of maternal depression and parenting stress. Efforts to increase fathers' participation in childcare and decrease marital conflict might be helpful to mitigate adverse impacts of unintended pregnancy on perinatal maternal mental health.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Risk factors of transient and persistent anxiety during pregnancy.",
        "key_reference_abstract": "## PURPOSE\nchronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada.\n## METHODS\nwomen with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup.\n## FINDINGS\nwomen with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85-13.39) were unique predictors of chronic depressive symptoms.\n## CONCLUSIONS\nknowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Are pregnancy planning and pregnancy timing associated with maternal psychiatric illness, psychological distress and support during pregnancy?",
        "key_reference_abstract": "## BACKGROUND\nPregnancy planning and timing may be associated with psychiatric illness, psychological distress and support during pregnancy.\n## METHODS\nWe performed secondary analyses of a prospective cohort of 2654 pregnant women evaluating the impact of depression on preterm birth. We used multivariable logistic regression to test associations between pregnancy planning (\"Was this pregnancy planned? Yes/No\") and/or timing (\"Do you think this is a good time for you to be pregnant?\") with Composite International Diagnostic Interview generated psychiatric diagnoses and measures of psychological distress and support.\n## RESULTS\n37% and 13% of participants reported an unplanned or poorly timed pregnancy, respectively. Unplanned pregnancies were associated with a Major Depressive Episode (MDE) (adjusted odds ratio (aOR) 1.69, 95%CI 1.23-2.32) and the Cohen Perceived Stress Scale's (CPSS) highest quartile (aOR 1.74, 95%CI 1.40-2.16). Poorly timed pregnancies were associated with a MDE (aOR 3.47, 95%CI 2.46-4.91) and the CPSS's highest quartile (aOR 5.20, 95%CI 3.93-6.87). Poorly timed pregnancies were also associated with General Anxiety Disorder (GAD; aOR 1.60, 95%CI 1.07-2.40), and the modified Kendler Social Support Inventory's (MKSSI) lowest quartile (aOR 1.64, 95%CI 1.25-2.16). Psychiatric conditions were strongly associated with planned pregnancies that were subsequently deemed poorly timed (MDE=aOR 5.08, 95%CI 2.52-10.25; GAD=aOR 2.28, 95%CI 1.04-5.03); high CPSS=aOR 6.48, 95%CI 3.59-11.69; and low MKSSI=aOR 3.19, 95%CI 1.81-5.62.\n## LIMITATIONS\nParticipant characteristics may limit generalizability of findings.\n## CONCLUSIONS\nPregnancy timing was a stronger predictor of maternal psychiatric illness, psychological distress and low social support than pregnancy planning in our cohort.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs).\n## METHODS\nUsing Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross-sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design.\n## RESULTS\nIn multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23-2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs.\n## CONCLUSIONS\nThis study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "The association between pregnancy intendedness and experiencing symptoms of postpartum depression among new mothers in the United States, 2009 to 2011: A secondary analysis of PRAMS data.",
        "key_reference_abstract": "Postpartum depression (PPD) is a form of major depressive disorder affecting approximately 13% of women worldwide. Unintended pregnancies, reaching close to 50% of the pregnancies in the United States, have become a major health concern. While many physiologic and psychosocial causes have been analyzed, few studies have examined the relationship between unintended pregnancy and symptoms of PPD.A cross-sectional study was conducted using surveillance data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2009 to 2011. The PRAMS population-based random sample included women who have had recent live births and is representative of 78% of the United States population. The chi-squared test was used to examine bivariate associations. Binary logistic regression was utilized to study unadjusted and adjusted associations between PPD and pregnancy intendedness, as well as other demographic and clinical characteristics of mothers in the sample. Multicollinearity in the adjusted model was evaluated using variance inflation factors. Sampling weights were used to account for PRAMS' complex sampling design.Of the 110,231 mothers included in the sample, only 32.3% reported desiring the pregnancy at the time of conception. Women with pregnancies categorized as mistimed: desired sooner, mistimed: desired later, or unwanted were 20% (adjusted odds ratio [AOR]\u200a=\u200a1.2; 95% confidence interval [CI]: 1.1-1.3), 30% (AOR\u200a=\u200a1.3; 95% CI: 1.2-1.4), and 50% (AOR\u200a=\u200a1.5; 95% CI: 1.3-1.7) more likely to experience symptoms of PPD, respectively, compared to women with desired pregnancies. Other factors found to be associated with experiencing symptoms of PPD were a gestational age of <27 weeks (AOR\u200a=\u200a3.1; 95% CI: 2.5-4.0), having a previous history of depression (AOR\u200a=\u200a1.8; 95% CI: 1.6-2.0), and being abused during or before pregnancy (AOR\u200a=\u200a1.6; 95% CI: 1.4-2.0).We found that women with mistimed or unwanted pregnancies were more likely to experience symptoms of PPD. Our findings support the current US Preventive Services Task Force and American Academy of Pediatrics recommendations for an integrated approach to screening for depression, aiding in the maximization of intervention and early referral for women at risk for PPD.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Psychosocial status and prenatal care of unintended pregnancies among low-income women.",
        "key_reference_abstract": "## BACKGROUND\nNearly half of all pregnancies in the United States are reported as unintended and rates are highest among women of low socioeconomic status. The purpose of this study was to examine the associations between unintended pregnancies and maternal mental health and timing of prenatal care among low-income women.\n## METHODS\nIn this cross-sectional study, 870 women, whom were participating in the First 1000\u2009Days program in three community health centers in the Boston area, were enrolled at their first prenatal visit from August 2016 - September 2017. We assessed pregnancy intention by self-report using the Pregnancy Risk Assessment Monitoring System. We used self-reported survey information and electronic health record data to assess the following outcomes: current stress, current depression, and timing of initial prenatal visit. We used multivariable logistic regression models to examine associations and adjusted for sociodemographic factors.\n## RESULTS\nWomen were a mean (SD) age of 29.3 (6.1), and 39.2% reported that their pregnancy was unintended. 50.6% of women were Hispanic, 28.4% were White, 10.1% were Black, and 10.9% were other races. 78.9% of women reported an annual household income <$50,000. Overall, 26.7% of women reported current stress, 8.2% reported current depression, and 18.3% of women initiated prenatal care after their first trimester. In multivariable analyses, women with unintended pregnancies had higher odds of experiencing current stress (OR: 1.72; 95% CI: 1.22, 2.41), current depression (OR: 1.83; 95% CI: 1.04, 3.20), and initiation of prenatal care post-first trimester (OR: 1.84; 95% CI: 1.23, 2.74).\n## CONCLUSIONS\nUnintended pregnancies were associated with current stress and depression, and delayed prenatal care in this sample of low-income women suggesting the importance of identifying high-risk women and tailoring interventions to support women's needs.\n## TRIAL REGISTRATION\nClinicalTrials.gov (NCT03191591; Retrospectively registered on June 19, 2017).",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "The Role of Father Involvement and Intimate Partner Violence on Postnatal Depression Among Women With Unintended Pregnancy.",
        "key_reference_abstract": "This study set out to fill the research gap by including various aspects of father involvement and intimate partner violence (IPV) in the examination of the association between unintended pregnancy and maternal postnatal depression (PND). This study aimed to examine the effect of father involvement and IPV on the association between unintended pregnancy and PND. A sample of 1,083 pregnant women who attended antenatal clinic at selected hospitals in Hong Kong completed two surveys to report on their pregnancy intention, antenatal depression, PND, IPV during pregnancy, their partner's (i.e., father's) involvement during pregnancy and after childbirth, and perceived social support. Comparisons were made between women with unintended pregnancy and those with intended pregnancy, and the effects of unintended pregnancy, father involvement, IPV, and other factors on maternal PND were examined. Results show that women with unintended pregnancy were more likely to report PND, IPV, fear, postnatal stress, lower degree of father involvement, and lower level of social support. Unintended pregnancy independently increased the risk of PND by 1.95 times (95% confidence interval [CI] = [1.15, 3.28]), after adjustment for all other variables. When father involvement was included in the regression model, the negative effects of IPV and the related fear on PND became nonsignificant. The positive association between unintended pregnancy and PND was robust. Father involvement might help promote maternal health by reducing the negative effects of IPV on PND.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Do Pregnancy Intentions Matter? A Research Note Revisiting Relationships Among Pregnancy, Birth, and Maternal Outcomes.",
        "key_reference_abstract": "The prevention of unplanned or unintended pregnancies continues to be a cornerstone of U.S. reproductive health policy, but the evidence that such pregnancies cause adverse maternal and child outcomes is limited. In this research note, we examine these relationships using recent large-scale data and inverse propensity weights estimated from generalized boosted models. We find that pregnancy timing is related to maternal experience during pregnancy, but not to infant outcomes at birth-both of which are consistent with prior research. In an addition to the literature, we show that pregnancy timing is relevant for a number of maternal outcomes, such as the onset of depression and intimate partner violence, changes in smoking behavior, and receipt of medical care. These findings suggest that policy intended to improve infant welfare by preventing unintended pregnancies has little empirical support, but that policy focused on increasing reproductive autonomy and maternal well-being has the potential to improve outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy planning and acceptance and maternal psychological distress during pregnancy: results from the National Perinatal Survey, France, 2016.",
        "key_reference_abstract": "## BACKGROUND\nStudies report heightened risks of mental health problems among women who experience an unintended pregnancy, but few consider the complexity of pregnancy intentions. In this study, we evaluate how different dimensions of pregnancy intentions (pregnancy planning and pregnancy acceptance) relate to two maternal depressive symptoms and perceived psychological distress.\n## METHODS\nThis study draws from a cross-sectional national survey conducted in all maternities in France over a one-week period in 2016. All mothers 18\u2009years and older who had a live birth during the study period were invited to participate. After excluding women who underwent infertility treatment, our analytical sample included 10,339 women. We first described levels and correlates of pregnancy planning and acceptance, defined in four categories; planned/welcomed, unplanned/welcomed, planned/unwelcomed, unplanned/unwelcomed. We then assessed the bivariate and multivariate associations between pregnancy planning and acceptance and two outcomes: women's self-perceived psychological health and the presence of two depressive symptoms during pregnancy. We used multivariate logistic regressions to evaluate these associations, after adjusting for socio-demographic and medical factors.\n## RESULTS\nAltogether 7.5 to 24.1% of mothers perceived their psychological health during pregnancy was poor, according to pregnancy planning and acceptance categories and 10.3 to 22.4% indicated feelings of sadness and loss of interest during pregnancy, according to pregnancy planning and acceptance categories. As compared to women with planned/welcomed pregnancies, the odds of perceived poor psychological health and depressive symptoms were 2.55 times (CI 2.20-2.95) and 1.75 times higher (CI 1.51-2.02), respectively, among unplanned/unwelcomed pregnancies and 2.02 (CI 1.61-2.53) and 2.07 (CI 1.7-2.5) higher, among planned/unwelcomed pregnancies. Among women with unplanned pregnancies, we also found higher odds of perceived poor psychological health among women whose pregnancy was unwelcomed while the odds of depressive symptoms were not different by pregnancy planning status among women with unwelcomed pregnancies.\n## CONCLUSIONS\nThese findings consolidate previous reports of the association between pregnancy intentions and maternal psychological distress, while further specifying the relationship, which mostly depends on the acceptance of pregnancy timing rather than on pregnancy planning. Identifying women with low pregnancy acceptance can potentially enhance current medical practice by improving early detection of maternal depression.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors.\n## METHODS\nIn 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy.\n## RESULTS\nWomen who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester.\n## CONCLUSIONS\nWomen with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Unintended pregnancy and intimate partner violence before and during pregnancy among Latina women in Los Angeles, California.",
        "key_reference_abstract": "The purpose of this paper was to examine the relationship between unintended pregnancy and intimate partner violence (IPV) before and during pregnancy among Latinas. A cross-sectional interview measuring pregnancy intent, IPV, and acculturation, using the Acculturation Rating Scale for Mexican Americans (ARSMA-II), was conducted among Latina women in their 2(nd) or 3(rd) trimester of pregnancy at clinics in Los Angeles (n = 313). Overall, 44% of women reported an unintended pregnancy. The prevalence of physical (any) and emotional (only) abuse 12 months before pregnancy was 11% and 22%, respectively. Although both types of IPV decreased during pregnancy (10% and 19%, respectively), most reports of physical IPV during pregnancy (53%) were among women who did not report physical abuse before pregnancy. After adjusting for other factors, physical IPV before pregnancy was not associated with unintended pregnancy (adjusted OR = 0.92; 95% CI = 0.40, 2.16). The prevalence of unintended pregnancy was highest (76%) among highly acculturated Latinas. However, when an unintended pregnancy occurred among less acculturated Latinas, who comprised the majority of the sample (n = 270), it was associated with greater risk of physical IPV during pregnancy (unadjusted OR = 2.57; 95% CI = 1.06, 6.23); although the confidence interval included one after adjusting for other factors (adjusted OR = 2.79; 95% CI = 0.98, 7.92). An unintended pregnancy may have a unique impact on relationships in the context of Latino culture, where family and pregnancy are highly valued. Pregnancy often creates an opportunity for providers to discuss issues related to abuse and family planning with women who do not regularly access care. The results from this study may be used to increase the cultural sensitivity with which violence and reproductive health are addressed among the diverse population of Latinas when they connect with prenatal services.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Severity of intimate partner abuse indicators as perceived by women in Mexico and the United States.",
        "key_reference_abstract": "## OBJECTIVE\nWomen in Cuernavaca, Mexico and Los Angeles, California were surveyed to examine differences in their perceptions of the severity of domestic violence indicators.\n## METHODS\nOne hundred twenty women in each country rated the severity of 26 domestic violence indicators which were part of an abuse screen used for an ongoing study of the prevalence of abuse. Rasch analysis was conducted to determine the linear relationship in the perceptions of the severity of each event between the two countries.\n## RESULTS\nThe Rasch calibrated logit values show that women in the US rated 24 of the 26 events as more severe than women in Mexico. However, items were ranked in similar order and a clear linear pattern was established. In both countries, being shot with a gun was the most severe event and a partner becoming jealous was the least severe.\n## CONCLUSION\nThe country of origin did not dictate which events were most severe but did influence how severe these events were perceived.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse.\n## METHODS\nA prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used.\n## RESULTS\nApproximately one-fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68).\n## CONCLUSION\nWomen who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Early Childhood Victimization and Physical Intimate Partner Violence During Pregnancy: A Developmental and Person-Oriented Approach.",
        "key_reference_abstract": "Intimate partner violence (IPV) victimization during pregnancy is a major public health concern, yet little is known about how risk factors for IPV during pregnancy may depend on whether women have histories of victimization dating back to early childhood (ages 0-5 years). This study examined whether risk factors for physical IPV victimization during pregnancy (a pregnancy that was not planned and prenatal substance use) differed for women with versus without early childhood victimization. Participants were 236 ethnically diverse, low-income biological mothers ( M = 30.94 years; 50.0% Latina, 16.9% Caucasian, 13.1% African American, and 16.9% multiracial) of children aged 0 to 6 years. Mothers were classified into four groups based on whether they had experienced early childhood victimization and physical IPV victimization during pregnancy with the target child. Multinomial logistic regressions, controlling for demographic characteristics, examined whether a pregnancy not planned and prenatal substance use predicted group membership. Compared to mothers with early victimization only, mothers with both early childhood victimization and physical IPV during pregnancy were more than 3 times as likely to report that their pregnancy with the target child was not planned. In follow-up analyses, mothers with early victimization and physical IPV during pregnancy also reported higher lifetime parity than mothers with physical IPV during pregnancy but no early victimization. Early childhood victimization may place women on a risk pathway to physical IPV during pregnancy, particularly if the pregnancy is not planned. Prevention and policy efforts should screen women for early childhood victimization to understand risks for physical IPV during pregnancy.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "The effect of pregnancy intention on child development.",
        "key_reference_abstract": "In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Unintended pregnancy and preterm birth.",
        "key_reference_abstract": "About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intention and its relationship to birth and maternal outcomes.",
        "key_reference_abstract": "## OBJECTIVE\nTo examine whether there are associations between pregnancy intention (intended, unwanted, mistimed, or ambivalent) and negative birth and maternal outcomes: low birth weight (less than 2,500 g), preterm delivery (fewer than 37 weeks), small for gestational age, premature labor, hypertension, and other maternal outcomes.\n## METHODS\nWe analyzed data from the population-based Pregnancy Risk Assessment Monitoring System, including 87,087 women who gave birth between 1996 and 1999 in 18 states. Information on pregnancy outcomes was derived from birth certificate data and a self-administered questionnaire completed postpartum. We employed SUDAAN (RTI International, Research Triangle Park, NC) for univariable and logistical regression analyses.\n## RESULTS\nIn analyses controlling for demographic and behavioral factors, women with unwanted pregnancies had an increased likelihood of preterm delivery (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33) and premature rupture of membranes (adjusted OR 1.37, 95% CI 1.01-1.85) compared with women with intended pregnancies. Women who were ambivalent toward their pregnancies had increased odds of delivering a low birth weight infant (adjusted OR 1.15, 95% CI 1.02-1.29); in contrast, women with mistimed pregnancies had a lower likelihood (adjusted OR 0.92, 95% CI 0.86-0.97).\n## CONCLUSION\nPregnancy intention, specifically unwanted and ambivalent, may be an indicator of increased risk for some poor birth and maternal outcomes and should be considered in interventions aimed at improving the health of the mother and child.\n## LEVEL OF EVIDENCE\nIII.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intention and preterm birth: differential associations among a diverse population of women.",
        "key_reference_abstract": "## CONTEXT\nStudies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups.\n## METHODS\nData from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics.\n## RESULTS\nIn unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites.\n## CONCLUSIONS\nWomen's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "The couple context of pregnancy and its effects on prenatal care and birth outcomes.",
        "key_reference_abstract": "The couple context of pregnancy and newborn health is gaining importance with the increase in births to unmarried couples, a disproportionate number of which were not intended. This study investigates the association of early prenatal care, preterm birth, and low birth weight with the couple relationship context, including partners' joint intentions for the pregnancy, their marital status at conception, and the presence of relationship problems during pregnancy. Data are drawn from the first wave of the Early Childhood Longitudinal Study--Birth Cohort, a representative study of births in 2001. The sample is composed of parents residing together with their biological child at the time the child is 9 months old, where both the mother and father completed the self-report interview (N = 5,788). Couple-level multivariate logistic regression models, weighted to account for the complex sampling design, were used in the analysis. Risk of inadequate prenatal care and preterm birth was increased when partners did not share intentions or when neither partner intended the pregnancy. Couples were at additional risk of inadequate prenatal care when the pregnancy was conceived nonmaritally and when the mother did not tell the father about the pregnancy, particularly when neither partner intended the pregnancy. The risk of premature birth was particularly high when the partners were unmarried and either or both did not intend the pregnancy. The couple context of pregnancy is important for a healthy pregnancy and birth. When the partner is present, practitioners and programs should maintain a focus on the couple, and researchers should make every effort to include the father's own perspective.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Assessing pregnancy intention and associated risks in pregnant adolescents.",
        "key_reference_abstract": "Unintended pregnancy and associated behaviors may play a substantial role in the increased risk of adverse maternal and neonatal outcomes associated with teen pregnancy. We evaluate a multi-dimensional measure of pregnancy intention among pregnant adolescents and quantify the association between intention dimensions and adverse outcomes and risk behaviors. Pregnancy intention measures were examined in a cohort of 300 pregnant adolescent women. We considered 18 items assessing elements of pregnancy intention including pregnancy planning, timing, emotional response, and readiness. Latent class analysis was performed to identify dimensions of pregnancy intention. Parsimonious scores were created by minimizing the number of covariates while maintaining substantial agreement with the latent class. Associations between intention measures and prenatal care, risk behaviors, and pregnancy outcomes were quantified using multivariable logistic regression. Two constructs of pregnancy intention were identified: planning and emotional readiness. Compared with emotionally ready adolescents, adolescents categorized as not emotionally ready had an increased odds of inadequate prenatal care (OR = 2.70, 95% CI:1.27-5.72), delayed prenatal care (OR = 2.54, 95% CI:1.27-5.09), and self-reported depression at the time of the first prenatal visit (OR = 2.21, 95% CI:1.03-4.77). Pregnancy planning was not associated with adverse pregnancy risk factors or outcomes. Among pregnant adolescents, emotional readiness for pregnancy and parenting was inversely associated with known risk factors for adverse pregnancy outcomes, suggesting that emotional readiness rather than pregnancy planning may be the more pertinent intention construct for adolescents.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy planning, smoking behaviour during pregnancy, and neonatal outcome: UK Millennium Cohort Study.",
        "key_reference_abstract": "## BACKGROUND\nPre-pregnancy health and care are important for the health of the future generations. Smoking during pregnancy has been well-researched and there is clear evidence of harm. But there has been little research on the health impact of planning for pregnancy. This study aims to investigate the independent effects of pregnancy planning and smoking during pregnancy on neonatal outcome.\n## METHODS\nThis analysis made use of data from the UK Millennium Cohort Study. The study sample consisted of 18,178 singleton babies born in UK between 2000 and 2001. The neonatal outcomes of interest were low birthweight (<2.5 Kg) and pre-term birth (<37 completed weeks gestation). Logistic regression was used to estimate the association between pregnancy planning and/or smoking and neonatal outcome. Adjusted odds ratios were used to calculate population attributable risk fractions (PAFs).\n## RESULTS\n43% of mothers did not plan their pregnancy and 34% were smoking just before and/or during pregnancy. Planners were half as likely to be smokers just before pregnancy, and more likely to give up or reduce the amount smoked if smokers. Unplanned pregnancies had 24% increased odds of low birth weight and prematurity compared to planned pregnancies (AORLBW1.24, 95% CI 1.04-1.48; AORPREM1.24, 95% CI 1.05-1.45), independent of smoking status. The odds of low birth weight for babies of mothers who were smoking just before pregnancy was 91% higher than that of mothers who were not (AORLBW1.91, 95% CI 1.56-2.34). Women who quit or reduced the amount smoked during pregnancy lowered the risk of a low birth weight baby by one third (AORLBW0.66, 95% CI 0.51-0.85) compared with women whose smoking level did not change. Smaller effects were found for prematurity. If all women planned their pregnancy and did not smoke before or during pregnancy, 30% of low birthweight and 14% of prematurity could, in theory, be avoided.\n## CONCLUSIONS\nPlanning a pregnancy and avoiding smoking during pregnancy has clear, independent, health benefits for babies. Quitting or reducing the amount smoked during pregnancy can reduce the risk of low birthweight.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Are pregnancy planning and timing associated with preterm or small for gestational age births?",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births.\n## DESIGN\nProspective cohort study.\n## SETTING\nNot applicable.\n## PATIENT(S)\nTwo thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy.\n## INTERVENTION(S)\nNone.\n## MAIN OUTCOME MEASURE(S)\nPreterm and small for gestational age births.\n## RESULT(S)\nIn adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age.\n## CONCLUSION(S)\nIn a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Maternal Outcomesa - Maternal violence",
        "key_reference_title": "Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma.",
        "key_reference_abstract": "Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed \u22652 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study identified correlates of self-reports of being very depressed in the months after delivery in a population-based sample of women.\n## METHODS\nWe analyzed data on 14,609 recent mothers from the Centers for Disease Control and Prevention's (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS). The sample included mothers who delivered a live birth in Colorado, New York State, and North Carolina from 1996 (New York only) to 1999. We assessed risk factors for self-reports of being very depressed in the months after delivery using logistic regression.\n## RESULTS\nOverall, 5.9% (95% CI = 5.3, 6.4) of new mothers reported being very depressed in the months after delivery. Women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life\" had the highest prevalence of reporting being very depressed in the months after delivery (24.9%, 95% CI = 21.3, 28.5) and, when all risk factors were adjusted for simultaneously, were 4.6 times (95% CI = 3.1, 6.3) more likely to report being very depressed in the months after delivery than other women. Other significant risk factors for self-reports of being very depressed in the months after delivery included experiencing partner-associated stress (OR = 1.9, 95% CI = 1.5, 2.5), physical abuse during pregnancy (OR = 1.6, 95% CI = 1.1, 2.4), and not breast-feeding (OR = 1.4, 95% CI = 1.1, 1.8).\n## CONCLUSIONS\nThe highest prevalence for self-reports of being very depressed in the months after delivery was in women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life.\" Clinicians need to be aware of the needs of some women for mental health services both during and after pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Confinement and other psychosocial factors in perinatal depression: a transcultural study in Singapore.",
        "key_reference_abstract": "## BACKGROUND\nTo investigate the prevalence, socio-cultural and psychosocial risk factors for perinatal depression in Singaporean women.\n## METHOD\nA prospective cohort of 559 women was interviewed antenatally and at six weeks' postpartum at a tertiary hospital. Women were interviewed for diagnosis of depression using a two-stage design, with a screening questionnaire and diagnostic interview.\n## RESULTS\nPostnatally, a negative confinement experience was associated with depression. Other independent factors included poor emotional support, a past history of depression, unplanned pregnancy and perceived potential conflicts with relatives over childcare antenatally and dissatisfaction, poor instrumental support postnatally. The prevalence of depression antenatally and postnatally was 12.2% and 6.8%, respectively.\n## LIMITATIONS\nMeasures of satisfaction with social support were based on self-report; there were high dropout rates at six weeks' postpartum; and other modulating social factors such as pre-existing interpersonal conflicts were not studied.\n## CONCLUSIONS\nPerinatal depression in Singaporean women is common. Contrary to expectations, a negative 'confinement' experience is a significant risk factor for postnatal depression, and is not universally welcomed by women. Depression is modulated by dissimilar sets of psychosocial factors antenatally and postnatally.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice.",
        "key_reference_abstract": "## OBJECTIVE\nData are scarce regarding the sociodemographic predictors of antenatal and postpartum depression. This study investigated whether race/ethnicity, age, finances, and partnership status were associated with antenatal and postpartum depressive symptoms.\n## SETTING\n1662 participants in Project Viva, a US cohort study.\n## DESIGN\nMothers indicated mid-pregnancy and six month postpartum depressive symptoms on the Edinburgh postpartum depression scale (EPDS). Associations of sociodemographic factors with odds of scoring >12 on the EPDS were estimated.\n## MAIN RESULTS\nThe prevalence of depressive symptoms was 9% at mid-pregnancy and 8% postpartum. Black and Hispanic mothers had a higher prevalence of depressive symptoms compared with non-Hispanic white mothers. These associations were explained by lower income, financial hardship, and higher incidence of poor pregnancy outcome among minority women. Young maternal age was associated with greater risk of antenatal and postpartum depressive symptoms, largely attributable to the prevalence of financial hardship, unwanted pregnancy, and lack of a partner. The strongest risk factor for antenatal depressive symptoms was a history of depression (OR = 4.07; 95% CI 3.76, 4.40), and the strongest risk for postpartum depressive symptoms was depressive symptoms during pregnancy (6.78; 4.07, 11.31) or a history of depression before pregnancy (3.82; 2.31, 6.31).\n## CONCLUSIONS\nFinancial hardship and unwanted pregnancy are associated with antenatal and postpartum depressive symptoms. Women with a history of depression and those with poor pregnancy outcomes are especially vulnerable to depressive symptoms during the childbearing year. Once these factors are taken in account, minority mothers have the same risk of antenatal and postpartum depressive symptoms as white mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intentions and happiness among pregnant black women at high risk for adverse infant health outcomes.",
        "key_reference_abstract": "## CONTEXT\nUnintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman's feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.\n## METHODS\nA sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.\n## RESULTS\nPregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby's father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).\n## CONCLUSIONS\nAdditional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father's desire to have this child, may help improve prenatal care services and prevent adverse health outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Factors related to depression during pregnancy: are there gender differences?",
        "key_reference_abstract": "## OBJECTIVE\nTo determine gender differences between women and their partners in the effect of psychosocial and personal factors on depression during the third trimester of pregnancy.\n## METHOD\nA cross-sectional survey was carried out among 687 women and their partners (n = 669) attending the prenatal programme of Valencia province (Spain). Data collection was carried out by means of a self-reported questionnaire. The outcome variable was depression during the third trimester of pregnancy measured by the Edinburgh Postnatal Depression Scale. Predictor variables were psychosocial (marital dissatisfaction, confidant and affective social support) and personal (previous history of depression, partner depression and unplanned pregnancy) variables. The adjusted odds ratios (aOR) and their 95% confidence intervals were calculated by fitting a logistic regression model.\n## RESULTS\nThe prevalence of pregnancy depression was higher among women (10.3%) than men (6.5%). In both sexes, the probability of depression during pregnancy was higher in those with marital dissatisfaction (aOR 3.05, 95% CI 1.59 to 5.82 for women and 3.14, 95% CI 1.24 to 7.99 for men) and among those whose with a previous history of depression (aOR 2.18, 95% CI 1.22 to 3.89 for women and 5.22, 95% CI 2.05 to 13.34 for men). Unplanned pregnancy did not increase the risk of pregnancy depression either in women or men. Gender differences were found on the impact of social support and partner's depression. Whereas among men low affective social support and partner depression were associated with a higher probability of reporting depression, none of these variables were related to women's depression.\n## CONCLUSION\nMost predictor factors of depression during pregnancy are similar for both sexes but a gender-different impact of social support and partner depression on pregnancy depression was appreciated. Health professionals should be aware of potentially vulnerable groups for early diagnosis of pregnancy depression and to provide effective interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Psychosocial risk factors for depression during pregnancy.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the prevalence of antenatal depressive disorder in different trimesters and to evaluate the relation of psychosocial risk factors to antenatal depressive disorder.\n## DESIGN\nCohort follow-up.\n## SETTING\nUniversity Hospital, Kaunas, Lithuania.\n## SAMPLE\nTwo hundred and thirty pregnant women consecutively admitted.\n## METHODS\nAt 12-16 weeks, 22-26 weeks, and 32-36 weeks of pregnancy, participants were screened for depression using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). Women who gave at least one positive answer to the CIDI-SF depression-screening question were evaluated for depressive disorder using the non-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). Psychosocial stressors and two Big Five Personality dimensions, neuroticism and extraversion, were also evaluated.\n## MAIN OUTCOME MEASURES\nPrevalence of depressive disorder.\n## RESULTS\nThe prevalence of the antenatal depressive disorder at 12-16 weeks' gestation was 6.1%, at 22-26 weeks 3.5%, and at 32-36 weeks 4.4%. In the first trimester, a greater prevalence of current depressive disorder was independently associated with unplanned and unwanted pregnancy, high neuroticism, low education, and a previous history of depression; in the second trimester with unplanned and unwanted pregnancy and high neuroticism; in the third trimester with unplanned and unwanted pregnancy, high neuroticism, and the occurrence of psychosocial stressors during the last year.\n## CONCLUSIONS\nThe highest prevalence of depressive disorders was found in the first trimester, the lowest in mid-pregnancy. Several determinants (unwanted and unplanned pregnancy, high neuroticism) were independent predictors of antenatal depressive disorders throughout whole pregnancy, while other determinants (low education, previous history of depression, the occurrence of psychosocial stressors at the end of pregnancy) were trimester specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Unintended pregnancy and associated maternal preconception, prenatal and postpartum behaviors.",
        "key_reference_abstract": "## BACKGROUND\nThis study was conducted to determine the relationship between unintended pregnancy and maternal behaviors before, during and after pregnancy.\n## STUDY DESIGN\nData were analyzed from a stratified random sample of 9048 mothers who delivered live born infants between 2001 and 2006 and completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey 2 to 9 months after delivery. Binary and ordinal logistic regression methods with appropriate survey weights were used to control for socio-demographic factors.\n## RESULTS\nCompared to women with intended pregnancies, mothers with unwanted pregnancies were more likely to consume less than the recommended amount of preconception folic acid [adjusted odds ratio (OR) 2.39, 95% confidence interval (CI) 1.7-3.2], smoke prenatally (OR 2.03, 95% CI 1.5-2.9), smoke postpartum (OR 1.86, 95% CI 1.35-2.55) and report postpartum depression (OR 1.98, 95% CI 1.48-2.64); they were less likely to initiate prenatal care during the first trimester (OR 0.34, 95% CI 0.3-0.5) and breastfeed for 8 or more weeks (OR 0.74, 95% CI 0.57-0.97). Compared to women with intended pregnancies, women with mistimed pregnancies were also more likely to consume inadequate folic acid, delay prenatal care and report postpartum depression.\n## CONCLUSION\nEven after controlling for multiple socio-demographic factors, unwanted and mistimed pregnancies were associated with unhealthy perinatal behaviors.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Antenatal depression and male gender preference in Asian women in the UK.",
        "key_reference_abstract": "## OBJECTIVE\nto identify the prevalence of antenatal depression among Asian women living in the UK in one antenatal clinic, and to investigate the possible association with a desire for a male child and other risk factors.\n## DESIGN\ncross-sectional questionnaire-based study.\n## SETTING\ngeneral antenatal clinic in a hospital in Birmingham.\n## PARTICIPANTS\n300 Asian women, irrespective of place of birth.\n## METHODS\nconsecutive Asian women attending routine antenatal appointments during the study period self-completed a questionnaire. The first part investigated socio-demographic, cultural and other possible risk factors, including gender preference. The second part comprised the Edinburgh Postnatal Depression Scale (EPDS).\n## MEASUREMENTS\nEPDS score greater than or equal to 12 indicating probable depression.\n## FINDINGS\nthe prevalence of depression was 30.7% (92/300, 95% confidence interval 25.4-35.9%). Maternal male gender preference was not common and was not associated with antenatal depression. Family male gender preference, unplanned pregnancy, a history of depression and feeling anxious in pregnancy were independently associated with an increased likelihood of depression, whilst support from family and friends, being satisfied with pregnancy and being multiparous were associated with a reduced likelihood of depression.\n## CONCLUSION\nrates of antenatal depression were very high in Asian women with some associated risk factors. However, male gender preference was not associated with antenatal depression.\n## IMPLICATIONS FOR PRACTICE\ngiven the high prevalence, screening Asian women for depression may be indicated to allow treatment.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intention, demographic differences, and psychosocial health.",
        "key_reference_abstract": "## OBJECTIVES\nWe explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies.\n## METHODS\nData from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes.\n## RESULTS\nSixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups.\n## CONCLUSIONS\nFully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Obstetric and psychosocial risk factors for depressive symptoms during pregnancy.",
        "key_reference_abstract": "We aimed to determine the psychosocial and obstetric correlates of depressive symptomatology during pregnancy in South-Eastern Hungary. A total of 1719 women were screened for depression in four counties in 2006 and 2007, based on a Leverton Questionnaire (LQ) score of \u226512 at 14-24 weeks of gestation. The LQ scores indicated a probable depressive illness (PDI) in 17.2% of the study group. The best predictors in a multiple regression analysis were history of major depression (adjusted odds ratio [AOR]=3.23), and major life events (AOR=2.43). A perceived lack of social support from partner (AOR=1.79) and lack of support by family (AOR=1.23) were also significant determinants. Lack of planning of pregnancy (AOR=1.12) and a history of unfavourable obstetric outcome (AOR=1.42) also seem to predispose to PDI. Overall, psychosocial factors appeared important in the prediction of PDI, whereas economic features did not.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Unintended pregnancy and postpartum depression among first-time mothers.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is a mental disorder that occurs after birth and has negative consequences for the mother, infant, and family. The objective of this secondary analysis was to examine whether pregnancy intention was associated with postpartum depression among first-time mothers.\n## METHODS\nThe First Baby Study is a prospective cohort study of women aged 18-35 having a first singleton birth in Pennsylvania. Baseline data were collected during the third trimester. Postpartum depressive symptoms were measured at 1-month postpartum using the Edinburgh Postnatal Depression Scale. Logistic regression was performed to examine the association between unintended pregnancy and postpartum depression, controlling for prepregnancy anxiety/depression and sociodemographic data.\n## RESULTS\nOf 2972 first-time mothers, 83.4% were white, 70.7% were married, and 56.9% were college educated. Nine hundred fifty-two women (32.0%) reported their pregnancy was unintended and 151 (5.1%) met the threshold for postpartum depression. The prevalence of postpartum depression was higher in women with unintended pregnancies compared to women with intended pregnancies (6.7% vs. 4.3%, p<0.01). However, after controlling for confounders, unintended pregnancy was no longer associated with postpartum depression (adjusted OR 1.41; 95% CI 0.91-2.18). Variables independently associated with postpartum depression included prepregnancy anxiety/depression, Asian race, and Hispanic ethnicity.\n## CONCLUSION\nPregnancy intention was not independently associated with postpartum depression among first time mothers in Pennsylvania.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "The effect of pregnancy intention on maternal prenatal behaviours and parent and child health: results of an irish cohort study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors.\n## METHODS\nThis study uses data from the first wave of the 'Growing Up in Ireland Study', a large nationally representative cohort study of more than 11\u2009000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours.\n## RESULTS\nThe study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]).\n## CONCLUSIONS\nAscertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "From antenatal to postnatal depression: associated factors and mitigating influences.",
        "key_reference_abstract": "## INTRODUCTION\nPostnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression.\n## METHODS\nThe study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables.\n## RESULTS\nRisk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression.\n## CONCLUSION\nThis study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Intendedness of pregnancy and other predictive factors for symptoms of prenatal depression in a population-based study.",
        "key_reference_abstract": "Prenatal depression (PD) as a risk factor for adverse birth outcomes is well documented. Less is known about maternal risks for PD, which could inform preventive strategies for perinatal and interconceptional care. This exploratory study investigates associations between prenatal depression symptoms and unintended and mistimed pregnancies and other maternal risk factors for PD. A subset of birth records from the New York Statewide Perinatal Data System (n = 19,219) was used in this secondary analysis of cross-sectional data. Univariate and multivariate multinomial regression was used to identify factors that are independently associated with four self-reported levels of prenatal depression symptoms. Women with unintended pregnancies were more likely (AOR, 95 % CI) to report severe (3.6, 2.6-5.1) or moderate (2.0, 1.6-2.5) prenatal depression symptoms and less likely to report no symptoms, compared to women with intended pregnancies. Likewise, women with mistimed pregnancies were more likely to report severe (2.7, 2.2-3.5) or moderate (1.7, 1.5-2.1) prenatal depression symptoms than no symptoms, compared to women with intended pregnancies. Low education, drug use, smoking, minority race, being unmarried and having Medicaid insurance were also significant, independent predictors of PD symptoms. Results suggest that routine screening for depression, intendedness of pregnancy and other associated risk factors such as smoking and drug use during prenatal and interconceptional care visits may enable coordinated interventions that can reduce prenatal depression and unintended and mistimed pregnancies and improve pregnancy outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Impact of unintended pregnancy on maternal mental health: a causal analysis using follow up data of the Panel Study on Korean Children (PSKC).",
        "key_reference_abstract": "## BACKGROUND\nPregnancy intention is important for maternal and child health outcomes. The purpose of this study was to examine the causal relation between pregnancy intention and maternal depression and parenting stress in Korean women who gave birth during 2008.\n## METHODS\nThis study is a retrospective evaluation of prospectively collected data from the Panel Study on Korean Children from 2008 to 2010. Causal analyses were conducted using propensity score matching and inverse probability of treatment weighted methods. In addition, mediation analyses were performed to test mitigating effects of marital conflict, fathers' participation in childcare, and mothers' knowledge of infant development on the relation between unintended pregnancy and adverse maternal mental health.\n## RESULTS\nResults showed that the overall effect of an unintended pregnancy on maternal depression and parenting stress was statistically significant. An unintended pregnancy was associated with 20-22% greater odds of maternal depression, 0.28-0.39 greater depression score, and 0.85-1.16 greater parenting stress score. Relations between pregnancy intention and maternal depression, maternal depression score and parenting stress score were moderately explained by marital conflict and fathers' participation in childcare.\n## CONCLUSIONS\nUnintended pregnancy contributed to increased risks of maternal depression and parenting stress. Efforts to increase fathers' participation in childcare and decrease marital conflict might be helpful to mitigate adverse impacts of unintended pregnancy on perinatal maternal mental health.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Risk factors of transient and persistent anxiety during pregnancy.",
        "key_reference_abstract": "## PURPOSE\nchronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada.\n## METHODS\nwomen with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup.\n## FINDINGS\nwomen with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85-13.39) were unique predictors of chronic depressive symptoms.\n## CONCLUSIONS\nknowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Are pregnancy planning and pregnancy timing associated with maternal psychiatric illness, psychological distress and support during pregnancy?",
        "key_reference_abstract": "## BACKGROUND\nPregnancy planning and timing may be associated with psychiatric illness, psychological distress and support during pregnancy.\n## METHODS\nWe performed secondary analyses of a prospective cohort of 2654 pregnant women evaluating the impact of depression on preterm birth. We used multivariable logistic regression to test associations between pregnancy planning (\"Was this pregnancy planned? Yes/No\") and/or timing (\"Do you think this is a good time for you to be pregnant?\") with Composite International Diagnostic Interview generated psychiatric diagnoses and measures of psychological distress and support.\n## RESULTS\n37% and 13% of participants reported an unplanned or poorly timed pregnancy, respectively. Unplanned pregnancies were associated with a Major Depressive Episode (MDE) (adjusted odds ratio (aOR) 1.69, 95%CI 1.23-2.32) and the Cohen Perceived Stress Scale's (CPSS) highest quartile (aOR 1.74, 95%CI 1.40-2.16). Poorly timed pregnancies were associated with a MDE (aOR 3.47, 95%CI 2.46-4.91) and the CPSS's highest quartile (aOR 5.20, 95%CI 3.93-6.87). Poorly timed pregnancies were also associated with General Anxiety Disorder (GAD; aOR 1.60, 95%CI 1.07-2.40), and the modified Kendler Social Support Inventory's (MKSSI) lowest quartile (aOR 1.64, 95%CI 1.25-2.16). Psychiatric conditions were strongly associated with planned pregnancies that were subsequently deemed poorly timed (MDE=aOR 5.08, 95%CI 2.52-10.25; GAD=aOR 2.28, 95%CI 1.04-5.03); high CPSS=aOR 6.48, 95%CI 3.59-11.69; and low MKSSI=aOR 3.19, 95%CI 1.81-5.62.\n## LIMITATIONS\nParticipant characteristics may limit generalizability of findings.\n## CONCLUSIONS\nPregnancy timing was a stronger predictor of maternal psychiatric illness, psychological distress and low social support than pregnancy planning in our cohort.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs).\n## METHODS\nUsing Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross-sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design.\n## RESULTS\nIn multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23-2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs.\n## CONCLUSIONS\nThis study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "The association between pregnancy intendedness and experiencing symptoms of postpartum depression among new mothers in the United States, 2009 to 2011: A secondary analysis of PRAMS data.",
        "key_reference_abstract": "Postpartum depression (PPD) is a form of major depressive disorder affecting approximately 13% of women worldwide. Unintended pregnancies, reaching close to 50% of the pregnancies in the United States, have become a major health concern. While many physiologic and psychosocial causes have been analyzed, few studies have examined the relationship between unintended pregnancy and symptoms of PPD.A cross-sectional study was conducted using surveillance data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2009 to 2011. The PRAMS population-based random sample included women who have had recent live births and is representative of 78% of the United States population. The chi-squared test was used to examine bivariate associations. Binary logistic regression was utilized to study unadjusted and adjusted associations between PPD and pregnancy intendedness, as well as other demographic and clinical characteristics of mothers in the sample. Multicollinearity in the adjusted model was evaluated using variance inflation factors. Sampling weights were used to account for PRAMS' complex sampling design.Of the 110,231 mothers included in the sample, only 32.3% reported desiring the pregnancy at the time of conception. Women with pregnancies categorized as mistimed: desired sooner, mistimed: desired later, or unwanted were 20% (adjusted odds ratio [AOR]\u200a=\u200a1.2; 95% confidence interval [CI]: 1.1-1.3), 30% (AOR\u200a=\u200a1.3; 95% CI: 1.2-1.4), and 50% (AOR\u200a=\u200a1.5; 95% CI: 1.3-1.7) more likely to experience symptoms of PPD, respectively, compared to women with desired pregnancies. Other factors found to be associated with experiencing symptoms of PPD were a gestational age of <27 weeks (AOR\u200a=\u200a3.1; 95% CI: 2.5-4.0), having a previous history of depression (AOR\u200a=\u200a1.8; 95% CI: 1.6-2.0), and being abused during or before pregnancy (AOR\u200a=\u200a1.6; 95% CI: 1.4-2.0).We found that women with mistimed or unwanted pregnancies were more likely to experience symptoms of PPD. Our findings support the current US Preventive Services Task Force and American Academy of Pediatrics recommendations for an integrated approach to screening for depression, aiding in the maximization of intervention and early referral for women at risk for PPD.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Psychosocial status and prenatal care of unintended pregnancies among low-income women.",
        "key_reference_abstract": "## BACKGROUND\nNearly half of all pregnancies in the United States are reported as unintended and rates are highest among women of low socioeconomic status. The purpose of this study was to examine the associations between unintended pregnancies and maternal mental health and timing of prenatal care among low-income women.\n## METHODS\nIn this cross-sectional study, 870 women, whom were participating in the First 1000\u2009Days program in three community health centers in the Boston area, were enrolled at their first prenatal visit from August 2016 - September 2017. We assessed pregnancy intention by self-report using the Pregnancy Risk Assessment Monitoring System. We used self-reported survey information and electronic health record data to assess the following outcomes: current stress, current depression, and timing of initial prenatal visit. We used multivariable logistic regression models to examine associations and adjusted for sociodemographic factors.\n## RESULTS\nWomen were a mean (SD) age of 29.3 (6.1), and 39.2% reported that their pregnancy was unintended. 50.6% of women were Hispanic, 28.4% were White, 10.1% were Black, and 10.9% were other races. 78.9% of women reported an annual household income <$50,000. Overall, 26.7% of women reported current stress, 8.2% reported current depression, and 18.3% of women initiated prenatal care after their first trimester. In multivariable analyses, women with unintended pregnancies had higher odds of experiencing current stress (OR: 1.72; 95% CI: 1.22, 2.41), current depression (OR: 1.83; 95% CI: 1.04, 3.20), and initiation of prenatal care post-first trimester (OR: 1.84; 95% CI: 1.23, 2.74).\n## CONCLUSIONS\nUnintended pregnancies were associated with current stress and depression, and delayed prenatal care in this sample of low-income women suggesting the importance of identifying high-risk women and tailoring interventions to support women's needs.\n## TRIAL REGISTRATION\nClinicalTrials.gov (NCT03191591; Retrospectively registered on June 19, 2017).",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "The Role of Father Involvement and Intimate Partner Violence on Postnatal Depression Among Women With Unintended Pregnancy.",
        "key_reference_abstract": "This study set out to fill the research gap by including various aspects of father involvement and intimate partner violence (IPV) in the examination of the association between unintended pregnancy and maternal postnatal depression (PND). This study aimed to examine the effect of father involvement and IPV on the association between unintended pregnancy and PND. A sample of 1,083 pregnant women who attended antenatal clinic at selected hospitals in Hong Kong completed two surveys to report on their pregnancy intention, antenatal depression, PND, IPV during pregnancy, their partner's (i.e., father's) involvement during pregnancy and after childbirth, and perceived social support. Comparisons were made between women with unintended pregnancy and those with intended pregnancy, and the effects of unintended pregnancy, father involvement, IPV, and other factors on maternal PND were examined. Results show that women with unintended pregnancy were more likely to report PND, IPV, fear, postnatal stress, lower degree of father involvement, and lower level of social support. Unintended pregnancy independently increased the risk of PND by 1.95 times (95% confidence interval [CI] = [1.15, 3.28]), after adjustment for all other variables. When father involvement was included in the regression model, the negative effects of IPV and the related fear on PND became nonsignificant. The positive association between unintended pregnancy and PND was robust. Father involvement might help promote maternal health by reducing the negative effects of IPV on PND.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Do Pregnancy Intentions Matter? A Research Note Revisiting Relationships Among Pregnancy, Birth, and Maternal Outcomes.",
        "key_reference_abstract": "The prevention of unplanned or unintended pregnancies continues to be a cornerstone of U.S. reproductive health policy, but the evidence that such pregnancies cause adverse maternal and child outcomes is limited. In this research note, we examine these relationships using recent large-scale data and inverse propensity weights estimated from generalized boosted models. We find that pregnancy timing is related to maternal experience during pregnancy, but not to infant outcomes at birth-both of which are consistent with prior research. In an addition to the literature, we show that pregnancy timing is relevant for a number of maternal outcomes, such as the onset of depression and intimate partner violence, changes in smoking behavior, and receipt of medical care. These findings suggest that policy intended to improve infant welfare by preventing unintended pregnancies has little empirical support, but that policy focused on increasing reproductive autonomy and maternal well-being has the potential to improve outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy planning and acceptance and maternal psychological distress during pregnancy: results from the National Perinatal Survey, France, 2016.",
        "key_reference_abstract": "## BACKGROUND\nStudies report heightened risks of mental health problems among women who experience an unintended pregnancy, but few consider the complexity of pregnancy intentions. In this study, we evaluate how different dimensions of pregnancy intentions (pregnancy planning and pregnancy acceptance) relate to two maternal depressive symptoms and perceived psychological distress.\n## METHODS\nThis study draws from a cross-sectional national survey conducted in all maternities in France over a one-week period in 2016. All mothers 18\u2009years and older who had a live birth during the study period were invited to participate. After excluding women who underwent infertility treatment, our analytical sample included 10,339 women. We first described levels and correlates of pregnancy planning and acceptance, defined in four categories; planned/welcomed, unplanned/welcomed, planned/unwelcomed, unplanned/unwelcomed. We then assessed the bivariate and multivariate associations between pregnancy planning and acceptance and two outcomes: women's self-perceived psychological health and the presence of two depressive symptoms during pregnancy. We used multivariate logistic regressions to evaluate these associations, after adjusting for socio-demographic and medical factors.\n## RESULTS\nAltogether 7.5 to 24.1% of mothers perceived their psychological health during pregnancy was poor, according to pregnancy planning and acceptance categories and 10.3 to 22.4% indicated feelings of sadness and loss of interest during pregnancy, according to pregnancy planning and acceptance categories. As compared to women with planned/welcomed pregnancies, the odds of perceived poor psychological health and depressive symptoms were 2.55 times (CI 2.20-2.95) and 1.75 times higher (CI 1.51-2.02), respectively, among unplanned/unwelcomed pregnancies and 2.02 (CI 1.61-2.53) and 2.07 (CI 1.7-2.5) higher, among planned/unwelcomed pregnancies. Among women with unplanned pregnancies, we also found higher odds of perceived poor psychological health among women whose pregnancy was unwelcomed while the odds of depressive symptoms were not different by pregnancy planning status among women with unwelcomed pregnancies.\n## CONCLUSIONS\nThese findings consolidate previous reports of the association between pregnancy intentions and maternal psychological distress, while further specifying the relationship, which mostly depends on the acceptance of pregnancy timing rather than on pregnancy planning. Identifying women with low pregnancy acceptance can potentially enhance current medical practice by improving early detection of maternal depression.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors.\n## METHODS\nIn 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy.\n## RESULTS\nWomen who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester.\n## CONCLUSIONS\nWomen with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Unintended pregnancy and intimate partner violence before and during pregnancy among Latina women in Los Angeles, California.",
        "key_reference_abstract": "The purpose of this paper was to examine the relationship between unintended pregnancy and intimate partner violence (IPV) before and during pregnancy among Latinas. A cross-sectional interview measuring pregnancy intent, IPV, and acculturation, using the Acculturation Rating Scale for Mexican Americans (ARSMA-II), was conducted among Latina women in their 2(nd) or 3(rd) trimester of pregnancy at clinics in Los Angeles (n = 313). Overall, 44% of women reported an unintended pregnancy. The prevalence of physical (any) and emotional (only) abuse 12 months before pregnancy was 11% and 22%, respectively. Although both types of IPV decreased during pregnancy (10% and 19%, respectively), most reports of physical IPV during pregnancy (53%) were among women who did not report physical abuse before pregnancy. After adjusting for other factors, physical IPV before pregnancy was not associated with unintended pregnancy (adjusted OR = 0.92; 95% CI = 0.40, 2.16). The prevalence of unintended pregnancy was highest (76%) among highly acculturated Latinas. However, when an unintended pregnancy occurred among less acculturated Latinas, who comprised the majority of the sample (n = 270), it was associated with greater risk of physical IPV during pregnancy (unadjusted OR = 2.57; 95% CI = 1.06, 6.23); although the confidence interval included one after adjusting for other factors (adjusted OR = 2.79; 95% CI = 0.98, 7.92). An unintended pregnancy may have a unique impact on relationships in the context of Latino culture, where family and pregnancy are highly valued. Pregnancy often creates an opportunity for providers to discuss issues related to abuse and family planning with women who do not regularly access care. The results from this study may be used to increase the cultural sensitivity with which violence and reproductive health are addressed among the diverse population of Latinas when they connect with prenatal services.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Severity of intimate partner abuse indicators as perceived by women in Mexico and the United States.",
        "key_reference_abstract": "## OBJECTIVE\nWomen in Cuernavaca, Mexico and Los Angeles, California were surveyed to examine differences in their perceptions of the severity of domestic violence indicators.\n## METHODS\nOne hundred twenty women in each country rated the severity of 26 domestic violence indicators which were part of an abuse screen used for an ongoing study of the prevalence of abuse. Rasch analysis was conducted to determine the linear relationship in the perceptions of the severity of each event between the two countries.\n## RESULTS\nThe Rasch calibrated logit values show that women in the US rated 24 of the 26 events as more severe than women in Mexico. However, items were ranked in similar order and a clear linear pattern was established. In both countries, being shot with a gun was the most severe event and a partner becoming jealous was the least severe.\n## CONCLUSION\nThe country of origin did not dictate which events were most severe but did influence how severe these events were perceived.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse.\n## METHODS\nA prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used.\n## RESULTS\nApproximately one-fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68).\n## CONCLUSION\nWomen who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Early Childhood Victimization and Physical Intimate Partner Violence During Pregnancy: A Developmental and Person-Oriented Approach.",
        "key_reference_abstract": "Intimate partner violence (IPV) victimization during pregnancy is a major public health concern, yet little is known about how risk factors for IPV during pregnancy may depend on whether women have histories of victimization dating back to early childhood (ages 0-5 years). This study examined whether risk factors for physical IPV victimization during pregnancy (a pregnancy that was not planned and prenatal substance use) differed for women with versus without early childhood victimization. Participants were 236 ethnically diverse, low-income biological mothers ( M = 30.94 years; 50.0% Latina, 16.9% Caucasian, 13.1% African American, and 16.9% multiracial) of children aged 0 to 6 years. Mothers were classified into four groups based on whether they had experienced early childhood victimization and physical IPV victimization during pregnancy with the target child. Multinomial logistic regressions, controlling for demographic characteristics, examined whether a pregnancy not planned and prenatal substance use predicted group membership. Compared to mothers with early victimization only, mothers with both early childhood victimization and physical IPV during pregnancy were more than 3 times as likely to report that their pregnancy with the target child was not planned. In follow-up analyses, mothers with early victimization and physical IPV during pregnancy also reported higher lifetime parity than mothers with physical IPV during pregnancy but no early victimization. Early childhood victimization may place women on a risk pathway to physical IPV during pregnancy, particularly if the pregnancy is not planned. Prevention and policy efforts should screen women for early childhood victimization to understand risks for physical IPV during pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "The effect of pregnancy intention on child development.",
        "key_reference_abstract": "In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Unintended pregnancy and preterm birth.",
        "key_reference_abstract": "About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intention and its relationship to birth and maternal outcomes.",
        "key_reference_abstract": "## OBJECTIVE\nTo examine whether there are associations between pregnancy intention (intended, unwanted, mistimed, or ambivalent) and negative birth and maternal outcomes: low birth weight (less than 2,500 g), preterm delivery (fewer than 37 weeks), small for gestational age, premature labor, hypertension, and other maternal outcomes.\n## METHODS\nWe analyzed data from the population-based Pregnancy Risk Assessment Monitoring System, including 87,087 women who gave birth between 1996 and 1999 in 18 states. Information on pregnancy outcomes was derived from birth certificate data and a self-administered questionnaire completed postpartum. We employed SUDAAN (RTI International, Research Triangle Park, NC) for univariable and logistical regression analyses.\n## RESULTS\nIn analyses controlling for demographic and behavioral factors, women with unwanted pregnancies had an increased likelihood of preterm delivery (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33) and premature rupture of membranes (adjusted OR 1.37, 95% CI 1.01-1.85) compared with women with intended pregnancies. Women who were ambivalent toward their pregnancies had increased odds of delivering a low birth weight infant (adjusted OR 1.15, 95% CI 1.02-1.29); in contrast, women with mistimed pregnancies had a lower likelihood (adjusted OR 0.92, 95% CI 0.86-0.97).\n## CONCLUSION\nPregnancy intention, specifically unwanted and ambivalent, may be an indicator of increased risk for some poor birth and maternal outcomes and should be considered in interventions aimed at improving the health of the mother and child.\n## LEVEL OF EVIDENCE\nIII.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intention and preterm birth: differential associations among a diverse population of women.",
        "key_reference_abstract": "## CONTEXT\nStudies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups.\n## METHODS\nData from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics.\n## RESULTS\nIn unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites.\n## CONCLUSIONS\nWomen's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "The couple context of pregnancy and its effects on prenatal care and birth outcomes.",
        "key_reference_abstract": "The couple context of pregnancy and newborn health is gaining importance with the increase in births to unmarried couples, a disproportionate number of which were not intended. This study investigates the association of early prenatal care, preterm birth, and low birth weight with the couple relationship context, including partners' joint intentions for the pregnancy, their marital status at conception, and the presence of relationship problems during pregnancy. Data are drawn from the first wave of the Early Childhood Longitudinal Study--Birth Cohort, a representative study of births in 2001. The sample is composed of parents residing together with their biological child at the time the child is 9 months old, where both the mother and father completed the self-report interview (N = 5,788). Couple-level multivariate logistic regression models, weighted to account for the complex sampling design, were used in the analysis. Risk of inadequate prenatal care and preterm birth was increased when partners did not share intentions or when neither partner intended the pregnancy. Couples were at additional risk of inadequate prenatal care when the pregnancy was conceived nonmaritally and when the mother did not tell the father about the pregnancy, particularly when neither partner intended the pregnancy. The risk of premature birth was particularly high when the partners were unmarried and either or both did not intend the pregnancy. The couple context of pregnancy is important for a healthy pregnancy and birth. When the partner is present, practitioners and programs should maintain a focus on the couple, and researchers should make every effort to include the father's own perspective.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Assessing pregnancy intention and associated risks in pregnant adolescents.",
        "key_reference_abstract": "Unintended pregnancy and associated behaviors may play a substantial role in the increased risk of adverse maternal and neonatal outcomes associated with teen pregnancy. We evaluate a multi-dimensional measure of pregnancy intention among pregnant adolescents and quantify the association between intention dimensions and adverse outcomes and risk behaviors. Pregnancy intention measures were examined in a cohort of 300 pregnant adolescent women. We considered 18 items assessing elements of pregnancy intention including pregnancy planning, timing, emotional response, and readiness. Latent class analysis was performed to identify dimensions of pregnancy intention. Parsimonious scores were created by minimizing the number of covariates while maintaining substantial agreement with the latent class. Associations between intention measures and prenatal care, risk behaviors, and pregnancy outcomes were quantified using multivariable logistic regression. Two constructs of pregnancy intention were identified: planning and emotional readiness. Compared with emotionally ready adolescents, adolescents categorized as not emotionally ready had an increased odds of inadequate prenatal care (OR = 2.70, 95% CI:1.27-5.72), delayed prenatal care (OR = 2.54, 95% CI:1.27-5.09), and self-reported depression at the time of the first prenatal visit (OR = 2.21, 95% CI:1.03-4.77). Pregnancy planning was not associated with adverse pregnancy risk factors or outcomes. Among pregnant adolescents, emotional readiness for pregnancy and parenting was inversely associated with known risk factors for adverse pregnancy outcomes, suggesting that emotional readiness rather than pregnancy planning may be the more pertinent intention construct for adolescents.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy planning, smoking behaviour during pregnancy, and neonatal outcome: UK Millennium Cohort Study.",
        "key_reference_abstract": "## BACKGROUND\nPre-pregnancy health and care are important for the health of the future generations. Smoking during pregnancy has been well-researched and there is clear evidence of harm. But there has been little research on the health impact of planning for pregnancy. This study aims to investigate the independent effects of pregnancy planning and smoking during pregnancy on neonatal outcome.\n## METHODS\nThis analysis made use of data from the UK Millennium Cohort Study. The study sample consisted of 18,178 singleton babies born in UK between 2000 and 2001. The neonatal outcomes of interest were low birthweight (<2.5 Kg) and pre-term birth (<37 completed weeks gestation). Logistic regression was used to estimate the association between pregnancy planning and/or smoking and neonatal outcome. Adjusted odds ratios were used to calculate population attributable risk fractions (PAFs).\n## RESULTS\n43% of mothers did not plan their pregnancy and 34% were smoking just before and/or during pregnancy. Planners were half as likely to be smokers just before pregnancy, and more likely to give up or reduce the amount smoked if smokers. Unplanned pregnancies had 24% increased odds of low birth weight and prematurity compared to planned pregnancies (AORLBW1.24, 95% CI 1.04-1.48; AORPREM1.24, 95% CI 1.05-1.45), independent of smoking status. The odds of low birth weight for babies of mothers who were smoking just before pregnancy was 91% higher than that of mothers who were not (AORLBW1.91, 95% CI 1.56-2.34). Women who quit or reduced the amount smoked during pregnancy lowered the risk of a low birth weight baby by one third (AORLBW0.66, 95% CI 0.51-0.85) compared with women whose smoking level did not change. Smaller effects were found for prematurity. If all women planned their pregnancy and did not smoke before or during pregnancy, 30% of low birthweight and 14% of prematurity could, in theory, be avoided.\n## CONCLUSIONS\nPlanning a pregnancy and avoiding smoking during pregnancy has clear, independent, health benefits for babies. Quitting or reducing the amount smoked during pregnancy can reduce the risk of low birthweight.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Are pregnancy planning and timing associated with preterm or small for gestational age births?",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births.\n## DESIGN\nProspective cohort study.\n## SETTING\nNot applicable.\n## PATIENT(S)\nTwo thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy.\n## INTERVENTION(S)\nNone.\n## MAIN OUTCOME MEASURE(S)\nPreterm and small for gestational age births.\n## RESULT(S)\nIn adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age.\n## CONCLUSION(S)\nIn a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Preterm birth",
        "key_reference_title": "Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma.",
        "key_reference_abstract": "Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed \u22652 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study identified correlates of self-reports of being very depressed in the months after delivery in a population-based sample of women.\n## METHODS\nWe analyzed data on 14,609 recent mothers from the Centers for Disease Control and Prevention's (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS). The sample included mothers who delivered a live birth in Colorado, New York State, and North Carolina from 1996 (New York only) to 1999. We assessed risk factors for self-reports of being very depressed in the months after delivery using logistic regression.\n## RESULTS\nOverall, 5.9% (95% CI = 5.3, 6.4) of new mothers reported being very depressed in the months after delivery. Women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life\" had the highest prevalence of reporting being very depressed in the months after delivery (24.9%, 95% CI = 21.3, 28.5) and, when all risk factors were adjusted for simultaneously, were 4.6 times (95% CI = 3.1, 6.3) more likely to report being very depressed in the months after delivery than other women. Other significant risk factors for self-reports of being very depressed in the months after delivery included experiencing partner-associated stress (OR = 1.9, 95% CI = 1.5, 2.5), physical abuse during pregnancy (OR = 1.6, 95% CI = 1.1, 2.4), and not breast-feeding (OR = 1.4, 95% CI = 1.1, 1.8).\n## CONCLUSIONS\nThe highest prevalence for self-reports of being very depressed in the months after delivery was in women who reported that their pregnancy was a \"very hard time\" or \"one of the worst times of my life.\" Clinicians need to be aware of the needs of some women for mental health services both during and after pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Confinement and other psychosocial factors in perinatal depression: a transcultural study in Singapore.",
        "key_reference_abstract": "## BACKGROUND\nTo investigate the prevalence, socio-cultural and psychosocial risk factors for perinatal depression in Singaporean women.\n## METHOD\nA prospective cohort of 559 women was interviewed antenatally and at six weeks' postpartum at a tertiary hospital. Women were interviewed for diagnosis of depression using a two-stage design, with a screening questionnaire and diagnostic interview.\n## RESULTS\nPostnatally, a negative confinement experience was associated with depression. Other independent factors included poor emotional support, a past history of depression, unplanned pregnancy and perceived potential conflicts with relatives over childcare antenatally and dissatisfaction, poor instrumental support postnatally. The prevalence of depression antenatally and postnatally was 12.2% and 6.8%, respectively.\n## LIMITATIONS\nMeasures of satisfaction with social support were based on self-report; there were high dropout rates at six weeks' postpartum; and other modulating social factors such as pre-existing interpersonal conflicts were not studied.\n## CONCLUSIONS\nPerinatal depression in Singaporean women is common. Contrary to expectations, a negative 'confinement' experience is a significant risk factor for postnatal depression, and is not universally welcomed by women. Depression is modulated by dissimilar sets of psychosocial factors antenatally and postnatally.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice.",
        "key_reference_abstract": "## OBJECTIVE\nData are scarce regarding the sociodemographic predictors of antenatal and postpartum depression. This study investigated whether race/ethnicity, age, finances, and partnership status were associated with antenatal and postpartum depressive symptoms.\n## SETTING\n1662 participants in Project Viva, a US cohort study.\n## DESIGN\nMothers indicated mid-pregnancy and six month postpartum depressive symptoms on the Edinburgh postpartum depression scale (EPDS). Associations of sociodemographic factors with odds of scoring >12 on the EPDS were estimated.\n## MAIN RESULTS\nThe prevalence of depressive symptoms was 9% at mid-pregnancy and 8% postpartum. Black and Hispanic mothers had a higher prevalence of depressive symptoms compared with non-Hispanic white mothers. These associations were explained by lower income, financial hardship, and higher incidence of poor pregnancy outcome among minority women. Young maternal age was associated with greater risk of antenatal and postpartum depressive symptoms, largely attributable to the prevalence of financial hardship, unwanted pregnancy, and lack of a partner. The strongest risk factor for antenatal depressive symptoms was a history of depression (OR = 4.07; 95% CI 3.76, 4.40), and the strongest risk for postpartum depressive symptoms was depressive symptoms during pregnancy (6.78; 4.07, 11.31) or a history of depression before pregnancy (3.82; 2.31, 6.31).\n## CONCLUSIONS\nFinancial hardship and unwanted pregnancy are associated with antenatal and postpartum depressive symptoms. Women with a history of depression and those with poor pregnancy outcomes are especially vulnerable to depressive symptoms during the childbearing year. Once these factors are taken in account, minority mothers have the same risk of antenatal and postpartum depressive symptoms as white mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intentions and happiness among pregnant black women at high risk for adverse infant health outcomes.",
        "key_reference_abstract": "## CONTEXT\nUnintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman's feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.\n## METHODS\nA sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.\n## RESULTS\nPregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby's father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).\n## CONCLUSIONS\nAdditional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father's desire to have this child, may help improve prenatal care services and prevent adverse health outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Factors related to depression during pregnancy: are there gender differences?",
        "key_reference_abstract": "## OBJECTIVE\nTo determine gender differences between women and their partners in the effect of psychosocial and personal factors on depression during the third trimester of pregnancy.\n## METHOD\nA cross-sectional survey was carried out among 687 women and their partners (n = 669) attending the prenatal programme of Valencia province (Spain). Data collection was carried out by means of a self-reported questionnaire. The outcome variable was depression during the third trimester of pregnancy measured by the Edinburgh Postnatal Depression Scale. Predictor variables were psychosocial (marital dissatisfaction, confidant and affective social support) and personal (previous history of depression, partner depression and unplanned pregnancy) variables. The adjusted odds ratios (aOR) and their 95% confidence intervals were calculated by fitting a logistic regression model.\n## RESULTS\nThe prevalence of pregnancy depression was higher among women (10.3%) than men (6.5%). In both sexes, the probability of depression during pregnancy was higher in those with marital dissatisfaction (aOR 3.05, 95% CI 1.59 to 5.82 for women and 3.14, 95% CI 1.24 to 7.99 for men) and among those whose with a previous history of depression (aOR 2.18, 95% CI 1.22 to 3.89 for women and 5.22, 95% CI 2.05 to 13.34 for men). Unplanned pregnancy did not increase the risk of pregnancy depression either in women or men. Gender differences were found on the impact of social support and partner's depression. Whereas among men low affective social support and partner depression were associated with a higher probability of reporting depression, none of these variables were related to women's depression.\n## CONCLUSION\nMost predictor factors of depression during pregnancy are similar for both sexes but a gender-different impact of social support and partner depression on pregnancy depression was appreciated. Health professionals should be aware of potentially vulnerable groups for early diagnosis of pregnancy depression and to provide effective interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Psychosocial risk factors for depression during pregnancy.",
        "key_reference_abstract": "## OBJECTIVE\nTo assess the prevalence of antenatal depressive disorder in different trimesters and to evaluate the relation of psychosocial risk factors to antenatal depressive disorder.\n## DESIGN\nCohort follow-up.\n## SETTING\nUniversity Hospital, Kaunas, Lithuania.\n## SAMPLE\nTwo hundred and thirty pregnant women consecutively admitted.\n## METHODS\nAt 12-16 weeks, 22-26 weeks, and 32-36 weeks of pregnancy, participants were screened for depression using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). Women who gave at least one positive answer to the CIDI-SF depression-screening question were evaluated for depressive disorder using the non-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). Psychosocial stressors and two Big Five Personality dimensions, neuroticism and extraversion, were also evaluated.\n## MAIN OUTCOME MEASURES\nPrevalence of depressive disorder.\n## RESULTS\nThe prevalence of the antenatal depressive disorder at 12-16 weeks' gestation was 6.1%, at 22-26 weeks 3.5%, and at 32-36 weeks 4.4%. In the first trimester, a greater prevalence of current depressive disorder was independently associated with unplanned and unwanted pregnancy, high neuroticism, low education, and a previous history of depression; in the second trimester with unplanned and unwanted pregnancy and high neuroticism; in the third trimester with unplanned and unwanted pregnancy, high neuroticism, and the occurrence of psychosocial stressors during the last year.\n## CONCLUSIONS\nThe highest prevalence of depressive disorders was found in the first trimester, the lowest in mid-pregnancy. Several determinants (unwanted and unplanned pregnancy, high neuroticism) were independent predictors of antenatal depressive disorders throughout whole pregnancy, while other determinants (low education, previous history of depression, the occurrence of psychosocial stressors at the end of pregnancy) were trimester specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Unintended pregnancy and associated maternal preconception, prenatal and postpartum behaviors.",
        "key_reference_abstract": "## BACKGROUND\nThis study was conducted to determine the relationship between unintended pregnancy and maternal behaviors before, during and after pregnancy.\n## STUDY DESIGN\nData were analyzed from a stratified random sample of 9048 mothers who delivered live born infants between 2001 and 2006 and completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey 2 to 9 months after delivery. Binary and ordinal logistic regression methods with appropriate survey weights were used to control for socio-demographic factors.\n## RESULTS\nCompared to women with intended pregnancies, mothers with unwanted pregnancies were more likely to consume less than the recommended amount of preconception folic acid [adjusted odds ratio (OR) 2.39, 95% confidence interval (CI) 1.7-3.2], smoke prenatally (OR 2.03, 95% CI 1.5-2.9), smoke postpartum (OR 1.86, 95% CI 1.35-2.55) and report postpartum depression (OR 1.98, 95% CI 1.48-2.64); they were less likely to initiate prenatal care during the first trimester (OR 0.34, 95% CI 0.3-0.5) and breastfeed for 8 or more weeks (OR 0.74, 95% CI 0.57-0.97). Compared to women with intended pregnancies, women with mistimed pregnancies were also more likely to consume inadequate folic acid, delay prenatal care and report postpartum depression.\n## CONCLUSION\nEven after controlling for multiple socio-demographic factors, unwanted and mistimed pregnancies were associated with unhealthy perinatal behaviors.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Antenatal depression and male gender preference in Asian women in the UK.",
        "key_reference_abstract": "## OBJECTIVE\nto identify the prevalence of antenatal depression among Asian women living in the UK in one antenatal clinic, and to investigate the possible association with a desire for a male child and other risk factors.\n## DESIGN\ncross-sectional questionnaire-based study.\n## SETTING\ngeneral antenatal clinic in a hospital in Birmingham.\n## PARTICIPANTS\n300 Asian women, irrespective of place of birth.\n## METHODS\nconsecutive Asian women attending routine antenatal appointments during the study period self-completed a questionnaire. The first part investigated socio-demographic, cultural and other possible risk factors, including gender preference. The second part comprised the Edinburgh Postnatal Depression Scale (EPDS).\n## MEASUREMENTS\nEPDS score greater than or equal to 12 indicating probable depression.\n## FINDINGS\nthe prevalence of depression was 30.7% (92/300, 95% confidence interval 25.4-35.9%). Maternal male gender preference was not common and was not associated with antenatal depression. Family male gender preference, unplanned pregnancy, a history of depression and feeling anxious in pregnancy were independently associated with an increased likelihood of depression, whilst support from family and friends, being satisfied with pregnancy and being multiparous were associated with a reduced likelihood of depression.\n## CONCLUSION\nrates of antenatal depression were very high in Asian women with some associated risk factors. However, male gender preference was not associated with antenatal depression.\n## IMPLICATIONS FOR PRACTICE\ngiven the high prevalence, screening Asian women for depression may be indicated to allow treatment.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intention, demographic differences, and psychosocial health.",
        "key_reference_abstract": "## OBJECTIVES\nWe explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies.\n## METHODS\nData from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes.\n## RESULTS\nSixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups.\n## CONCLUSIONS\nFully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Obstetric and psychosocial risk factors for depressive symptoms during pregnancy.",
        "key_reference_abstract": "We aimed to determine the psychosocial and obstetric correlates of depressive symptomatology during pregnancy in South-Eastern Hungary. A total of 1719 women were screened for depression in four counties in 2006 and 2007, based on a Leverton Questionnaire (LQ) score of \u226512 at 14-24 weeks of gestation. The LQ scores indicated a probable depressive illness (PDI) in 17.2% of the study group. The best predictors in a multiple regression analysis were history of major depression (adjusted odds ratio [AOR]=3.23), and major life events (AOR=2.43). A perceived lack of social support from partner (AOR=1.79) and lack of support by family (AOR=1.23) were also significant determinants. Lack of planning of pregnancy (AOR=1.12) and a history of unfavourable obstetric outcome (AOR=1.42) also seem to predispose to PDI. Overall, psychosocial factors appeared important in the prediction of PDI, whereas economic features did not.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Unintended pregnancy and postpartum depression among first-time mothers.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is a mental disorder that occurs after birth and has negative consequences for the mother, infant, and family. The objective of this secondary analysis was to examine whether pregnancy intention was associated with postpartum depression among first-time mothers.\n## METHODS\nThe First Baby Study is a prospective cohort study of women aged 18-35 having a first singleton birth in Pennsylvania. Baseline data were collected during the third trimester. Postpartum depressive symptoms were measured at 1-month postpartum using the Edinburgh Postnatal Depression Scale. Logistic regression was performed to examine the association between unintended pregnancy and postpartum depression, controlling for prepregnancy anxiety/depression and sociodemographic data.\n## RESULTS\nOf 2972 first-time mothers, 83.4% were white, 70.7% were married, and 56.9% were college educated. Nine hundred fifty-two women (32.0%) reported their pregnancy was unintended and 151 (5.1%) met the threshold for postpartum depression. The prevalence of postpartum depression was higher in women with unintended pregnancies compared to women with intended pregnancies (6.7% vs. 4.3%, p<0.01). However, after controlling for confounders, unintended pregnancy was no longer associated with postpartum depression (adjusted OR 1.41; 95% CI 0.91-2.18). Variables independently associated with postpartum depression included prepregnancy anxiety/depression, Asian race, and Hispanic ethnicity.\n## CONCLUSION\nPregnancy intention was not independently associated with postpartum depression among first time mothers in Pennsylvania.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "The effect of pregnancy intention on maternal prenatal behaviours and parent and child health: results of an irish cohort study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors.\n## METHODS\nThis study uses data from the first wave of the 'Growing Up in Ireland Study', a large nationally representative cohort study of more than 11\u2009000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours.\n## RESULTS\nThe study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]).\n## CONCLUSIONS\nAscertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "From antenatal to postnatal depression: associated factors and mitigating influences.",
        "key_reference_abstract": "## INTRODUCTION\nPostnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression.\n## METHODS\nThe study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables.\n## RESULTS\nRisk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression.\n## CONCLUSION\nThis study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Intendedness of pregnancy and other predictive factors for symptoms of prenatal depression in a population-based study.",
        "key_reference_abstract": "Prenatal depression (PD) as a risk factor for adverse birth outcomes is well documented. Less is known about maternal risks for PD, which could inform preventive strategies for perinatal and interconceptional care. This exploratory study investigates associations between prenatal depression symptoms and unintended and mistimed pregnancies and other maternal risk factors for PD. A subset of birth records from the New York Statewide Perinatal Data System (n = 19,219) was used in this secondary analysis of cross-sectional data. Univariate and multivariate multinomial regression was used to identify factors that are independently associated with four self-reported levels of prenatal depression symptoms. Women with unintended pregnancies were more likely (AOR, 95 % CI) to report severe (3.6, 2.6-5.1) or moderate (2.0, 1.6-2.5) prenatal depression symptoms and less likely to report no symptoms, compared to women with intended pregnancies. Likewise, women with mistimed pregnancies were more likely to report severe (2.7, 2.2-3.5) or moderate (1.7, 1.5-2.1) prenatal depression symptoms than no symptoms, compared to women with intended pregnancies. Low education, drug use, smoking, minority race, being unmarried and having Medicaid insurance were also significant, independent predictors of PD symptoms. Results suggest that routine screening for depression, intendedness of pregnancy and other associated risk factors such as smoking and drug use during prenatal and interconceptional care visits may enable coordinated interventions that can reduce prenatal depression and unintended and mistimed pregnancies and improve pregnancy outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Impact of unintended pregnancy on maternal mental health: a causal analysis using follow up data of the Panel Study on Korean Children (PSKC).",
        "key_reference_abstract": "## BACKGROUND\nPregnancy intention is important for maternal and child health outcomes. The purpose of this study was to examine the causal relation between pregnancy intention and maternal depression and parenting stress in Korean women who gave birth during 2008.\n## METHODS\nThis study is a retrospective evaluation of prospectively collected data from the Panel Study on Korean Children from 2008 to 2010. Causal analyses were conducted using propensity score matching and inverse probability of treatment weighted methods. In addition, mediation analyses were performed to test mitigating effects of marital conflict, fathers' participation in childcare, and mothers' knowledge of infant development on the relation between unintended pregnancy and adverse maternal mental health.\n## RESULTS\nResults showed that the overall effect of an unintended pregnancy on maternal depression and parenting stress was statistically significant. An unintended pregnancy was associated with 20-22% greater odds of maternal depression, 0.28-0.39 greater depression score, and 0.85-1.16 greater parenting stress score. Relations between pregnancy intention and maternal depression, maternal depression score and parenting stress score were moderately explained by marital conflict and fathers' participation in childcare.\n## CONCLUSIONS\nUnintended pregnancy contributed to increased risks of maternal depression and parenting stress. Efforts to increase fathers' participation in childcare and decrease marital conflict might be helpful to mitigate adverse impacts of unintended pregnancy on perinatal maternal mental health.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Risk factors of transient and persistent anxiety during pregnancy.",
        "key_reference_abstract": "## PURPOSE\nchronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada.\n## METHODS\nwomen with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup.\n## FINDINGS\nwomen with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85-13.39) were unique predictors of chronic depressive symptoms.\n## CONCLUSIONS\nknowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Are pregnancy planning and pregnancy timing associated with maternal psychiatric illness, psychological distress and support during pregnancy?",
        "key_reference_abstract": "## BACKGROUND\nPregnancy planning and timing may be associated with psychiatric illness, psychological distress and support during pregnancy.\n## METHODS\nWe performed secondary analyses of a prospective cohort of 2654 pregnant women evaluating the impact of depression on preterm birth. We used multivariable logistic regression to test associations between pregnancy planning (\"Was this pregnancy planned? Yes/No\") and/or timing (\"Do you think this is a good time for you to be pregnant?\") with Composite International Diagnostic Interview generated psychiatric diagnoses and measures of psychological distress and support.\n## RESULTS\n37% and 13% of participants reported an unplanned or poorly timed pregnancy, respectively. Unplanned pregnancies were associated with a Major Depressive Episode (MDE) (adjusted odds ratio (aOR) 1.69, 95%CI 1.23-2.32) and the Cohen Perceived Stress Scale's (CPSS) highest quartile (aOR 1.74, 95%CI 1.40-2.16). Poorly timed pregnancies were associated with a MDE (aOR 3.47, 95%CI 2.46-4.91) and the CPSS's highest quartile (aOR 5.20, 95%CI 3.93-6.87). Poorly timed pregnancies were also associated with General Anxiety Disorder (GAD; aOR 1.60, 95%CI 1.07-2.40), and the modified Kendler Social Support Inventory's (MKSSI) lowest quartile (aOR 1.64, 95%CI 1.25-2.16). Psychiatric conditions were strongly associated with planned pregnancies that were subsequently deemed poorly timed (MDE=aOR 5.08, 95%CI 2.52-10.25; GAD=aOR 2.28, 95%CI 1.04-5.03); high CPSS=aOR 6.48, 95%CI 3.59-11.69; and low MKSSI=aOR 3.19, 95%CI 1.81-5.62.\n## LIMITATIONS\nParticipant characteristics may limit generalizability of findings.\n## CONCLUSIONS\nPregnancy timing was a stronger predictor of maternal psychiatric illness, psychological distress and low social support than pregnancy planning in our cohort.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## BACKGROUND\nPostpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs).\n## METHODS\nUsing Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross-sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design.\n## RESULTS\nIn multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23-2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs.\n## CONCLUSIONS\nThis study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "The association between pregnancy intendedness and experiencing symptoms of postpartum depression among new mothers in the United States, 2009 to 2011: A secondary analysis of PRAMS data.",
        "key_reference_abstract": "Postpartum depression (PPD) is a form of major depressive disorder affecting approximately 13% of women worldwide. Unintended pregnancies, reaching close to 50% of the pregnancies in the United States, have become a major health concern. While many physiologic and psychosocial causes have been analyzed, few studies have examined the relationship between unintended pregnancy and symptoms of PPD.A cross-sectional study was conducted using surveillance data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2009 to 2011. The PRAMS population-based random sample included women who have had recent live births and is representative of 78% of the United States population. The chi-squared test was used to examine bivariate associations. Binary logistic regression was utilized to study unadjusted and adjusted associations between PPD and pregnancy intendedness, as well as other demographic and clinical characteristics of mothers in the sample. Multicollinearity in the adjusted model was evaluated using variance inflation factors. Sampling weights were used to account for PRAMS' complex sampling design.Of the 110,231 mothers included in the sample, only 32.3% reported desiring the pregnancy at the time of conception. Women with pregnancies categorized as mistimed: desired sooner, mistimed: desired later, or unwanted were 20% (adjusted odds ratio [AOR]\u200a=\u200a1.2; 95% confidence interval [CI]: 1.1-1.3), 30% (AOR\u200a=\u200a1.3; 95% CI: 1.2-1.4), and 50% (AOR\u200a=\u200a1.5; 95% CI: 1.3-1.7) more likely to experience symptoms of PPD, respectively, compared to women with desired pregnancies. Other factors found to be associated with experiencing symptoms of PPD were a gestational age of <27 weeks (AOR\u200a=\u200a3.1; 95% CI: 2.5-4.0), having a previous history of depression (AOR\u200a=\u200a1.8; 95% CI: 1.6-2.0), and being abused during or before pregnancy (AOR\u200a=\u200a1.6; 95% CI: 1.4-2.0).We found that women with mistimed or unwanted pregnancies were more likely to experience symptoms of PPD. Our findings support the current US Preventive Services Task Force and American Academy of Pediatrics recommendations for an integrated approach to screening for depression, aiding in the maximization of intervention and early referral for women at risk for PPD.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Psychosocial status and prenatal care of unintended pregnancies among low-income women.",
        "key_reference_abstract": "## BACKGROUND\nNearly half of all pregnancies in the United States are reported as unintended and rates are highest among women of low socioeconomic status. The purpose of this study was to examine the associations between unintended pregnancies and maternal mental health and timing of prenatal care among low-income women.\n## METHODS\nIn this cross-sectional study, 870 women, whom were participating in the First 1000\u2009Days program in three community health centers in the Boston area, were enrolled at their first prenatal visit from August 2016 - September 2017. We assessed pregnancy intention by self-report using the Pregnancy Risk Assessment Monitoring System. We used self-reported survey information and electronic health record data to assess the following outcomes: current stress, current depression, and timing of initial prenatal visit. We used multivariable logistic regression models to examine associations and adjusted for sociodemographic factors.\n## RESULTS\nWomen were a mean (SD) age of 29.3 (6.1), and 39.2% reported that their pregnancy was unintended. 50.6% of women were Hispanic, 28.4% were White, 10.1% were Black, and 10.9% were other races. 78.9% of women reported an annual household income <$50,000. Overall, 26.7% of women reported current stress, 8.2% reported current depression, and 18.3% of women initiated prenatal care after their first trimester. In multivariable analyses, women with unintended pregnancies had higher odds of experiencing current stress (OR: 1.72; 95% CI: 1.22, 2.41), current depression (OR: 1.83; 95% CI: 1.04, 3.20), and initiation of prenatal care post-first trimester (OR: 1.84; 95% CI: 1.23, 2.74).\n## CONCLUSIONS\nUnintended pregnancies were associated with current stress and depression, and delayed prenatal care in this sample of low-income women suggesting the importance of identifying high-risk women and tailoring interventions to support women's needs.\n## TRIAL REGISTRATION\nClinicalTrials.gov (NCT03191591; Retrospectively registered on June 19, 2017).",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "The Role of Father Involvement and Intimate Partner Violence on Postnatal Depression Among Women With Unintended Pregnancy.",
        "key_reference_abstract": "This study set out to fill the research gap by including various aspects of father involvement and intimate partner violence (IPV) in the examination of the association between unintended pregnancy and maternal postnatal depression (PND). This study aimed to examine the effect of father involvement and IPV on the association between unintended pregnancy and PND. A sample of 1,083 pregnant women who attended antenatal clinic at selected hospitals in Hong Kong completed two surveys to report on their pregnancy intention, antenatal depression, PND, IPV during pregnancy, their partner's (i.e., father's) involvement during pregnancy and after childbirth, and perceived social support. Comparisons were made between women with unintended pregnancy and those with intended pregnancy, and the effects of unintended pregnancy, father involvement, IPV, and other factors on maternal PND were examined. Results show that women with unintended pregnancy were more likely to report PND, IPV, fear, postnatal stress, lower degree of father involvement, and lower level of social support. Unintended pregnancy independently increased the risk of PND by 1.95 times (95% confidence interval [CI] = [1.15, 3.28]), after adjustment for all other variables. When father involvement was included in the regression model, the negative effects of IPV and the related fear on PND became nonsignificant. The positive association between unintended pregnancy and PND was robust. Father involvement might help promote maternal health by reducing the negative effects of IPV on PND.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Do Pregnancy Intentions Matter? A Research Note Revisiting Relationships Among Pregnancy, Birth, and Maternal Outcomes.",
        "key_reference_abstract": "The prevention of unplanned or unintended pregnancies continues to be a cornerstone of U.S. reproductive health policy, but the evidence that such pregnancies cause adverse maternal and child outcomes is limited. In this research note, we examine these relationships using recent large-scale data and inverse propensity weights estimated from generalized boosted models. We find that pregnancy timing is related to maternal experience during pregnancy, but not to infant outcomes at birth-both of which are consistent with prior research. In an addition to the literature, we show that pregnancy timing is relevant for a number of maternal outcomes, such as the onset of depression and intimate partner violence, changes in smoking behavior, and receipt of medical care. These findings suggest that policy intended to improve infant welfare by preventing unintended pregnancies has little empirical support, but that policy focused on increasing reproductive autonomy and maternal well-being has the potential to improve outcomes.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy planning and acceptance and maternal psychological distress during pregnancy: results from the National Perinatal Survey, France, 2016.",
        "key_reference_abstract": "## BACKGROUND\nStudies report heightened risks of mental health problems among women who experience an unintended pregnancy, but few consider the complexity of pregnancy intentions. In this study, we evaluate how different dimensions of pregnancy intentions (pregnancy planning and pregnancy acceptance) relate to two maternal depressive symptoms and perceived psychological distress.\n## METHODS\nThis study draws from a cross-sectional national survey conducted in all maternities in France over a one-week period in 2016. All mothers 18\u2009years and older who had a live birth during the study period were invited to participate. After excluding women who underwent infertility treatment, our analytical sample included 10,339 women. We first described levels and correlates of pregnancy planning and acceptance, defined in four categories; planned/welcomed, unplanned/welcomed, planned/unwelcomed, unplanned/unwelcomed. We then assessed the bivariate and multivariate associations between pregnancy planning and acceptance and two outcomes: women's self-perceived psychological health and the presence of two depressive symptoms during pregnancy. We used multivariate logistic regressions to evaluate these associations, after adjusting for socio-demographic and medical factors.\n## RESULTS\nAltogether 7.5 to 24.1% of mothers perceived their psychological health during pregnancy was poor, according to pregnancy planning and acceptance categories and 10.3 to 22.4% indicated feelings of sadness and loss of interest during pregnancy, according to pregnancy planning and acceptance categories. As compared to women with planned/welcomed pregnancies, the odds of perceived poor psychological health and depressive symptoms were 2.55 times (CI 2.20-2.95) and 1.75 times higher (CI 1.51-2.02), respectively, among unplanned/unwelcomed pregnancies and 2.02 (CI 1.61-2.53) and 2.07 (CI 1.7-2.5) higher, among planned/unwelcomed pregnancies. Among women with unplanned pregnancies, we also found higher odds of perceived poor psychological health among women whose pregnancy was unwelcomed while the odds of depressive symptoms were not different by pregnancy planning status among women with unwelcomed pregnancies.\n## CONCLUSIONS\nThese findings consolidate previous reports of the association between pregnancy intentions and maternal psychological distress, while further specifying the relationship, which mostly depends on the acceptance of pregnancy timing rather than on pregnancy planning. Identifying women with low pregnancy acceptance can potentially enhance current medical practice by improving early detection of maternal depression.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.",
        "key_reference_abstract": "## OBJECTIVE\nThis study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors.\n## METHODS\nIn 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy.\n## RESULTS\nWomen who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester.\n## CONCLUSIONS\nWomen with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Unintended pregnancy and intimate partner violence before and during pregnancy among Latina women in Los Angeles, California.",
        "key_reference_abstract": "The purpose of this paper was to examine the relationship between unintended pregnancy and intimate partner violence (IPV) before and during pregnancy among Latinas. A cross-sectional interview measuring pregnancy intent, IPV, and acculturation, using the Acculturation Rating Scale for Mexican Americans (ARSMA-II), was conducted among Latina women in their 2(nd) or 3(rd) trimester of pregnancy at clinics in Los Angeles (n = 313). Overall, 44% of women reported an unintended pregnancy. The prevalence of physical (any) and emotional (only) abuse 12 months before pregnancy was 11% and 22%, respectively. Although both types of IPV decreased during pregnancy (10% and 19%, respectively), most reports of physical IPV during pregnancy (53%) were among women who did not report physical abuse before pregnancy. After adjusting for other factors, physical IPV before pregnancy was not associated with unintended pregnancy (adjusted OR = 0.92; 95% CI = 0.40, 2.16). The prevalence of unintended pregnancy was highest (76%) among highly acculturated Latinas. However, when an unintended pregnancy occurred among less acculturated Latinas, who comprised the majority of the sample (n = 270), it was associated with greater risk of physical IPV during pregnancy (unadjusted OR = 2.57; 95% CI = 1.06, 6.23); although the confidence interval included one after adjusting for other factors (adjusted OR = 2.79; 95% CI = 0.98, 7.92). An unintended pregnancy may have a unique impact on relationships in the context of Latino culture, where family and pregnancy are highly valued. Pregnancy often creates an opportunity for providers to discuss issues related to abuse and family planning with women who do not regularly access care. The results from this study may be used to increase the cultural sensitivity with which violence and reproductive health are addressed among the diverse population of Latinas when they connect with prenatal services.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Severity of intimate partner abuse indicators as perceived by women in Mexico and the United States.",
        "key_reference_abstract": "## OBJECTIVE\nWomen in Cuernavaca, Mexico and Los Angeles, California were surveyed to examine differences in their perceptions of the severity of domestic violence indicators.\n## METHODS\nOne hundred twenty women in each country rated the severity of 26 domestic violence indicators which were part of an abuse screen used for an ongoing study of the prevalence of abuse. Rasch analysis was conducted to determine the linear relationship in the perceptions of the severity of each event between the two countries.\n## RESULTS\nThe Rasch calibrated logit values show that women in the US rated 24 of the 26 events as more severe than women in Mexico. However, items were ranked in similar order and a clear linear pattern was established. In both countries, being shot with a gun was the most severe event and a partner becoming jealous was the least severe.\n## CONCLUSION\nThe country of origin did not dictate which events were most severe but did influence how severe these events were perceived.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study.",
        "key_reference_abstract": "## BACKGROUND\nUnintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse.\n## METHODS\nA prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used.\n## RESULTS\nApproximately one-fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68).\n## CONCLUSION\nWomen who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Early Childhood Victimization and Physical Intimate Partner Violence During Pregnancy: A Developmental and Person-Oriented Approach.",
        "key_reference_abstract": "Intimate partner violence (IPV) victimization during pregnancy is a major public health concern, yet little is known about how risk factors for IPV during pregnancy may depend on whether women have histories of victimization dating back to early childhood (ages 0-5 years). This study examined whether risk factors for physical IPV victimization during pregnancy (a pregnancy that was not planned and prenatal substance use) differed for women with versus without early childhood victimization. Participants were 236 ethnically diverse, low-income biological mothers ( M = 30.94 years; 50.0% Latina, 16.9% Caucasian, 13.1% African American, and 16.9% multiracial) of children aged 0 to 6 years. Mothers were classified into four groups based on whether they had experienced early childhood victimization and physical IPV victimization during pregnancy with the target child. Multinomial logistic regressions, controlling for demographic characteristics, examined whether a pregnancy not planned and prenatal substance use predicted group membership. Compared to mothers with early victimization only, mothers with both early childhood victimization and physical IPV during pregnancy were more than 3 times as likely to report that their pregnancy with the target child was not planned. In follow-up analyses, mothers with early victimization and physical IPV during pregnancy also reported higher lifetime parity than mothers with physical IPV during pregnancy but no early victimization. Early childhood victimization may place women on a risk pathway to physical IPV during pregnancy, particularly if the pregnancy is not planned. Prevention and policy efforts should screen women for early childhood victimization to understand risks for physical IPV during pregnancy.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "The effect of pregnancy intention on child development.",
        "key_reference_abstract": "In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Unintended pregnancy and preterm birth.",
        "key_reference_abstract": "About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intention and its relationship to birth and maternal outcomes.",
        "key_reference_abstract": "## OBJECTIVE\nTo examine whether there are associations between pregnancy intention (intended, unwanted, mistimed, or ambivalent) and negative birth and maternal outcomes: low birth weight (less than 2,500 g), preterm delivery (fewer than 37 weeks), small for gestational age, premature labor, hypertension, and other maternal outcomes.\n## METHODS\nWe analyzed data from the population-based Pregnancy Risk Assessment Monitoring System, including 87,087 women who gave birth between 1996 and 1999 in 18 states. Information on pregnancy outcomes was derived from birth certificate data and a self-administered questionnaire completed postpartum. We employed SUDAAN (RTI International, Research Triangle Park, NC) for univariable and logistical regression analyses.\n## RESULTS\nIn analyses controlling for demographic and behavioral factors, women with unwanted pregnancies had an increased likelihood of preterm delivery (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33) and premature rupture of membranes (adjusted OR 1.37, 95% CI 1.01-1.85) compared with women with intended pregnancies. Women who were ambivalent toward their pregnancies had increased odds of delivering a low birth weight infant (adjusted OR 1.15, 95% CI 1.02-1.29); in contrast, women with mistimed pregnancies had a lower likelihood (adjusted OR 0.92, 95% CI 0.86-0.97).\n## CONCLUSION\nPregnancy intention, specifically unwanted and ambivalent, may be an indicator of increased risk for some poor birth and maternal outcomes and should be considered in interventions aimed at improving the health of the mother and child.\n## LEVEL OF EVIDENCE\nIII.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intention and preterm birth: differential associations among a diverse population of women.",
        "key_reference_abstract": "## CONTEXT\nStudies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups.\n## METHODS\nData from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics.\n## RESULTS\nIn unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites.\n## CONCLUSIONS\nWomen's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "The couple context of pregnancy and its effects on prenatal care and birth outcomes.",
        "key_reference_abstract": "The couple context of pregnancy and newborn health is gaining importance with the increase in births to unmarried couples, a disproportionate number of which were not intended. This study investigates the association of early prenatal care, preterm birth, and low birth weight with the couple relationship context, including partners' joint intentions for the pregnancy, their marital status at conception, and the presence of relationship problems during pregnancy. Data are drawn from the first wave of the Early Childhood Longitudinal Study--Birth Cohort, a representative study of births in 2001. The sample is composed of parents residing together with their biological child at the time the child is 9 months old, where both the mother and father completed the self-report interview (N = 5,788). Couple-level multivariate logistic regression models, weighted to account for the complex sampling design, were used in the analysis. Risk of inadequate prenatal care and preterm birth was increased when partners did not share intentions or when neither partner intended the pregnancy. Couples were at additional risk of inadequate prenatal care when the pregnancy was conceived nonmaritally and when the mother did not tell the father about the pregnancy, particularly when neither partner intended the pregnancy. The risk of premature birth was particularly high when the partners were unmarried and either or both did not intend the pregnancy. The couple context of pregnancy is important for a healthy pregnancy and birth. When the partner is present, practitioners and programs should maintain a focus on the couple, and researchers should make every effort to include the father's own perspective.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Assessing pregnancy intention and associated risks in pregnant adolescents.",
        "key_reference_abstract": "Unintended pregnancy and associated behaviors may play a substantial role in the increased risk of adverse maternal and neonatal outcomes associated with teen pregnancy. We evaluate a multi-dimensional measure of pregnancy intention among pregnant adolescents and quantify the association between intention dimensions and adverse outcomes and risk behaviors. Pregnancy intention measures were examined in a cohort of 300 pregnant adolescent women. We considered 18 items assessing elements of pregnancy intention including pregnancy planning, timing, emotional response, and readiness. Latent class analysis was performed to identify dimensions of pregnancy intention. Parsimonious scores were created by minimizing the number of covariates while maintaining substantial agreement with the latent class. Associations between intention measures and prenatal care, risk behaviors, and pregnancy outcomes were quantified using multivariable logistic regression. Two constructs of pregnancy intention were identified: planning and emotional readiness. Compared with emotionally ready adolescents, adolescents categorized as not emotionally ready had an increased odds of inadequate prenatal care (OR = 2.70, 95% CI:1.27-5.72), delayed prenatal care (OR = 2.54, 95% CI:1.27-5.09), and self-reported depression at the time of the first prenatal visit (OR = 2.21, 95% CI:1.03-4.77). Pregnancy planning was not associated with adverse pregnancy risk factors or outcomes. Among pregnant adolescents, emotional readiness for pregnancy and parenting was inversely associated with known risk factors for adverse pregnancy outcomes, suggesting that emotional readiness rather than pregnancy planning may be the more pertinent intention construct for adolescents.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy planning, smoking behaviour during pregnancy, and neonatal outcome: UK Millennium Cohort Study.",
        "key_reference_abstract": "## BACKGROUND\nPre-pregnancy health and care are important for the health of the future generations. Smoking during pregnancy has been well-researched and there is clear evidence of harm. But there has been little research on the health impact of planning for pregnancy. This study aims to investigate the independent effects of pregnancy planning and smoking during pregnancy on neonatal outcome.\n## METHODS\nThis analysis made use of data from the UK Millennium Cohort Study. The study sample consisted of 18,178 singleton babies born in UK between 2000 and 2001. The neonatal outcomes of interest were low birthweight (<2.5 Kg) and pre-term birth (<37 completed weeks gestation). Logistic regression was used to estimate the association between pregnancy planning and/or smoking and neonatal outcome. Adjusted odds ratios were used to calculate population attributable risk fractions (PAFs).\n## RESULTS\n43% of mothers did not plan their pregnancy and 34% were smoking just before and/or during pregnancy. Planners were half as likely to be smokers just before pregnancy, and more likely to give up or reduce the amount smoked if smokers. Unplanned pregnancies had 24% increased odds of low birth weight and prematurity compared to planned pregnancies (AORLBW1.24, 95% CI 1.04-1.48; AORPREM1.24, 95% CI 1.05-1.45), independent of smoking status. The odds of low birth weight for babies of mothers who were smoking just before pregnancy was 91% higher than that of mothers who were not (AORLBW1.91, 95% CI 1.56-2.34). Women who quit or reduced the amount smoked during pregnancy lowered the risk of a low birth weight baby by one third (AORLBW0.66, 95% CI 0.51-0.85) compared with women whose smoking level did not change. Smaller effects were found for prematurity. If all women planned their pregnancy and did not smoke before or during pregnancy, 30% of low birthweight and 14% of prematurity could, in theory, be avoided.\n## CONCLUSIONS\nPlanning a pregnancy and avoiding smoking during pregnancy has clear, independent, health benefits for babies. Quitting or reducing the amount smoked during pregnancy can reduce the risk of low birthweight.",
        "truth": "True"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Are pregnancy planning and timing associated with preterm or small for gestational age births?",
        "key_reference_abstract": "## OBJECTIVE\nTo investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births.\n## DESIGN\nProspective cohort study.\n## SETTING\nNot applicable.\n## PATIENT(S)\nTwo thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy.\n## INTERVENTION(S)\nNone.\n## MAIN OUTCOME MEASURE(S)\nPreterm and small for gestational age births.\n## RESULT(S)\nIn adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age.\n## CONCLUSION(S)\nIn a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.",
        "truth": "False"
    },
    {
        "pmid": "36318133",
        "meta_analysis_title": "Associations of Unintended Pregnancy With Maternal and Infant Health Outcomes: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Is unintended pregnancy associated with adverse maternal and infant health conditions during pregnancy and post partum in the US?",
        "criteria": "Investigators independently dual reviewed abstracts and full-text articles to identify studies meeting prespecified eligibility criteria. Discrepancies were resolved by discussion and consensus. Published studies were eligible for the meta-analysis if they evaluated associations of unintended pregnancy with maternal and infant health outcomes occurring during pregnancy and post partum by comparing participants with unintended vs intended pregnancies and reported estimates that adjusted for confounders. Unintended pregnancy was determined by maternal self-report. To optimize applicability to US practice, eligible studies included populations in countries considered very high on the 2018 Human Development Index. While the search and eligibility criteria used an inclusive definition of women (ie, pregnant and postpartum populations that included all gender identities), studies referred to their populations as women. Investigators managed references in an EndNote database (Thomson Reuters).",
        "subgroup": "Infant Outcomesa - Low birth weight",
        "key_reference_title": "Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma.",
        "key_reference_abstract": "Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed \u22652 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Sexual violence among adolescent\u00a0girls and young women in Malawi: a cluster-randomized controlled implementation trial of empowerment self-defense training.",
        "key_reference_abstract": "## BACKGROUND\nGlobally,\u00a0sexual violence is prevalent, particularly for adolescent women. This cluster-randomized controlled implementation trial examines empowerment self-defense (ESD) for sexual assault risk reduction among school-age women in Malawi.\n## METHODS\nThe unit of randomization and analysis was the school (n\u2009=\u2009141). Intervention participants received a 12-h intervention over 6\u2009weeks, with refreshers. Primary outcomes were past-year prevalence and incident rate of sexual violence. Secondary outcomes included confidence, self-defense knowledge, and, for those victimized, violence disclosure. Interaction effects on outcomes were evaluated with Poisson models with school-correlated robust variance estimates for risk ratios and incident rate ratios (baseline n\u2009=\u20096644, follow-up n\u2009=\u20094278).\n## RESULTS\nPast-year sexual assault prevalence was reduced among intervention students (risk ratio [RR] 0.68, 95% CI 0.56, 0.82), but not control students (interaction effect p\u2009<\u20090.001). Significant increases in self-defense knowledge were observed solely among intervention students (RR 3.33, 95% CI 2.76, 4.02; interaction effect p\u2009<\u20090.001). Significant changes in sexual violence prevalence and knowledge were observed for both primary and secondary students. Favorable reductions were also observed in sexual violence incident rate among students overall (interaction effect p\u2009=\u20090.01).\n## CONCLUSIONS\nThis intervention reduced sexual violence victimization in both primary and secondary school settings. Results support the effectiveness of ESD to address sexual violence, and approach the elimination of violence against women and girls set forth with Sustainable Development Goal #5. Implementation within the education system can enable sustainability and reach.\n## TRIAL REGISTRATION\nPan African Clinical Trials Registry PACTR201702002028911 . Registered 09 February 2017. Retrospectively registered.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Does the Good Schools Toolkit Reduce Physical, Sexual and Emotional Violence, and Injuries, in Girls and Boys equally? A Cluster-Randomised Controlled Trial.",
        "key_reference_abstract": "We aimed to investigate whether the Good School Toolkit reduced emotional violence, severe physical violence, sexual violence and injuries from school staff to students, as well as emotional, physical and sexual violence between peers, in Ugandan primary schools. We performed a two-arm cluster randomised controlled trial with parallel assignment. Forty-two schools in one district were allocated to intervention (n\u00a0=\u00a021) or wait-list control (n\u00a0=\u00a021) arms in 2012. We did cross-sectional baseline and endline surveys in 2012 and 2014, and the Good School Toolkit intervention was implemented for 18\u00a0months between surveys. Analyses were by intention to treat and are adjusted for clustering within schools and for baseline school-level proportions of outcomes. The Toolkit was associated with an overall reduction in any form of violence from staff and/or peers in the past week towards both male (aOR\u00a0=\u00a00.34, 95%CI 0.22-0.53) and female students (aOR\u00a0=\u00a00.55, 95%CI 0.36-0.84). Injuries as a result of violence from school staff were also lower in male (aOR\u00a0=\u00a00.36, 95%CI 0.20-0.65) and female students (aOR\u00a0=\u00a00.51, 95%CI 0.29-0.90). Although the Toolkit seems to be effective at reducing violence in both sexes, there is some suggestion that the Toolkit may have stronger effects in boys than girls. The Toolkit is a promising intervention to reduce a wide range of different forms of violence from school staff and between peers in schools, and should be urgently considered for scale-up. Further research is needed to investigate how the intervention could engage more successfully with girls.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Effects of an Interactive School-Based Program for Preventing Adolescent Sexual Harassment: A Cluster-Randomized Controlled Evaluation Study.",
        "key_reference_abstract": "Many adolescents experience sexual harassment and victims of sexual harassment have higher risks regarding well-being and health behaviors such as higher risks of suicidal thoughts, suicidal ideation and feeling unsafe at school. A peer-performed play and school lessons on preventing sexual harassment behavior were presented to secondary school students. We evaluated its effectiveness, using a cluster-randomized controlled design to assign schools to an experimental condition [n = 14 schools; 431 students (51 % female)] and a control condition [n = 11 schools; 384 students (51 % female)]. To measure the effects of the intervention at first post-test and 6-month follow-up, our multilevel analyses used a two-level random intercept model. Outcome measures were sexual harassment behaviors, behavioral determinants and distal factors influencing these behaviors. At post-test, students in the experimental group reported a reduced intention to commit sexual harassment behavior and higher self-efficacy in rejecting it. At post-test and follow-up there was a significant positive effect on social norms for rejecting sexual harassment behavior. At follow-up, sexual self-esteem was higher in students in the experimental group than in the control group. Effects on these determinants will benefit adolescents' future sexual behaviors. In combination, the play and lessons, possibly together with continued sexual health education and skills programs on social-emotional learning in subsequent school years, have potential for preventing sexual harassment behavior.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Assessing the effects of the dating violence prevention program \"safe dates\" using random coefficient regression modeling.",
        "key_reference_abstract": "The Safe Dates Project is a randomized trial for evaluating a school-based adolescent dating violence prevention program. Five waves of data were used to examine the effects of Safe Dates over time including primary and secondary prevention effects, moderators, and mediators of program effects. Using random coefficients models, with multiple imputation of missing data, significant program effects were found at all four follow-up periods on psychological, moderate physical, and sexual dating violence perpetration and moderate physical dating violence victimization. Marginal effects were found on sexual victimization. Effects on severe physical perpetration at all four follow-up periods were moderated by prior involvement in that type of violence. Primary and secondary prevention effects were found and the program was equally effective for males and females and for whites and non-whites. Program effects were mediated by changes in dating violence norms, gender-role norms, and awareness of community services.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Effect of a Behavioral Intervention on Perpetrating and Experiencing Forced Sex Among South African Adolescents: A Secondary Analysis of a Cluster Randomized Trial.",
        "key_reference_abstract": "## IMPORTANCE\nScant research has investigated interventions to reduce forced sexual intercourse among adolescents. The need for such interventions is especially great in South Africa, which has some of the highest rates of sexual assault in the world.\n## OBJECTIVES\nTo determine whether an HIV/sexually transmitted disease risk-reduction intervention that reduced sexual risk behavior and sexually transmitted disease prevalence also reduced the perpetration and experience of forced sex among South African adolescents.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cluster randomized clinical trial, at schools located in a township and a semirural area, Eastern Cape Province, South Africa. Matched pairs of schools were randomly selected (9 of 17); of 1118 students in sixth grade at these 18 schools who had parent or guardian consent, 1057 (94%) were enrolled, and those not reporting forced sex perpetration before the intervention were included in the analyses (n\u2009=\u20091052). Post hoc secondary analysis of a cluster randomized clinical trial was performed, with baseline and 3-, 6-, 12-, 42-, and 54-month postintervention assessments between October 4, 2004, and June 30, 2010. Generalized estimating equation Poisson regression analyses adjusting for gender and clustering within schools were conducted between August 23, 2017, and April 30, 2018. Recruiters and data collectors, but not intervention facilitators, were blind to the participants' intervention assignment.\n## INTERVENTIONS\nTheory-based, culturally adapted, 6-session HIV/sexually transmitted disease risk-reduction intervention (Let Us Protect Our Future intervention) and attention-matched, chronic disease prevention control intervention implemented by specially trained man and woman cofacilitators from the community.\n## MAIN OUTCOMES AND MEASURES\nStudy outcomes for this secondary analysis (planned after the data were collected) are self-reports of perpetrating and experiencing forced vaginal intercourse.\n## RESULTS\nParticipants included 1052 adolescents (557 girls [53%]; mean [SD] age, 12.4 [1.2] years) reporting not perpetrating forced sex at baseline. Fewer intervention than control participants reported forced sex perpetration postintervention compared with the control group at 3 months (9 of 561 [2%] vs 20 of 491 [4%]; risk ratio [RR], 0.978; 95% CI, 0.959-0.997), 6 months (17 of 561 [3%] vs 35 of 491 [7%]; RR, 0.964; 95% CI, 0.941-0.988), 12 months (21 of 561 [4%] vs 42 of 491 [9%]; RR, 0.959; 95% CI, 0.934-0.985), 42 months (41 of 561 [7%] vs 56 of 491 [11%]; RR, 0.967; 95% CI, 0.937-0.998), and 54 months (52 of 561 [9%] vs 68 of 491 [14%]; RR, 0.964; 95% CI, 0.932-0.997).\n## CONCLUSIONS AND RELEVANCE\nIn settings with high rates of sexual assault, the use of theory-based culturally adapted interventions with early adolescents may reduce rates of perpetrating and experiencing forced sex.\n## TRIAL REGISTRATION\nClinicalTrials.gov Identifier: NCT00559403.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Effects of PREPARE, a Multi-component, School-Based HIV and Intimate Partner Violence (IPV) Prevention Programme on Adolescent Sexual Risk Behaviour and IPV: Cluster Randomised Controlled Trial.",
        "key_reference_abstract": "Young South Africans, especially women, are at high risk of HIV. We evaluated the effects of PREPARE, a multi-component, school-based HIV prevention intervention to delay sexual debut, increase condom use and decrease intimate partner violence (IPV) among young adolescents. We conducted a cluster RCT among Grade eights in 42 high schools. The intervention comprised education sessions, a school health service and a school sexual violence prevention programme. Participants completed questionnaires at baseline, 6 and 12\u00a0months. Regression was undertaken to provide ORs or coefficients adjusted for clustering. Of 6244 sampled adolescents, 55.3\u00a0% participated. At 12\u00a0months there were no differences between intervention and control arms in sexual risk behaviours. Participants in the intervention arm were less likely to report IPV victimisation (35.1 vs. 40.9\u00a0%; OR 0.77, 95\u00a0% CI 0.61-0.99; t(40)\u00a0=\u00a02.14) suggesting the intervention shaped intimate partnerships into safer ones, potentially lowering the risk for HIV.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "\"Coaching boys into men\": a cluster-randomized controlled trial of a dating violence prevention program.",
        "key_reference_abstract": "## PURPOSE\nDating violence (DV)--physical, sexual, and psychological aggression in adolescent romantic relationships--is prevalent among youth. Despite broad calls for primary prevention, few programs with demonstrated effectiveness exist. This cluster-randomized trial examined the effectiveness of a DV perpetration prevention program targeting coaches and high school male athletes.\n## METHODS\nThe unit of randomization was the high school (16 schools), and the unit of analysis was the athlete (N = 2,006 students). Primary outcomes were intentions to intervene, recognition of abusive behaviors, and gender-equitable attitudes. Secondary outcomes explored bystander behaviors and abuse perpetration. Regression models for clustered, longitudinal data assessed between-arm differences in over-time changes in mean levels of continuous outcomes in 1,798 athletes followed up at 3 months.\n## RESULTS\nIntervention athletes' changes in intentions to intervene were positive compared with control subjects, resulting in an estimated intervention effect of .12 (95% CI: .003, .24). Intervention athletes also reported higher levels of positive bystander intervention behavior than control subjects (.25, 95% CI: .13, .38). Changes in gender-equitable attitudes, recognition of abusive behaviors, and DV perpetration were not significant. Secondary analyses estimated intervention impacts according to intensity of program implementation. Compared with control subjects, athletes exposed to full-intensity implementation of the intervention demonstrated improvements in intentions to intervene (.16, 95% CI: .04, .27), recognition of abusive behaviors (.13, 95% CI: .003, .25), and positive bystander intervention (.28, 95% CI: .14, .41).\n## CONCLUSION\nThis cluster-randomized controlled trial supports the effectiveness of a school athletics-based prevention program as one promising strategy to reduce DV perpetration.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Effect of a Community-Based Gender Norms Program on Sexual Violence Perpetration by Adolescent Boys and Young Men: A Cluster Randomized Clinical Trial.",
        "key_reference_abstract": "## IMPORTANCE\nEngaging adolescent boys and young men in preventing violence against women is a potentially impactful public health strategy.\n## OBJECTIVE\nTo evaluate the effectiveness of a community-based, gender-transformative program (ie, Manhood 2.0) on perpetration of gender-based violence by adolescent boys and young men.\n## DESIGN, SETTING, AND PARTICIPANTS\nIn this unblinded cluster randomized clinical trial, neighborhoods were designated as the unit of clustering (1:1 allocation). Three-month (ie, time point 2 [T2]) and 9-month (ie, time point 3 [T3]) follow-ups were conducted. The trial took place in 20 Pittsburgh, Pennsylvania, neighborhoods and 1 centrally located site with concentrated disadvantage. Pittsburgh-based adolescent boys and young men (ages 13 to 19 years) were recruited between July 27, 2015, and June 5, 2017, through youth-serving organizations and community-based alternatives to residential placement for juvenile justice-involved youth. Intention-to-treat analysis was conducted from June 2018 to November 2019.\n## INTERVENTIONS\nManhood 2.0, an international program adapted for adolescent boys and young men in US urban communities, encourages these individuals to challenge gender norms that foster violence against women and unhealthy sexual relationships. Individuals in the control population received job-readiness training. Each program was 18 hours.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was change in participant-level perpetration of sexual violence (SV) or adolescent relationship abuse (ARA) at T3.\n## RESULTS\nAmong 866 participants, 465 individuals (54%) enrolled in 11 intervention clusters and 401 individuals (46%) enrolled in 10 control clusters. In the intervention group, 325 participants (70%) were analyzed at T2 and 334 participants (72%) were analyzed at T3; in the control group, 262 participants (65%) were analyzed at T2 and 301 participants (75%) were analyzed at T3. Mean (SD) age was 15.5 (1.6) years; 609 participants (70%) self-identified as non-Hispanic Black, and 178 (20%) self-identified as Hispanic, multiracial, or other race/ethnicity other than White. Among individuals in the intervention group, 296 participants (64%) reported any SV or ARA perpetration at baseline, and 173 participants (52%) reported any SV or ARA perpetration at T3. Among individuals in the control group, 213 participants (53%) reported any SV or ARA perpetration at baseline, and 124 participants (41%) reported any SV or ARA perpetration at T3). The difference in reduction between groups was not significant. There was no evidence of an intervention effect for the primary outcome (adjusted odds ratio [OR], 1.32; 95% CI, 0.86-2.01; P\u2009=\u2009.20).\n## CONCLUSIONS AND RELEVANCE\nThe findings from this evaluation of a community-based gender-transformative program for adolescent boys and young men did not show a significant intervention effect in reducing SV or ARA perpetration between Manhood 2.0 and a job-readiness control program. Combining gender-transformative approaches with job-readiness programs may be relevant for violence prevention in low-resource urban settings. Attention to improving implementation and strategies to sustain such community-based efforts are needed.\n## TRIAL REGISTRATION\nClinicalTrials.gov Identifier: NCT02427061.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "An Athletic Coach-Delivered Middle School Gender Violence Prevention Program: A Cluster Randomized Clinical Trial.",
        "key_reference_abstract": "## IMPORTANCE\nAdolescent relationship abuse (ARA) and sexual violence (SV) reported among adolescents point to the need for prevention among middle school-age youths.\n## OBJECTIVE\nTo test an athletic coach-delivered relationship abuse and sexual violence prevention program among middle school male athletes.\n## DESIGN, SETTING, AND PARTICIPANTS\nAn unblinded cluster randomized clinical trial from spring 2015 to fall 2017 at 41 middle schools (38 clusters). The study included 973 male middle school athletes (ages 11-14 years; grades 6-8; participation rate 50%) followed up for 1 year (retention 86%).\n## INTERVENTIONS\nCoaching Boys Into Men (CBIM) is a prevention program that trains athletic coaches to talk to male athletes about (1) respectful relationship behaviors, (2) promoting more gender-equitable attitudes, and (3) positive bystander intervention when harmful behaviors among peers are witnessed.\n## MAIN OUTCOMES AND MEASURES\nThe primary outcome was change in positive bystander behaviors (ie, intervening in peers' disrespectful or harmful behaviors); secondary outcomes were changes in recognition of what constitutes abusive behavior, intentions to intervene, gender-equitable attitudes, and reduction in recent ARA/SV perpetration (at end of sports season and 1-year follow up).\n## RESULTS\nOf the 973 participants, 530 were white (54.5%), 282 were black (29.0%), 14 were Hispanic (1.4%), and the remainder were multiracial, other race/ethnicity, or not reported. Positive bystander behaviors increased at end of sports season and at 1-year follow-up (relative risk, 1.51; 95% CI, 1.06-2.16 and 1.53; 95% CI, 1.10-2.12, respectively) as did recognition of abuse (mean risk difference, 0.14; 95% CI, 0.01-0.27 and 0.14; 95% CI, 0.00-0.28, respectively). At 1-year follow-up, among those who ever dated, athletes on teams receiving CBIM had lower odds of reporting recent ARA/SV perpetration (odds ratio, 0.24; 95% CI, 0.09-0.65). Gender attitudes and intentions to intervene did not differ between study arms. In exploratory intensity-adjusted and per protocol analyses, athletes on teams receiving CBIM were more likely to report positive bystander behaviors and to endorse equitable gender attitudes and less likely to report ARA and sexual harassment perpetration 1 year later.\n## CONCLUSIONS AND RELEVANCE\nAn athletic coach-delivered program for middle school male athletes is an effective strategy for reducing relationship abuse among younger adolescents.\n## TRIAL REGISTRATION\nClinicalTrials.gov Identifier: NCT02331238.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Preventing Sexual Violence in Adolescence: Comparison of a Scientist-Practitioner Program and a Practitioner Program Using a Cluster-Randomized Design.",
        "key_reference_abstract": "Numerous school-based prevention programs have been developed by scientists and practitioners to address sexual violence in adolescence. However, such programs struggle with two major challenges. First, the effectiveness of many well-established practitioner programs has not been rigorously evaluated. Second, effective scientific programs may be hard to implement into everyday school practice. Combining the knowledge of scientists and practitioners in a scientist-practitioner program could be a helpful compromise. The aim of the present study is to evaluate the effects of a scientist-practitioner program and a practitioner program using a cluster-randomized experimental design. Twenty-seven school classes were randomly assigned to either one of two programs or a control group. Outcome variables (knowledge, attitudes, behavior, and iatrogenic effects) were assessed at pretest, posttest, and a 6-month follow-up for 453 adolescents (55% female,",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Girl Empower - A gender transformative mentoring and cash transfer intervention to promote adolescent wellbeing: Impact findings from a cluster-randomized controlled trial in Liberia",
        "key_reference_abstract": "## Background: We evaluated Girl Empower - an intervention that aimed to equip adolescent girls with the skills to make healthy, strategic life choices and to stay safe from sexual abuse using a cluster-randomized controlled trial with three arms: control, Girl Empower (GE), and GE+.\n ## Methods: GE delivered a life skills curriculum to girls aged 13-14 in Liberia, facilitated by local female mentors. In the GE + variation, a cash incentive payment was offered to caregivers for girls' participation in the program. We evaluated the impact of the program on seven pre-specified domains using standardized indices: sexual violence, schooling, sexual and reproductive health (SRH), psychosocial wellbeing, gender attitudes, life skills, and protective factors.\n ## Findings: Participation rates in the program were high in both GE and GE+, with the average participant attending 28 out of 32 sessions. At 24 months, the standardized effects of both GE and GE+, compared to control, on sexual violence, schooling, psychosocial wellbeing, and protective factors were small (\u03b2, \u2264 0.11 standard deviations [SD]) and not statistically significant at the 95% level of confidence. However, we found positive standardized effects on Gender Attitudes (GE: \u03b2, 0.206 SD, p<0.05; GE+: \u03b2, 0.228 SD, p<0.05), Life Skills (GE: \u03b2, 0.224 SD, p<0.05; GE+: \u03b2, 0.289 SD, p<0.01), and SRH (GE: \u03b2, 0.244 SD, p<0.01; GE+: \u03b2, 0.372 SD, p<0.01; F-test for GE = GE+: p = 0.075).\n ## Interpretation: Girl Empower led to sustained improvements in several important domains, including SRH, but did not reduce sexual violence among the target population.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Effects of Government-Implemented Cash Plus Model on Violence Experiences and Perpetration Among Adolescents in Tanzania, 2018\u20122019.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Adolescent Dating Violence Prevention Program for Early Adolescents: The Me & You Randomized Controlled Trial, 2014-2015.",
        "key_reference_abstract": "Objectives. To test the efficacy of Me & You, a multilevel technology-enhanced adolescent dating violence (DV) intervention, in reducing DV perpetration and victimization among ethnic-minority early adolescent youths. We assessed secondary impact for specific DV types and psychosocial outcomes.Methods. We conducted a group-randomized controlled trial of 10 middle schools from a large urban school district in Southeast Texas in 2014 to 2015. We used multilevel regression modeling; the final analytic sample comprised 709 sixth-grade students followed for 1 year.Results. Among the total sample, odds of DV perpetration were lower among intervention students than among control students (adjusted odds ratio = 0.46; 95% confidence interval = 0.28, 0.74). Odds of DV victimization were not significantly different. There were significant effects on some specific DV types.Conclusions. Me & You is effective in reducing DV perpetration and decreasing some forms of DV victimization in early middle-school ethnic-minority students.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "The Effects of a Health Care-Based Brief Intervention on Dating Abuse Perpetration: Results of a Randomized Controlled Trial.",
        "key_reference_abstract": "Dating abuse (DA) is prevalent and consequential, yet there are no evidence-based interventions for the health care setting that prevent perpetration. The current study's purpose was to test a one-session brief motivational interview-style intervention to decrease DA perpetration. We conducted a two-arm RCT of the Real Talk intervention with follow-up at 3 and 6\u00a0months. Participants were 172 youth ages 15-19\u00a0years old, recruited from the pediatric emergency department or outpatient care services of an urban hospital in the USA in 2014-2017. The primary outcome was change in self-reported DA perpetration, including subtypes of DA such as physical, sexual, psychological, and cyber DA. Youth in both intervention and control arms reduced DA perpetration over time. GEE models indicated no overall intervention effects for any, physical, sexual, or psychological DA. There were overall effects for cyber DA (RR 0.49, 95% CI 0.27, 0.87). There were also effects at 3\u00a0months for psychological DA (RR 0.24, 95% CI 0.06, 0.93) and cyber DA (RR 0.39, 95% CI 0.19, 0.79). Analyses stratified by gender also found overall effects for males for any DA (RR 0.20, 95% CI 0.07, 0.55), physical DA (RR 0.30, 95% CI 0.10, 0.89), and cyber DA (RR 0.04, 95% CI 0.01, 0.27). For males, intervention effects on any DA persisted to 6\u00a0months (RR 0.13, 95% CI 0.02, 1.01). This health care-based one-session DA intervention is a potentially promising approach to reduce DA perpetration among adolescents.Clinical trial registration: This study is registered at www.clinicaltrials.gov NCT02080923.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Reducing sexual victimization among adolescent girls: a randomized controlled pilot trial of my voice, my choice.",
        "key_reference_abstract": "Despite extensive efforts to develop and implement programs to prevent sexual violence, few programs have empirically-demonstrated efficacy. The primary exceptions are programs that emphasize risk-reduction skills; yet even these programs are not consistently effective. This study seeks to add to the literature by evaluating the effects of My Voice, My Choice (MVMC), a 90-minute assertive resistance training program that emphasizes skill practice in an immersive virtual environment (IVE). We hypothesized that MVMC would reduce male-to-female sexual victimization among adolescent girls over a 3-month follow-up period. We also examined whether these results would generalize to other forms of male-to-female relationship violence and to girls' psychological distress. Eighty-three female students from an urban public high school were randomized to MVMC (n=47) or to a wait-list control condition (n=36); 78 provided data over the 3-month follow-up period. Participants assigned to MVMC were less likely than control participants to report sexual victimization during the follow-up period. Our results also suggest that MVMC reduced risk for psychological victimization and for psychological distress among participants with greater prior victimization at baseline. The promising results of this pilot trial suggest that MVMC may help girls evade male-to-female relationship violence.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Preventing violence against refugee adolescent girls: findings from a cluster randomised controlled trial in Ethiopia.",
        "key_reference_abstract": "## INTRODUCTION\nInterpersonal violence is a critical public health concern in humanitarian contexts, but evidence of effective violence prevention programmes targeting adolescent girls is lacking. We investigated the efficacy of a life skills and safe spaces programme to reduce adolescent girls' experiences of interpersonal violence in a refugee setting.\n## METHODS\nIn this two-arm, single-blinded, cluster randomised controlled trial, we recruited 919 Sudanese and South Sudanese girls ages 13-19 years residing in refugee camps in Ethiopia. Girls were divided into 31 clusters, with 457 and 462 participants assigned to the intervention and control arms, respectively. Intervention clusters received 30 life skills sessions delivered in safe spaces and 8 complementary sessions for caregivers. The primary outcome was exposure to sexual violence in the previous 12 months. Secondary outcomes included disaggregated forms of sexual violence, physical violence, emotional violence, transactional sex, child marriage, feelings of safety, attitudes around rites of passage and perceptions of social support. Intent-to-treat analysis was used.\n## RESULTS\nAt 12-month follow-up, the intervention was not significantly associated with reduction in exposure to sexual violence (adjusted OR =0.96, 95% \u2009CI 0.59 to 1.57), other forms of violence, transactional sex or feelings of safety. The intervention was associated with improvements in attitudes around rites of passage and identified social supports. Additionally, the intervention showed a decrease in reported child marriage among girls who were married at baseline.\n## CONCLUSION\nWhile the intervention impacted key markers along the causal pathway to violence reduction, further research and programmatic adaptations are needed to prevent violence towards adolescents in humanitarian contexts.\n## TRIAL REGISTRATION\nNCT02506543.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Shifting Boundaries: an experimental evaluation of a dating violence prevention program in middle schools.",
        "key_reference_abstract": "We randomly assigned the Shifting Boundaries interventions to 30 public middle schools in New York City, enrolling 117 sixth and seventh grade classes (over 2,500 students) to receive a classroom, a building, a combined, or neither intervention. The classroom intervention included a six-session curriculum emphasizing the laws and consequences for perpetrators of dating violence and sexual harassment (DV/H), the social construction of gender roles, and healthy relationships. The building-based intervention included the use of building-based restraining orders, higher levels of faculty/security presence in safe/unsafe \"hot spots\" mapped by students, and posters to increase DV/H awareness and reporting. Student surveys were implemented at baseline, immediately after the intervention, and 6-months post-intervention. As hypothesized, behaviors improved as a result of the interventions. The building-only and the combined interventions were effective in reducing sexual violence victimization involving either peers or dating partners at 6-months post-intervention. This was mirrored by reductions in sexual violence perpetration by peers in the building-only intervention. While the preponderance of results indicates that the interventions were effective, an anomalous result (increase in sexual harassment victimization reports that was contradicted by lower frequency estimates) did emerge. However, after analysis these anomalous results were deemed to be most likely spurious. The success of the building-only intervention alone is important because it can be implemented with very few extra costs to schools.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Evaluation of a Youth-Led Program for Preventing Bullying, Sexual Harassment, and Dating Aggression in Middle Schools.",
        "key_reference_abstract": "Although youth-led programs (YLP) have been successful in many areas of public health, youth leadership is rarely used in the prevention of peer aggression. A YLP to reduce bullying, sexual harassment, and dating aggression was compared experimentally with the board-mandated usual practice (UP). Four middle schools in an urban Canadian school division were randomly assigned to a YLP or to UP programs led by adults. Knowledge, attitudes, victimization, and emotional school adjustment (anxiety and school connectedness) were assessed in the fall (pretest) and spring (posttest) among 509 Grades 7 and 8 students (51.4% female, X age = 12.37). Significant improvements were found in knowledge and attitudes in both programs. Students receiving the YLP showed significant reductions in anxiety and maintained their school connectedness (all ps < .05). The results suggest that youth-led prevention is an effective approach for tackling peer aggression in school settings.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Clinical trial of Second Step middle-school program: impact on aggression and victimization.",
        "key_reference_abstract": "School-based social-emotional (SEL) programs that address interpersonal conflict and teach emotion management have succeeded in reducing youth aggression among elementary school youth, with few studies in middle schools. Results of a two-year cluster-randomized (36 schools) clinical trial of Second Step Middle School Program (Committee for Children, 2008) on reducing aggression and victimization are presented. Teachers implemented 28 lessons (6th & 7th-grade) that focused on social emotional learning skills (e.g., empathy, problem-solving). All 6th graders (n = 3658) completed self-report measures assessing bullying, aggression, homophobic name-calling and sexual harassment at three waves. Multilevel analyses revealed significant intervention effects for two of the seven outcomes. Students in intervention schools were 56% less likely to self-report homophobic name-calling victimization and 39% less likely to report sexual violence perpetration than students in control schools in one state. SS-SSTP holds promise as an efficacious program to reduce homophobic name-calling and sexual violence in adolescent youth.",
        "truth": "True"
    },
    {
        "pmid": "36346627",
        "meta_analysis_title": "Assessment of Psychosocial Programs to Prevent Sexual Violence During Adolescence: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are psychosocial prevention programs associated with reduced sexual violence during adolescence?",
        "criteria": "Studies were selected if they (1) were randomized trials; (2) examined the efficacy of a psychosocial prevention program in reducing any type of sexual violence, such as sexual harassment, unwanted touching, or rape; (3) the program was compared with a control group, which could include no intervention, wait-list, or active controls (ie, minimal interventions, lectures on health, usual practice); and (4) was delivered to adolescents. Adolescents were defined as middle or high school students or individuals aged 10 to 19 years, as described by the World Health Organization.15 We excluded reviews, qualitative studies, nonrandomized studies, quasi-experimental studies, and articles that were not published in peer-reviewed journals. We also excluded studies or group comparisons that (1) were not psychosocial programs, such as those based only on cash transfers or on the legislation of sexual-related crimes; (2) did not follow up with the same cohort of participants; (3) compared different prevention programs with no control group; (4) targeted college or university students; (5) assessed sexual violence outcomes by behavioral counts or through official records; or (6) did not include enough information to compute effect sizes and raw data could not be retrieved after contacting the authors of the study.",
        "subgroup": "Efficacy of Prevention Programs on Any Sexual Violence - All",
        "key_reference_title": "Exploring gender differences in dating violence/harassment prevention programming in middle schools: results from a randomized experiment.",
        "key_reference_abstract": "In this study, we randomly assigned 123 sixth and seventh grade classrooms from seven middle schools in the greater Cleveland area to one of two five-session curricula addressing gender violence/sexual harassment (GV/SH) or to a no-treatment control group. A baseline survey and two follow-up surveys were administered immediately after the treatment (Wave 2) and about six months post-treatment (Wave 3). In an earlier paper, we demonstrated the effectiveness of two approaches to youth GV/SH prevention programming (a fact-based, law and justice curriculum and an interaction-based curriculum). In this paper, we explored whether these largely positive findings remain for both girls and boys, including whether girls experience higher levels of GV/SH than boys. Most of our statistical models proved to be non-statistically significant. However, in 2 of our 48 victimization/ perpetration (any violence, sexual violence and non-sexual violence) models (across two post-intervention follow-up points), we observed that the interventions reduced peer (male or female, non-dating partner) sexual violence victimization and reduced peer perpetration, but another outcome model indicated that the interventions increased dating perpetration. These mixed findings will need to be explored further in future research. Regarding our primary research question, we observed no statistically significant differences for the treatment multiplied by gender interaction terms for any of the perpetration or victimization outcome models, suggesting that the treatment had similar effects on girls and boys. However, we did observe that boys are more involved in violence than girls: both as victims and perpetrators. Boys experienced significantly more of three types of victimization from peers and dating partners compared to what girls experienced at the hands of their peers and dating partners. As perpetrators, boys committed more sexual victimization against peers (immediately post-intervention only) and more sexual victimization against dating partners than girls. The implications of these results are discussed.",
        "truth": "True"
    }
]