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Introduction | SARS-CoV-2 infection | SARS-COV-2 INFECTION | As point-of-care tests (POCTs), lateral flow device antigen (LFD-Ag) tests provide rapid results that avoid the delays and costs associated with laboratory testing [There are concerns about the diagnostic accuracy of LFD-Ag devices and in particular LFD-Ag test performance when used by front-line community-based healthcare workers in usual care settings. False negatives are more damaging in the community as ambulatory patients can potentially propel community transmission, whilst false positives in otherwise healthy individuals could hamper efforts to maintain employment and education and result in inappropriate management [Whilst the evidence base for LFD-Ag SARS-CoV-2 testing has steadily increased since early 2020 [We aimed to conduct a community based prospective diagnostic accuracy study of POCTs for SARS-CoV-2 infection in symptomatic patients performed by front-line healthcare workers. | PMC10361479 |
Methods | PMC10361479 | |||
Design | RAPTOR-C19 (RApid community Point-of-care Testing fOR COVID-19) is the community testbed for diagnostic testing for SARS-CoV-2 within the UK’s COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR) [ | PMC10361479 | ||
Ethical approval | OF DISEASE TRANSMISSION | This study was approved by the North West-Liverpool Central Research Ethics Committee (20/NW/0282). Participants were provided with information about the study via electronic participant information accessible online. All participants (or their parent or guardian, where applicable) gave informed consent via an e-consent process conducted online to minimise the risk of disease transmission, with the completed consent form emailed to the participant. | PMC10361479 | |
Recruitment and participant eligibility | infection | INFECTION, RECRUITMENT | The main setting for this study was UK primary care. Nineteen general practices were recruited after email invitation for expressions of interest, following the sharing of Research Information Sheets for GP surgeries to practices identified through the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) and the National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN). To increase recruitment, two COVID-19 community testing centres for symptomatic individuals were added as additional recruitment sites in the spring of 2021. Participants were adults and children presenting with symptoms of active infection consistent with suspected current COVID-19 (see [ | PMC10361479 |
Baseline and follow-up assessments | ADVERSE EVENTS, RECRUITMENT | In addition to undergoing testing for the index test(s) and reference standard described below, further participant information was collected at the time of recruitment using an electronic case report form (eCRF). Variables included age, sex, ethnicity, presence and duration of specified symptoms within the preceding 14 days, vaccine status, household contacts diagnosed with SARS-CoV-2, and the timing and results of previous tests for SARS-CoV-2. Adult participants (age ≥ 16 years) recruited from general practices were asked to provide a venous blood sample for antibody testing, collected by appropriately trained staff. These participants were also invited to attend a second visit, or be visited at home by a research nurse, after 28 days to provide a second sample for repeat antibody testing. Adult participants were asked to complete an online daily symptom diary for 28 days after recruitment, but as completion rates were low, no diary data are reported here. Linked electronic health records provided collateral information about subsequent hospitalisation, SARS-CoV-2 test results (in addition to those performed for this study) and mortality within 28 days. Serious adverse events related to test usage were reported by study sites to the RAPTOR-C19 coordination centre via adverse events reporting forms, which were evaluated by clinical staff. | PMC10361479 | |
Index tests | ™ Q SARS-CoV-2 | This paper presents results from two POCTs. The SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test (REF 9901-NCOV-01G, branded and distributed by Roche Diagnostics GmbH, Mannheim, Germany) was used from the start of the study. This test incorporates an internal quality control and is read and interpreted manually by the user following the prescribed assay incubation period [ | PMC10361479 | |
Reference standard | infection | INFECTION, DISEASE | The reference test for active infection was an in-house validated reverse transcription quantitative PCR (RT-PCR) for the detection of ORF1ab and E gene regions of SARS-CoV-2. The assay incorporated ORF1ab primers and probes as published by the Chinese Center for Disease Control and Prevention and E gene primers and probe published by Corman et al. [ | PMC10361479 |
Sample size | The sample size was based on a target of 150 reference standard positive individuals, for each index test. If the true sensitivity of an index test were 90% or higher, a similar number of positive samples (144) would yield a standard error of the estimate of the sensitivity of ≤2.5%, and a 95% confidence interval width of ±5%. This would have ≥90% power to detect a difference from a level of 80% sensitivity (the level specified as “desired” by the MHRA Target Product Profile [ | PMC10361479 | ||
Statistical methods | DISEASE, RECRUITMENT | A Statistical Analysis Plan was written before the analysis was performed and is available in Supplemental Material. We calculated the prevalence of positive RT-PCR results, and the sensitivity, specificity and predictive values for each index test alongside exact 95% confidence intervals. Index test results were presented graphically in relation to the RT-PCR cycle threshold. Prespecified subgroup analyses split results by participant characteristics including age, sex, ethnicity, spectrum of disease, recruitment method and recruiting practice. We also performed a post-hoc analysis of diagnostic performance against time since symptom onset. We summarised recruitment rates, variation in disease prevalence over time, and baseline characteristics and symptom progression using appropriate summary statistics and graphs, with the number of participants with missing data reported separately.We used two methods to allow for imperfect reference standard bias. Firstly, for individuals with discordant results between either index test and the reference standard, we created an enhanced composite reference standard using a combination of antibody testing results, additional RT-PCR test results, and linked hospitalisation and mortality records [To allow for discrepancies between recorded recruitment date and recorded swab dates from some participants, two sensitivity analyses were performed: firstly, a stricter scenario excluding all individuals for whom these dates did not match exactly, and secondly, a less strict scenario in which date discrepancies of up to a week were allowed (as discrepancies may have reflected date recording errors).Statistical analysis was performed using RStudio 2022.02.3 including the epiR package [ | PMC10361479 | |
Patient and public involvement | RAPTOR was supported from inception by the CONDOR steering committee public co-chairs for Patient and Public Involvement and Engagement (PPIE) who co-developed the CONDOR platform and its PPIE strategy. Additional PPIE contributors provided pre-funding feedback on the value of the study, reviewed plain language text, and reviewed and co-developed patient information materials. Contributors favourably reviewed the potential burden on patients of involvement in the study. | PMC10361479 | ||
Results | PMC10361479 | |||
Recruitment | RECRUITMENT | A total of 763 participants consented to recruitment between 29th October 2020 and 12th October 2021 ( | PMC10361479 | |
Participant characteristics | 42% of participants recruited were male, mean age was 41 years, the majority (81%) were white, and 26% were contacts of a household member who had tested positive for SARS-CoV-2 ( | PMC10361479 | ||
Baseline characteristics (number (%) or mean (standard deviation)). | * Vaccinated with at least one dose (booster doses were not recorded)† Calculated among participants who reported at least one specific symptom within the preceding 14 days‡ For 6% of participants, no specific symptoms were recorded in the eCRF | PMC10361479 | ||
Diagnostic accuracy (primary outcome) | The prevalence of SARS-CoV-2 positive RT-PCR tests among participants included in the primary analysis was 39.2% (260/663, 95% CI 35.5% to 43.0%). The SD Biosensor POCT had a sensitivity of 84.0% (178/212, 95% CI 78.3% to 88.6%) and specificity of 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had a sensitivity of 76.5% (127/166, 69.3% to 82.7%) and specificity of 98.8% (249/252, 96.6% to 99.8%) ( | PMC10361479 | ||
Summary of results for each POCT compared to the reference test result. | SDB | DISEASE | SDB = SD Biosensor, BDV = BD Veritor.Of the 300 participants who had results for both POCTs and the reference test, 85 had concordant positive results from both POCTs and RT-PCR and 179 had concordant negative results. Patterns of discordance are shown in Pre-specified subgroup analyses found some variation in test performance according to certain participant characteristics reported (S1 Table 1 in Among sites that recruited at least 10 participants, sensitivity and specificity estimates were largely similar, although the prevalence of disease varied substantially between sites (S1 Fig 1 in There were two main circulating variants of SARS-CoV-2 during the study period in the UK, VOC Alpha GRY (B.1.1.7+Q.) then VOC Delta GK (B.1.617.2+AY.) (S1 Fig 2 in | PMC10361479 |
Summary of diagnostic performance in relation to RT-PCR cycle threshold. | There was no clear trend in diagnostic performance in relation to the number of days since first reported symptom among those who commenced participation less than a week after symptom onset, but there was some indication of a decrease in the sensitivity of both index tests among the small number of participants with positive RT-PCR results and a longer symptom duration (Estimated sensitivity (upper two panels) and specificity (lower two panels), with 95% confidence intervals, by number of days since first reported symptom (x-axis), for SD Biosensor (left two panels) and BD Veritor (right two panels). The number of individuals correctly diagnosed by the POCT out of the total are shown towards the bottom of each plot. Participants who did not report specific symptoms and those for whom the timing of symptom onset was unclear are excluded. | PMC10361479 | ||
Diagnostic accuracy (enhanced reference standard) | A summary of findings using the composite enhanced reference standard among individuals with discordant result between either index test and the RT-PCR reference standard is provided in S1 Table 3 in Results of the statistical adjustment method for imperfect reference standard bias are shown in S1 Fig 6 and S1 Table 4 in | PMC10361479 | ||
Secondary outcomes | hMPV, NL63 | CORONAVIRUS, ADVERSE EVENTS, RECRUITMENT, INFLUENZA | Of the 403 participants who had a negative RT-PCR for SARS-CoV-2, RSV was detected in 12 participants (7 subtype A, 5 subtype B), hMPV in 1 participant and seasonal coronavirus in 8 participants (4 species #NL63, 3 #OC43, 1 #229E). No participants tested positive for influenza (subtypes A or B). Among the 260 participants who had a positive RT-PCR for SARS-CoV-2, co-infection with RSV was detected in 2 participants (both subtype B), seasonal coronavirus in 2 (both #OC43) and hMPV in 1.There were no serious adverse events related to study procedures. Three participants were recorded as having been hospitalised within 28 days of a positive COVID-19 test at recruitment with COVID-19 the primary reason for admission, and all were discharged within two weeks. One participant was hospitalised within 28 days of recruitment for an unrelated injury. | PMC10361479 |
Sensitivity analysis | SENSITIVITY | Sensitivity analyses allowing for different date mismatching scenarios did not show a large impact on estimated diagnostic accuracy measures (S1 Table 5 in | PMC10361479 | |
Discussion | infection | RECRUITMENT, VIRUS, SARS-COV-2 INFECTION, DISEASE, RECRUITMENT, INFECTION | The results of this prospective diagnostic accuracy evaluation of two POCTs for the detection of SARS-CoV-2 in symptomatic patients in primary care fall within the wide range of previous studies in other settings [The minimum target for acceptable performance in the target product profile of the Medicines and Healthcare products Regulatory Agency, is sensitivity of 80% and specificity of 95% [Diagnostic performance was strongly associated with RT-PCR cycle threshold. Performance declined at higher cycle thresholds, which are associated with the presence of lower intact sample viral RNA, a proxy for viral load. Test sensitivity declined among individuals whose symptoms began more than one week before recruitment. Correlation has been proposed between higher viral load distributions, LFD positive results and infectiousness of individuals [Venekamp et al’s community-based study in the Netherlands of tests including SD Biosensor and BD Veritor recruited until June 2021, before the Delta variant became dominant [Other studies have shown substantial decreases in test sensitivity in asymptomatic individuals, including those recruited as close contacts of cases [This study prospectively recruited a large cohort of symptomatic participants attending primary healthcare and two COVID-19 testing centres, and therefore reflects real-world diagnostic accuracy. Understanding performance in primary healthcare is likely to be increasingly important as we cope with waves of endemic infection, and this is one of the few studies to report performance for any POCT in this setting and to our knowledge the only one based in UK primary care.Recruitment met recommended sample sizes. Further, this study benefitted from contemporaneous swabbing for all tests, and blinding of index test results from those who were performing the reference test (and vice versa), as recommended in diagnostic accuracy studies [This study also has some limitations. Because of low recruitment from some sites, a testing centre was added as a recruitment site and so the population tested overall may be less unwell than those who would contact the GP surgery. Prevalence of SARS-CoV-2 infection varied substantially by practice, suggesting there may have been differences in the way in which practices identified participants for recruitment. However, throughout the study recruited patients were required to be symptomatic and diagnostic performance did not change when restricted to participants recruited via the testing centre. This study does not assess diagnostic performance in asymptomatic patients, in whom viral load may be lower and there may be a consequent effect on diagnostic performance. It assesses performance when testing was carried out by clinical staff, rather than via self-swabbing, and performance might decline if not always done according to manufacturers’ instructions and performed by a trained operator. Consistent with other studies, we have used RT-PCR cycle threshold as a proxy for viral load and did not apply a calibration and conversion to provide absolute estimates. Fully quantitative assays require a calibrated standard curve, which was not incorporated as an element of this study, as the results were intended to be binary in recognition of how diagnostic decisions are made in the real world.This study represents 12 months of recruitment, during which time the prevalence of SARS-CoV-2 fluctuated, and results cannot necessarily be extrapolated to future variants should they emerge. For example, some studies have suggested that some assays may have impaired detection for Omicron variants [The number of missing test results was higher than anticipated, and RT-PCR results were unobtainable for 40 samples, most of which were from participants who received the SD Biosensor POCT during the early period of recruitment. The effect of this was explored in sensitivity analyses, which did not show substantial changes in the major results. The principal reason for missing RT-PCR data was because of postal delays during the pandemic period in the early set-up of the study. As such we consider these data to be missing completely at random and do not expect this to bias the results.In a population with symptoms of COVID-19 presenting to community settings, SD Biosensor and BD Veritor POCTs performed by healthcare professionals are highly specific and so could be used to rule in COVID-19. However the proportion of patients with positive RT-PCR test results who received false negative POCT results was 16.0% for SD Biosensor and 23.5% for BD Veritor, which could result in onward transmission and inappropriate management unless population prevalence of disease is very low. Performance was improved in patients with more symptoms and those with low RT-PCR Ct values. Tests should be interpreted with more caution outside of this clinical phenotype. Though this strategy was not tested, it may be sensible to repeat the POCT in 12 or 24 hours in patients with a clinical phenotype for COVID-19 who test negative since viral counts may rise over time. This strategy should be studied since identifying true negatives as well as positives is important as waves of this virus continue. | PMC10361479 |
References | PMC10361479 | |||
1. Introduction | acute infection, pneumonia, chronic kidney disease, cardiovascular diseases, inflammation, long-term sequelae, fibrosis, liver disease, COVID-19-associated pneumonia, MR, coronavirus disease 2019 | ACUTE INFECTION, VIRUS, CORONAVIRUS DISEASE 2019, PNEUMONIA, LUNG FIBROSIS, ISCHEMIC HEART DISEASE, CARDIOVASCULAR DISEASES, COVID-19 PNEUMONIA, DISEASE, INFLAMMATION, FIBROSIS, LIVER DISEASE, SECONDARY, CONGESTIVE HEART FAILURE, HYPERTENSION, PATHOGENESIS | In March 2020, the World Health Organization (WHO) announced a global pandemic of coronavirus disease 2019 (COVID-19) that presented mainly as an acute infection of the lower respiratory tract (pneumonia), with multiple long-term consequences, including lung fibrosis. The aim of this study was to evaluate the influence of potassium canrenoate on inflammatory markers in the treatment of COVID-19 pneumonia. A randomized clinical trial (RCT) of intravenous potassium canrenoate vs. placebo was performed between December 2020 and November 2021. This study is a secondary analysis of that RCT. In the final analysis, a total of 49 hospitalized patients were included (24 allocated to the potassium canrenoate group and 25 to the placebo group). Patients were assessed by serum testing and blood cell cytometry on day 1 and day 7 of the intervention. Age, sex, and body mass index were not significantly different between the placebo group and intervention group. Although there was a significantly higher rate of ischemic heart disease in the placebo group, rates of other preexisting comorbidities were not significantly different. There were no significant differences in the inflammatory parameters between the potassium canrenoate and placebo groups on day 1 and day 7. However, the intragroup comparisons using Wilcoxon’s test showed significant differences between day 1 and day 7. The CD3% for potassium canrenoate increased significantly between day 1 and day 7 (12.85 ± 9.46; 11.55 vs. 20.50 ± 14.40; 17.80; In March 2020, following the emergence of the SARS-CoV-2 virus initially identified in December 2019, the World Health Organization (WHO) declared a worldwide pandemic of coronavirus disease 2019 (COVID-19). This disease predominantly manifested as an acute infection affecting the lower respiratory tract, often presenting as pneumonia [It has been shown that severe COVID-19 is associated with a significant derangement in proinflammatory cytokines, namely, IL-1β, IL-2, IL-6, IL-8, or TNF-α, often referred to as the “cytokine storm” [A prolonged increase in the level of IL-6 contributes to long COVID symptoms, so reducing IL-6 levels is particularly important during early COVID to prevent long-term sequelae [The renin–angiotensin–aldosterone (RAA) system is a major player in the pathogenesis of COVID-19. The entry of SARS-CoV-2 virus into the cells is possible only as a result of the expression of the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease 2 (TMPRSS2) [Under physiological conditions, the activator of the mineralocorticoid receptor (MR) is aldosterone. Its higher concentration can lead to hypertension, aggravation of cardiovascular diseases and also increased inflammation and tissue fibrosis [There are studies suggesting a beneficial effect of mineralocorticoid receptor antagonists (MRAs) in the treatment of COVID-19 [Potassium canrenoate is a mineralocorticoid receptor (MR) antagonist and a diuretic frequently used in practice for patients with chronic kidney disease, congestive heart failure or liver disease [Therefore, the purpose of the current study was to assess the influence of potassium canrenoate, an intravenous formula of mineralocorticoid receptor antagonist, on the change in inflammatory markers in patients with severe COVID-19-associated pneumonia. | PMC10532011 |
2. Results | PMC10532011 | |||
2.1. Baseline Patient Characteristics | There were no significant differences observed in age, gender, or body mass index between the placebo group and the intervention group. | PMC10532011 | ||
2.2. Basic Laboratory Tests | No statistically significant differences were observed between the groups in the results of basic initial laboratory tests conducted on day 1 or in the levels of serum inflammatory markers, which include C-reactive protein, procalcitonin, and interleukin-6, as detailed in There were no significant differences between the groups regarding the basic laboratory tests obtained on day 7 and serum inflammatory markers, including C-reactive protein and procalcitonin ( | PMC10532011 | ||
2.3. Immunophenotype Analysis on Day 1 and Day 7 | There were no significant differences between the groups in day 1 cell cytometry, including CD3+ blood cell or CD4+ lymphocyte percentage, IL-1ß, IL-2, TNF-α-positive cell percentage in general, lymphocytes specifically, or IL-6 level (There were no significant differences between the groups in control day 7 cell cytometry, including CD3+ blood cell or CD4+ lymphocyte percentage or IL-1ß, IL-2, TNF-α-positive cell percentage in general and on lymphocytes specifically, as well as IL-6 level ( | PMC10532011 | ||
2.4. Intragroup Comparisons between Potassium Canrenoate and Placebo Groups on Day 1 versus Day 7 | Intragroup comparisons using Wilcoxon’s test were performed to specify if the assessment of the dynamics of change between potassium canrenoate and placebo group or intragroup showed significant differences between day 1 and day 7. The results are shown in The CD3% for potassium canrenoate increased significantly between day 1 and day 7 (12.85 ± 9.46; 11.55 vs. 20.50 ± 14.40; 17.80; The interleukin-1ß total count (%) increased significantly over time for both potassium canrenoate (0.68 ± 0.58; 0.45 vs. 1.27 ± 0.83; 1.20; TNF-α total count (%) decreased significantly for potassium canrenoate between day 1 and day 7 (0.54 ± 0.45; 0.40 vs. 0.25 ± 0.23; 0.10; Interleukin-6 (pg/mL) showed a significant decrease between day 1 and day 7 for potassium canrenoate (64.97 ± 72.52; 41.00 vs. 24.20 ± 69.38; 5.30; | PMC10532011 | ||
3. Discussion | SARS-CoV-2 infection, pulmonary interstitial edema, hyperkaliemia, inflammation, hyponatremia, infections, infection, acute lung injury, hyperkalemia, lung tissue damage, hypovolemia | VIRUS, SARS-COV-2 INFECTION, ISCHEMIC HEART DISEASE, SIDE EFFECT, ADVERSE EVENTS, COVID-19 PNEUMONIA, DISEASE, INFLAMMATION, INFECTIONS, HYPONATREMIA, INFECTION, COMPLICATIONS, INFLAMMATORY RESPONSE | The increasing number of infections with the SARS-CoV-2 virus has created the need not only to treat the disease itself but also to develop a way to prevent long-term complications of infection deriving from immunological imbalance. In our study, we evaluated the effects of potassium canrenoate on inflammatory markers in the treatment of COVID-19.There were no significant differences between the placebo and potassium canrenoate regarding CD3+ blood cell or CD4+ lymphocyte percentage, IL-1ß, IL-2, TNF-α positive cell percentage in general, or lymphocytes specifically on day 1 or on day 7. Similarly, the levels of Il-6 between the group did not differ in terms of statistical significance. However, the level of Il-6 between the placebo group and the intervention was higher in the intervention group on day 1 (46.68 ± 56.79 pg/mL vs. 64.97 ± 72.52 pg/mL, IL-6 is a cytokine characterized by its pro-inflammatory and pro-fibrotic properties. It plays a role in the development of pulmonary interstitial edema and triggers a severe inflammatory response by activating neutrophils and facilitating their accumulation at the injury site. This, in turn, leads to the release of both proteases and oxygen-free radicals, contributing to the overall inflammatory process [While our study did not demonstrate a statistically significant benefit of administering additional potassium canrenoate therapy to patients with moderate to severe COVID-19 pneumonia, it is important to consider several potential explanations for this outcome. Spironolactone is one of the inhibitors of the renin–angiotensin–aldosterone (RAA) system, particularly preferred in COVID-19 [There have been reports suggesting a potential beneficial effect of potassium canrenoate in mitigating endothelial inflammation in individuals with SARS-CoV-2 infection [The optimal timing and duration of potassium canrenoate intervention for COVID-19 pneumonia remain uncertain. In our study, patient inclusion was contingent upon having a blood oxygen saturation level below 94%, suggesting some degree of lung tissue damage. This criterion may have resulted in a delay in the timing of intervention. There is a legitimate concern that early immunomodulation could potentially suppress the host’s antiviral response and slow down viral clearance, whereas delayed immunomodulation may prove ineffective in the context of advanced acute lung injury [In our study, there was no significant increase in adverse events after administration of potassium canrenoate. Despite the reporting of some adverse events, such as hyperkaliemia, hyponatremia and hypovolemia, blood iron levels did not differ significantly between groups. Nevertheless, there was a trend towards hyperkalemia in the intervention group, which is the most common side effect of potassium canrenoate.This study is not without limitations. Firstly, although the study was randomized, it was single-center, which may have contributed to the occurrence of biases. Secondly, it should be noted that the study was relatively small and the number of patients who completed the study was small. Thirdly, apart from the cytokines evaluated by our group (CD3+ blood cell or CD4+ lymphocyte percentage and IL-1ß, IL-2, TNF-α-positive cell percentage in general and on lymphocytes), other factors should be evaluated in future trials, including TGF-β, MMP-1 or MMP-7. Moreover, there was a significantly higher rate of ischemic heart disease in the placebo group, which might have affected the study results. Although some positive trends were observed in the potassium canrenoate group, none of these observations reached statistical significance. Further studies in a larger group of patients are needed to confirm the possible protective effect of potassium canrenoate. | PMC10532011 |
4. Materials and Methods | PMC10532011 | |||
4.1. Ethics | SECONDARY, POLAND | This secondary analysis stems from a prospective phase IV randomized placebo-controlled clinical trial (RCT) conducted at University Hospital no. 2 of the Pomeranian Medical University in Szczecin, Poland, spanning from December 2020 to August 2021. The study garnered approval from the Ethics Committee Board at the Pomeranian Medical University in Szczecin, Poland (ICE consent 0012/100/2020, issued on 29 June 2020), and it was duly registered on | PMC10532011 | |
4.2. Study Population | The study enrolled hospitalized patients of all genders, ranging in age from 18 to 90 years, following comprehensive disclosure of study particulars and obtaining their signed informed consent forms. The research adhered to the principles outlined in the Declaration of Helsinki.In this study, a comprehensive assessment was conducted on a total of 430 patients to determine their eligibility. Following the application of exclusion criteria, 55 patients were selected for randomization, with 49 ultimately included in the final analysis. Among these, 24 were assigned to the intervention group and 25 were allocated to the control group, as illustrated in | PMC10532011 | ||
4.3. Inclusion Criteria | COVID-19 infection, diabetes | HYPERTENSION, CARDIOVASCULAR DISEASE, COVID-19 INFECTION, DIABETES | Individuals of all genders, aged between 18 and 90 years.Patients requiring oxygen therapy with a blood oxygen saturation level below 94%.Confirmed diagnosis of COVID-19 infection through rt-PCR testing.Presence of at least one documented risk factor for heightened COVID-19 mortality, as outlined in current scientific literature, such as smoking, hypertension, diabetes, or cardiovascular disease.Well-documented informed consent in accordance with ICH-GCP guidelines and national regulations. | PMC10532011 |
4.4. Exclusion Criteria | mental illness, hyponatremia, dementia, emphysema, ARDS, hyperkalemia, Porphyria, trauma | CHRONIC RENAL FAILURE, PORPHYRIA, ADRENAL CRISIS, HYPONATREMIA, CHRONIC BRONCHITIS, HYPERSENSITIVITY, EMPHYSEMA, OTHER VIRAL INFECTION, ANURIA, INTERSTITIAL LUNG DISEASE, ARDS | Patients with a history of chronic bronchitis, emphysema, interstitial lung disease, or any other preexisting lung conditions.Individuals with contraindications for the use of spironolactone.Hypersensitivity to spironolactone or any of its components.Pregnant individuals (with mandatory pregnancy testing for those of reproductive age) or breastfeeding mothers.Patients with mental illness or dementia who are unable to provide informed consent for participation in the study.ARDS resulting from another viral infection (testing negative for SARS-CoV-2).ARDS caused by other factors or trauma.Presence of ionic imbalances, such as hyperkalemia or hyponatremia.Adrenal crisis.Acute or chronic renal failure, with a creatinine clearance rate below 30 mL/min.Anuria.Porphyria.Chronic use of mineralocorticoid receptor antagonist (MRA) medications from the spironolactone group. | PMC10532011 |
4.5. Clinical Experiment Measures | TNF-α | LYSING, EVENTS, APC, FRANKLIN | Consecutive patients in the study were randomly assigned to one of two groups using a computer-generated list of numbers. The first group, referred to as the intervention group, received 200 mg of potassium canrenoate (Aldactone) dissolved in 100 mL of 0.9% sodium chloride intravenously twice daily for a duration of 7 days. The second group, known as the placebo group, received 100 mL of 0.9% sodium chloride intravenously twice daily for the same 7-day period.For the above-mentioned groups of patients, a detailed immunophenotype analysis of blood cell cytometry on day 1 and day 7 of the intervention was performed, including parameters such as T CD4+ lymphocytes, T CD3+ lymphocytes, IL-1ß on lymphocytes, total count of IL-1ß and IL-2 on lymphocytes, and total count of IL-2 and TNF-α on lymphocytes vs. total count of TNF-α. Immunophenotyping results were compared with those from the control group. For flow cytometrical analysis, peripheral blood samples for frequency analysis were collected in ethylenediaminetetraacetic acid-containing tubes. The cells were examined based on unstained control, FMO control, and stained cells with monoclonal antibodies conjugated with fluorescent dyes using 3-color labeling with the following surface antibodies: mouse fluorescein isothiocyanate (FITC)-conjugated anti-human CD4 (clone SK3)/mouse peridinin chlorophyll protein (PerCP)-conjugated anti-CD3 (clone SK7) to determine the proportion of the CD4 + CD3+ T lymphocytes (Becton Dickinson, East Rutherford, NJ, USA), anti-human IL-1β (PE) (BD FastImmune, San Jose, CA, USA), anti-human TNF-α (PE) (FastImmune, San Jose, CA, USA) and anti-human IL-2 (APC) (FastImmune, San Jose, CA, USA). Cells were incubated with an Fc receptor (FcR) blocking reagent (Miltenyi Biotec, Auburn, CA, USA) for 10 min at room temperature to block specific FcR-mediated binding of antibodies. Next, the cells were incubated for 20 min at room temperature with 20 μL of each mAb per sample for 30 min at 4 °C in the dark. After staining of samples with antibodies, cells were treated with lysing solution (Becton Dickinson) and incubated for 15 min at 4 °C in the dark. The cells were then washed twice with phosphate-buffered saline. Cell subsets were detected using cell labeling and gating methods, which start by removing doublets (FSC-A vs. FSC-H), followed by a dot plot, in which lymphocyte populations were defined (FSC vs. SSC). The data were collected on an eight-colour FACSCantoII flow cytometer (BD Biosciences, Franklin Lakes, NJ, USA). Diva software (BD Biosciences, Franklin Lakes, NJ, USA) was used for data analysis, and the percentage of positive cells was recorded. At least 10,000 total events in the physical parameters were acquired for each sample. The percentage of IL-1, IL-2 and TNF-positive cells was calculated from the total number of lymphocytes. Levels of IL-6 have been routinely assessed by hospital laboratory using ELISA as part of the local treatment protocol. | PMC10532011 |
4.6. Outcome Measures | PMC10532011 | |||
4.6.1. Primary Outcome Measures for Primary Analysis | Duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy (observation time 30 days).Duration of passive oxygen therapy (observation time 30 days). | PMC10532011 | ||
4.6.2. Secondary Outcome Measures for Primary Analysis | Intensive care unit length of stay (LOS) (time frame 30 days).Total hospital length of stay (LOS) (time frame 90 days).Assessment of the dynamics of recovery of changes in lung ultrasound at 7 days.Assessment of the dynamics of recovery of changes in lung ultrasound at 30 days.Assessment of the dynamics of recovery of changes in chest computed tomography (CT) at 3 months (90 days).Assessment of mortality at 30 days.Assessment of mortality at 90 days.Six-minute walking test (6MWT) at 30 days.Six-minute walking test (6MWT) at 90 days. | PMC10532011 | ||
4.6.3. Outcome Measures for Secondary Analysis | TNF-α | Assessment of the dynamics of change in T CD4+ lymphocyte count at 7 days.Assessment of the dynamics of change in T CD3+ lymphocytes count at 7 days.Assessment of the dynamics of change in IL-1ß on lymphocytes and total count of IL-1ß at 7 days.Assessment of the dynamics of change in IL-2 on lymphocytes and total count of IL-2 at 7 days.Assessment of the dynamics of change in TNF-α on lymphocytes and total count of TNF-α at 7 days.Assessment of the dynamics of change in IL-6 serum level at 7 days. | PMC10532011 | |
4.7. Statistical Analysis | SECONDARY | For the secondary analysis, we used data from the primary analysis. Categorical variables are presented as proportions and were compared using the chi-square test. In the case of small numbers in groups, the Yates correction was applied. Continuous variables are presented as means with standard deviation and medians and first and third quartiles. When assessing statistical significance, Student’s For the primary analysis, the sample size was calculated to demonstrate statistical significance of differences in the assessment of the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy (hours) at 48 h after admission, assuming the standard significance level of the test | PMC10532011 | |
Author Contributions | Conceptualization, I.K., J.S., W.D. and K.K.; methodology, I.K., K.K., K.L. and P.N.-R.; software, I.K.; validation, A.S. and P.N.-R.; formal analysis, I.K., K.K. and P.N.-R.; investigation, R.H. and P.N.-R.; resources, I.K.; data curation, I.K., R.H., K.L. and P.N.-R.; writing—original draft preparation, I.K., K.K., K.L. and A.S.; writing—review and editing, I.K., R.H., K.K., K.L., P.N.-R., A.S., J.S. and W.D.; visualization, I.K. and A.S.; supervision, K.K., W.D. and J.S.; project administration, K.K.; funding acquisition, K.K. and J.S. All authors have read and agreed to the published version of the manuscript. | PMC10532011 | ||
Institutional Review Board Statement | POLAND | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Pomeranian Medical University in Szczecin, Poland (ICE consent, 0012/100/2020, date 29 June 2020) and was registered at | PMC10532011 | |
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10532011 | ||
Data Availability Statement | The dataset is not available in a public database due to legal reasons. Anonymous data may be provided by the corresponding author upon a reasonable request from a researcher. | PMC10532011 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC10532011 | ||
References | TUMOR NECROSIS | CD3% for potassium canrenoate vs. placebo between day 1 and day 7; Interleukin-1ß total count [%] for potassium canrenoate vs. placebo between day 1 and day 7; TNF-α total count [%] for potassium canrenoate vs. placebo between day 1 and day 7; Interleukin-6 [pg/mL] for potassium canrenoate vs. placebo between day 1 and day 7; Study flowchart.Baseline characteristics.Legend: BMI—body mass index, CFS—Clinical Frailty Scale, Me—median, SD—standard deviation, Laboratory results on day 1.Legend: Me—median, SD—standard deviation, Laboratory results on day 7.Legend: Me—median, SD—standard deviation, Immunophenotype analysis on day 1.Legend: CD—cluster of differentiation, IL—interleukin, TNF—tumor necrosis factor, Me—median, SD—standard deviation, Immunophenotype on day 7.Legend: CD—cluster of differentiation, IL—interleukin, TNF—tumor necrosis factor, Me—median, SD—standard deviation, Intragroup comparisons on day 1 versus day 7.Legend: CD—cluster of differentiation, IL—interleukin, TNF—tumor necrosis factor, Me—median, SD—standard deviation, | PMC10532011 | |
Keywords | PMC10570224 | |||
Introduction | anxiety, pain | Many children feel anxious when they need to undergo a medical examination or intervention. In particular, needle related procedures cause anxiety and fear in children [In adults, the use of communication techniques based on hypnosis can be used to reduce pain and anxiety [Children experience medical procedures within the context of their family [This study assesses the effects of therapeutic communication (TC) versus standard communication (SC). TC is based on Comfort Talk | PMC10570224 | |
Methods and materials | PMC10570224 | |||
Study design | CMO | After ethical approval (Ethics Committee CMO Arnhem-Nijmegen, Number 2019-5488), this single-blinded intervention study was performed in an outpatient clinic in a tertiary care hospital in Nijmegen, the Netherlands. The study was registered in the Dutch Trial Register (NL8221). Data was collected between January 2020 and October 2020. | PMC10570224 | |
Participants | intellectual disabilities | Children who needed to undergo venipuncture at the outpatient clinic were asked to participate in this study. Inclusion criteria were age between 5 and 18 years, use of topical anesthesia on the presumed needle insertion site (EMLA, Aspen, The Netherlands), and the ability to communicate in Dutch language by child and parent or guardian. Written informed consent was obtained prior to the study. For children in the age of 5 to 12 years or children with intellectual disabilities, informed consent was provided by parent or guardian. For children aged 12 to 16 years, it was provided by the child and parent or guardian, and for children up to and including 16 years, it was provided by the child. | PMC10570224 | |
Procedure | The study consisted of two groups that were subsequently studied: a SC group and a TC group. The SC group was studied in January and February 2020, and the TC group in September and October 2020. For the SC group, blood sampling procedures were performed according to standardized protocol and baseline data were obtained. After having included 51 patients, all personnel was trained in patient-centered TC. The training consisted of an eight-hours classroom session in which theoretical lectures about the scientific background were interchanged with practical demonstrations, exercises, and role-playing. Medical personnel was trained in how to establish quick empathic contact by matching nonverbal and verbal behavior, avoidance of negative verbal suggestions, the use of hypnotic language and expression of positive expectations (Supplementary Table Flowchart of the study | PMC10570224 | ||
Measures | PMC10570224 | |||
Demographic data | Anxiety, ADHD, anxiety, neurodivergent disorders | DISEASE | Demographic data was obtained prior to venipuncture (e.g. age, gender, underlying disease, amount of previous venipunctures and the presence of neurodivergent disorders (e.g. ADHD, ASD). To measure anxiety the child’s trait level of anxiety and the parents’ trait and state level of anxiety were obtained by the Spielberger State-Trait Anxiety questionnaire for children (STAI-C) and the Dutch version of the State-Trait Anxiety Inventory (STAI-Y), named ZBV for the parents [ | PMC10570224 |
Primary outcome measure | PMC10570224 | |||
Self-reported pain | pain | Self-reported pain was measured directly after venipuncture with the Faces Pain Scale-Revised (FPS-R) [ | PMC10570224 | |
Secondary outcome measures | PMC10570224 | |||
Observed pain | NRS, pain | Directly after the venipuncture parents or guardians and medical professionals scored the observed pain of the child on a NRS (Numeric Rating Scale; 0 = no pain, 10 = worst pain ever). | PMC10570224 | |
Anxiety during venipuncture | anxiety | Children 8 years or older reported their anxiety levels during venipuncture on a NRS (0 = no anxiety, 10 = worst anxiety ever). Parents or guardians and medical professionals scored the observed anxiety of the child and anxiety of the parent on the same NRS. | PMC10570224 | |
Satisfaction | Children 8 years or older, their parents or guardians and medical personnel reported their satisfaction about the procedure on a NRS (0 = unsatisfied, 10 = very satisfied). | PMC10570224 | ||
Procedural time | The time the child spent in the room during venipuncture was measured in minutes. | PMC10570224 | ||
Statistical analysis | pain | For data analysis, IBM SPSS Statistics 26 was used. A power analysis was performed to determine the sample size that was needed to provide a 95% probability of detecting differences between groups. One face (i.e., 2 points, translating to an effect size of Baseline group differences for demographic characteristics were determined with independent sample To answer the primary research aim, namely to assess whether self-reported pain was lower after TC than SC, an independent sample | PMC10570224 | |
Results | PMC10570224 | |||
Primary outcome measure | PMC10570224 | |||
Self-reported pain by children | pain | There was no difference in self-reported pain by children between the TC group (Child pain outcomes. | PMC10570224 | |
Secondary outcome measures | PMC10570224 | |||
Observed pain | pain | NRS pain scores observed by parents and by medical personnel did not significantly differ between the TC and SC group (Table | PMC10570224 | |
Anxiety during venipuncture | Anxiety, anxiety | For anxiety scores scored by the child, we found that children in the therapeutic communication group reported lower anxiety Anxiety outcomes. | PMC10570224 | |
Satisfaction | There were no group differences in satisfaction for parents and children (Table Satisfaction outcomes. | PMC10570224 | ||
Procedural time | Procedural time in the TC group was shorter (6min0s) than in the SC group (8min36s), Procedural time. | PMC10570224 | ||
Mediation analyses | anxiety, pain | REGRESSION | Two mediation analyses were conducted to test the direct effect (parental procedural anxiety on child pain) and indirect effects (parental procedural anxiety on child pain via child anxiety) for the TC group and the SC group. The regression models were significant for the SC group (Standardized regression coefficients between parent procedural anxiety, child procedural anxiety and child reported pain for the standard communication group ( | PMC10570224 |
Subgroup analysis neurodivergence | psychiatric, anxiety | DISORDER | Based on the significant outcome of child anxiety, the subgroup analysis was performed with anxiety as outcome. There were no differential effects of TC on anxiety for neurodivergent children versus non-neurodivergent children (i.e., no diagnosis of a psychiatric disorder), | PMC10570224 |
Discussion | ADHD, anxiety, pain | SECONDARY | The objective of this study was to examine whether patient-centric TC positively affects children’s comfort during venipuncture. Comfort is defined as a ''transient and dynamic state characterized by ease from pain, emotional and physical distress and an emerging sense of positivity, safety, strength and acceptance of one’s situation that is underpinned and sustained by feeling valued, cared for, confident and accepting treatment. Patients seek to be as comfortable as they can be, under the circumstances of their healthcare interaction'' [No difference in self-reported pain was found between the SC and the TC group. For the secondary outcomes, however, scores significantly improved for anxiety, time in the room and satisfaction of the medical personnel. For the third research question, namely whether parental anxiety influences the child’s pain via the child’s anxiety, no mediation effect was found. For the fourth research question, we found that TC had the same effect on anxiety as in non-neurodivergent children.The absence of significant self-reported pain results may be attributed to the overall low pain scores (95% CI [1.1, 2.4]), and these low pain scores did not indicate clinically relevant pain according to the optimal cut points for the FPS-R [All anxiety scores for the child (scored by child 8 years or older), parent and medical personnel) were lower in the TC group than in the SC group. The parents also scored lower self-reported NRS anxiety scores when TC was used. NRS anxiety for the parent scored by the medical personnel did not differ significantly between groups. Moreover, this study investigated the influence of parental anxiety on the relationship between the child’s anxiety and pain experience. No mediation effects were found (parental procedural anxiety on child pain via child anxiety) in both groups. This is in contrast with the study results of Bearden et al. (2012) where a mediation effect was found of preprocedural anxiety and procedural pain of the child, which in turn heightened the child’s pain [ Finally, because a large proportion of patient undergoing venipuncture is neurodivergent (28.6% in our sample), and because of the limited research conducted on this topic, we performed a subgroup analysis to find out if TC was also effective in the neurodivergent children (e.g., with ASD or ADHD) in our study. The results showed similar effects in anxiety reduction for neurodivergent children as non-neurodivergent children. However, this result must be interpreted with caution, as this analysis was exploratory and the sample of the subgroup analysis was relatively small (n = 30).One of the strengths of this study was that when examining comfort during venipuncture, this study captured the multi-faceted context of this procedure. Different outcomes were measured (e.g., pain, anxiety, and satisfaction) from different perspectives (children, parents and medical personnel) thereby adopting an overall integrative approach. Moreover, this study aimed to contribute to the scarce literature of venipuncture comfort for neurodivergent children. However, adopting this integrative approach induces bias. Given the large amount of outcome measures, the likelihood of incorrectly rejecting a null hypothesis (i.e., making a Type I error) increases [To conclude, our study found that with just a small change in communication style, the comfort of the child during venipuncture improves. This was mainly reflected by reduced anxiety scores and shorter procedural times, making the use of TC during venipuncture promising for the outpatient setting.
| PMC10570224 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (PDF 127 KB) | PMC10570224 | ||
Authors’ contributions | LAMA and GJvG contributed to the conception and design of the study. Data collection was performed by LAMA and EV. Data analysis was carried out by RMS. The first draft of the manuscript was written by LAMA and RMS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. | PMC10570224 | ||
Funding | Author R.M.S. has received research support from the National Health Care Institute (2017045964). | PMC10570224 | ||
Declarations | PMC10570224 | |||
Ethics approval | MAY | This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the medical ethical committee CMO region Arnhem-Nijmegen (May 24, 2019/N0 2019-5488). | PMC10570224 | |
Consent to participate | Informed consent was obtained from all individual participants included in the study | PMC10570224 | ||
Consent to publish | The authors affirm that human research participants provided informed consent for publication | PMC10570224 | ||
Competing interests | The authors have no relevant financial or non-financial interests to disclose. | PMC10570224 | ||
Storage of data | Subject, code and patient identification were saved in an identification log. A key file with password for the identifying personal data, linked to the study code, was saved on a separate file and was only accessible for the researchers. On the Case Report Form and in the database (Castor EDC) only coded data was used, no personal identification data. Data was saved for 15 years. | PMC10570224 | ||
References | PMC10570224 | |||
Acknowledgments | Dear Editor:We read with interest the study by Xiaoqin Li et al. that evaluated the effectiveness of probiotic supplementation on immune parameters and gut microbiota in healthy adults (a randomized controlled trial).First, as the authors described in the Study design, “Eligible participants were equally and randomly assigned into two groups using computer generated random numbers after stratification by gender and BMI (<24 or ≥24 kg/mSecond, the results of this trial suggest that synbiotic supplementation resulted in statistically significant reductions in C-reactive protein (CRP) and interferon-gamma (IFN-γ) levels at both week 4 and week 8. While describing the results as “these reductions were greater than those observed in the placebo group (A total of 106 patients were included in this article, which is a small sample study. This paper would have been improved if statistical efficiency or/and power could have been calculated. Furthermore, the interaction is an action in which two or more objects affect each other and play an essential role in this paper.Consumption per capita and average beer price.In conclusion, we thank the authors for this excellent work, which provides direct evidence for personalized supplementation of immune regulation in healthy individuals. However, we believe that the conclusions of the study would have been stronger if the previously mentioned issues had been further addressed.Our deepest gratitude goes to the authors for this excellent work, which provides important evidence. | PMC10540646 | ||
Disclosure statement | No potential conflict of interest was reported by the author(s). | PMC10540646 | ||
Authors’ contributions | Conceptualization, Y.L.; Writing-Original draft preparation, Y.L.; Project administration, Y.L.; Writing – Review & Editing, Y.L. | PMC10540646 | ||
Ethics approval and consent to participate | This study is a bioinformatics study, which does not use the information of human or animal tissues or cases, so there is no need for ethical approval. All authors have read and agreed to the published version of the manuscript. | PMC10540646 | ||
References | PMC10540646 | |||
Purpose | death | We aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specific mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates. | PMC10195723 | |
Methods | β-carotenes | Using baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—vitamins C and E, β-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity—we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were fitted to evaluate the association between the OBS and mortality. | PMC10195723 | |
Results | cancer, deaths, CVD | CVD, CANCER, CARDIOVASCULAR DISEASE | A total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3–14.9), 421 deaths were identified, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confidence interval (CIs) between the highest quartile (predominance of antioxidants) | PMC10195723 |
Conclusion | cancer | CVD, CANCER | Our findings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality risk. | PMC10195723 |
Study registry number | Dynamic Mediterranean Prospective Cohort: the SUN Project; NCT02669602. | PMC10195723 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00394-023-03099-8. | PMC10195723 | ||
Keywords | Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. | PMC10195723 | ||
Introduction | deaths, death, cancer | CANCER, DISEASES, OXIDATIVE STRESS | Non-communicable diseases (NCDs) are currently the leading causes of death in the world. Approximately 41 million people (71% of all deaths globally) die each year due to NCDs [Oxidative stress—the imbalance between oxidative and anti-oxidative components that leads to oxidative damage [The main objective of this study was to prospectively investigate the association between an OBS—based on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—with all-cause, cardiovascular, and cancer mortality risk among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of middle-aged Spanish adults. | PMC10195723 |
Methods | PMC10195723 | |||
Study population | RECRUITMENT | The SUN Project (From December 1999 until December 2019, a total of 22,894 participants were recruited. The exclusion criteria applied were: participants recruited < 2 years and 9 months since the end of the recruitment in the database (Flowchart of participants in the Seguimiento Universidad de Navarra Project, 1999 to 2019 | PMC10195723 | |
The oxidative balance score (OBS) | The OBS was constructed using baseline dietary information from a semi-quantitative 136-item food-frequency questionnaire (FFQ) repeatedly validated in Spain [This novel OBS was based on 12 a priori selected components including dietary and non-dietary lifestyle factors associated with oxidative balance, as either pro- or antioxidant exposures (Additional File 1: Table s1). The selection of these components was based on the latest existing evidence and information available from the FFQ and lifestyle questionnaire. Dietary intakes included total vitamin C, total vitamin E, beta-carotenes, selenium, total zinc, heme iron, polyphenol antioxidant content (PAC) score, and total antioxidant capacity (TAC), whereas lifestyle included BMI, alcohol intake, smoking status, and an 8-item physical activity score. Total intakes of vitamin C, vitamin E, and zinc included both diet and supplement intakes. The novelty of this OBS lies in the inclusion of supplementary intakes, and TAC and PAC components, which have not been previously included in other published OBS. PAC score was calculated based on a previous published score that assessed the polyphenol intake with a 7-item score by generating deciles of intakes for the included polyphenols class and subclass (flavonols, anthocyanins, flavanones, flavones, flavanols, isoflavonoids, and lignans intake) [ | PMC10195723 |
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