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CONFLICT OF INTEREST | The authors declare no conflict of interest. | PMC10098273 | ||
ACKNOWLEDGMENTS | We thank the staff from the pediatric department at Damascus University for facilitating the procedure during this study. This research has received no external funding. | PMC10098273 | ||
DATA AVAILABILITY STATEMENT | Data are available on request due to privacy from the corresponding author. | PMC10098273 | ||
REFERENCES | PMC10098273 | |||
Key Points | PMC10466168 | |||
Question | gestational diabetes | GESTATIONAL DIABETES | Does receiving group prenatal care vs individual prenatal care reduce the risk of gestational diabetes (GD)? | PMC10466168 |
Findings | In this large randomized clinical trial including 2348 participants, pregnant individuals receiving group prenatal care had a similar risk of developing GD as those receiving traditional individual prenatal care. | PMC10466168 | ||
Meaning | These findings suggest that individuals receiving both group prenatal care and traditional individual prenatal care had similar risk of developing GD, indicating that group prenatal care may be a possible treatment option for some individuals. | PMC10466168 | ||
Importance | gestational diabetes | GESTATIONAL DIABETES | The impact of group-based prenatal care (GPNC) model in the US on the risk of gestational diabetes (GD) and related adverse obstetric outcomes is unknown. | PMC10466168 |
Objective | To determine the effects of the GPNC model on risk of GD, its progression, and related adverse obstetric outcomes. | PMC10466168 | ||
Design, Setting, and Participants | This is a single-site, parallel-group, randomized clinical trial conducted between February 2016 and March 2020 at a large health care system in Greenville, South Carolina. Participants were individuals aged 14 to 45 years with pregnancies earlier than 21 weeks’ gestational age; follow-up continued to 8 weeks post partum. This study used an intention-to-treat analysis, and data were analyzed from March 2021 to July 2022. | PMC10466168 | ||
Interventions | Eligible participants were randomized to receive either CenteringPregnancy, a widely used GPNC model, with 10 group-based sessions or traditional individual prenatal care (IPNC). | PMC10466168 | ||
Main Outcomes and Measures | GD-related adverse | SECONDARY, PREECLAMPSIA | The primary outcome was the incidence of GD diagnosed between 24 and 30 weeks of gestation. The secondary outcomes included progression to A2 GD (ie, GD treated with medications) and GD-related adverse obstetric outcomes (ie, preeclampsia, cesarean delivery, and large for gestational age). Log binomial models were performed to estimate risk differences (RDs), 95% CIs, and | PMC10466168 |
Results | preeclampsia | PREECLAMPSIA | Of all 2348 participants (mean [SD] age, 25.1 [5.4] years; 952 Black participants [40.5%]; 502 Hispanic participants [21.4%]; 863 White participants [36.8%]), 1176 participants were randomized to the GPNC group and 1174 were randomized to the IPNC group. Among all participants, 2144 (91.3%) completed a GD screening (1072 participants [91.3%] in GPNC vs 1071 [91.2%] in IPNC). Overall, 157 participants (6.7%) developed GD, and there was no difference in GD incidence between the GPNC (83 participants [7.1%]) and IPNC (74 participants [6.3%]) groups, with an adjusted RD of 0.7% (95% CI, −1.2% to 2.7%). Among participants with GD, GPNC did not reduce the risk of progression to A2 GD (adjusted RD, −6.1%; 95% CI, −21.3% to 9.1%), preeclampsia (adjusted RD, −7.9%; 95% CI, −17.8% to 1.9%), cesarean delivery (adjusted RD, −8.2%; 95% CI, −12.2% to 13.9%), and large for gestational age (adjusted RD, −1.2%; 95% CI, −6.1% to 3.8%) compared with IPNC. | PMC10466168 |
Conclusions and Relevance | SECONDARY | In this secondary analysis of a randomized clinical trial among medically low-risk pregnant individuals, the risk of GD was similar between participants who received GPNC intervention and traditional IPNC, indicating that GPNC may be a feasible treatment option for some patients. | PMC10466168 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10466168 | ||
Introduction | Gestational diabetes | GESTATIONAL DIABETES, PREGNANCY COMPLICATIONS | Gestational diabetes (GD) is 1 of the most common pregnancy complications, affecting 4% to 8% of all pregnancies depending on diagnostic criteria and study populations.Lifestyle interventions (ie, diet and physical activity) have achieved a modest effect on improving rates of GD. | PMC10466168 |
Methods | PMC10466168 | |||
Study Design and Participants | SECONDARY | This study is a secondary analysis of the CRADLE study, | PMC10466168 | |
Centering and Racial Disparities Trial Diagram | Enrollment for the CRADLE study began on February 24, 2016, and ended on March 16, 2020, when our capacity for safe in-person GPNC sessions was limited by the COVID-19 pandemic. | PMC10466168 | ||
Randomization and Blinding | Eligible participants were randomly assigned in a 1:1 allocation, stratified by race and ethnicity, to receive either GPNC (intervention) or IPNC (control) as their prenatal care. Due to the nature of the intervention, participants and practitioners were not blinded to group assignments. However, the study analysts were blinded to group assignments to reduce bias. | PMC10466168 | ||
Interventions | COMPLICATED PREGNANCIES | Participants in the IPNC group (control) received traditional prenatal care (an average 15 minutes for each visit) following the schedule of prenatal care visits recommended by the American College of Obstetricians and Gynecologists, which typically recommends a total of 13 visits for uncomplicated pregnancies. | PMC10466168 | |
Data Collection and Measures | Over the course of the study, 2 surveys were administered: survey 1 at baseline (<24 gestational weeks) and survey 2 between 30 and 36 gestational weeks. Both surveys were designed and administered using REDCap (Research Electronic Data Capture) software version 11.4.4 and delivered via tablet computers (iPad; Apple) during clinic visits. | PMC10466168 | ||
Primary and Secondary Outcomes | proteinuria, preeclampsia | PREECLAMPSIA | Incidence of GD was the primary outcome for this study and was diagnosed according to the American College of Obstetricians and Gynecologists recommendation using 2-step screening, which was the standard practice at the clinical site.Secondary outcomes included progression from the White classificationWe evaluated adverse obstetric outcomes associated with poor glycemic control individually. These outcomes included primary cesarean delivery, preeclampsia (ie, onset at >20 gestational weeks, 24-hour proteinuria ≥30 mg/day, a protein concentration ≥30 mg in at least 2 random urine samples, or a systolic/diastolic blood pressure ≥140 mm Hg/≥90 mm Hg), | PMC10466168 |
Statistical Analysis | SPONTANEOUS ABORTION, SECONDARY | The primary analyses compared the primary and secondary outcomes between GPNC and IPNC groups using the ITT approach. The ITT sample included all study participants according to their randomized assignment, regardless of missed visits, crossover between IPNC and GPNC, or transfer out of the practice. In the sensitivity analyses, a mITT approach was used, excluding participants with (1) spontaneous abortion, (2) intrauterine fetal demise, (3) incomplete information on the number of prenatal care visits, and (4) no postrandomization prenatal care visits in their assigned study group. According to our previously published observational study,For the description of baseline characteristics and prognostic factors, continuous variables were described by mean (SD), and categorical variables were described by count (percentage). The missingness of the baseline characteristics and prognostic factors were mainly due to participants’ preference of not answering. The missingness of marital status (516 participants [22.0%]), annual household income (714 participants [30.4%]), and health insurance (270 participants [11.5%]) were greater than 10% and were kept as a separate category during the statistical analysis. Missing data of other variables were lower than 7%, ranging from 2 participants [0.1%] for prepregnancy BMI to 63 participants [6.9%] for GWG. Log binomial models were performed to estimate risk differences (RDs), 95% CIs, and | PMC10466168 | |
Results | Among 2350 enrolled participants (1176 participants randomized to the GPNC group and 1174 randomized to the IPNC group), 2 twin pregnancies (1 in GPNC and 1 in IPNC) were identified after randomization and excluded, given the study eligibility criteria, resulting in a total of 2348 participants (mean [SD] age 25.1 [5.4] years] with 1175 participants in the GPNC group and 1173 in the IPNC group in the ITT sample ( | PMC10466168 | ||
Baseline and Prognostic Characteristics | The study population was racially diverse, with 952 Black participants (40.5%), 502 Hispanic participants (21.4%), 863 White participants (36.8%), and 31 participants (1.3%) who identified as other race or multiracial. Baseline characteristics and prognostic factors were similar between the 2 groups ( | PMC10466168 | ||
Baseline Characteristics and Associated Factors for Gestational Diabetes in the Centering and Racial Disparities Study | SI conversion factor: To convert pounds to kilograms, multiply by 0.45.The analyses were conducted among the intention-to-treat sample.Other indicated Asian, Native Hawaiian, Other Pacific Islander, or unknown race.Prepregnancy body mass index was measured at first prenatal care visit and was calculated as weight in kilograms divided by height in meters squared. | PMC10466168 | ||
Primary Outcome: GD Incidence | Overall, 157 (6.7%) participants developed GD, and there was no difference between incidence of GD in the GPNC group (83 participants [7.1%]) and IPNC group (74 participants [6.3%]) groups (adjusted RD, 0.7%; 95% CI, −1.2% to 2.7%) ( | PMC10466168 | ||
Comparing the Risk of Gestational Diabetes by Intervention Type in the Centering and Racial Disparities Study | REGRESSION | The analyses were conducted among the intention-to-treat sample.The regression model was adjusted for all baseline characteristics including smoking before pregnancy, race and ethnicity, maternal age, body mass index (calculated as weight in kilograms divided by height in meters squared) at enrollment, education, employment, student status for the past year, annual household income, had dental visit within the last 2 years, had insurance for the past year, parity, marital status, and unintended pregnancy. | PMC10466168 | |
Secondary Outcomes | Overall, 49.0% of participants (76 of 157 participants) with GD progressed to A2 GD. The incidence of A2 GD was 48.2% (39 of 83 participants) in the GPNC group and 50.0% (37 of 74 participants) in the IPNC group. The adjusted RD was −6.1% (95% CI, −21.3% to 9.1%) after controlling for all baseline characteristics ( | PMC10466168 | ||
Comparing the Risks of Progression to A2 GD and GD–Related Obstetric Outcomes by Intervention Type in the Centering and Racial Disparities Study | REGRESSION, GESTATIONAL DIABETES | Abbreviations: GD, gestational diabetes.The analyses were conducted among the intention-to-treat sample.The regression model was adjusted for all baseline characteristics including smoking before pregnancy, race and ethnicity, maternal age, body mass index (calculated as weight in kilograms divided by height in meters squared) at enrollment, education, employment, student status for the past year, annual household income, had a dental visit within the last 2 years, had insurance for the past year, parity, marital status, and unintended pregnancy.A2 GD refers to GD managed with medication. | PMC10466168 | |
Sensitivity Analyses | For sensitivity analyses, 825 participants in the GPNC group and 1099 in the IPNC group were left in the mITT sample (eFigure in We tracked 171 participants (85 in GPNC and 86 in IPNC) who were enrolled before March 17, 2020, whose study participation could have been influenced by the pandemic. Excluding these 171 participants yielded similar results (eTable 4 and eTable 5 in | PMC10466168 | ||
Discussion | GD-related adverse | SECONDARY | In this secondary analysis of a large RCT, among 2348 pregnant participants from a single health care system, we found the risks of GD, progression to A2 GD, and GD-related adverse obstetric outcomes were similar between GPNC and IPNC groups. We did not find that the effect of GPNC on the risk of developing GD was different across participants of different races and ethnicities.Our RCT design is an important contribution to the understanding of the impact of GPNC on the risk of developing GD. Our team previously reported that participants receiving the GPNC had 42% lower odds of developing GD (odds ratio, 0.58; 95% CI, 0.38-0.89), compared with participants receiving IPNC in a large retrospective cohort of racially diverse pregnant participants.The diverse study population allowed us to explore potential variations in the benefits of GPNC among participants of different races and ethnicities. In our previous observational study,A few observational studiesA unique strength of this study is the eligibility criteria were consistent with what practitioners generally apply when recruiting for GPNC and therefore reflected the typical clinical context and maximized the generalizability of the study findings. Our study site has extensive experience in offering CenteringPregnancy GPNC for pregnant participants (ie, the site has been continuously certified by the Centering Healthcare Institute since 2009), indicating a high degree of fidelity to the model. In the current study, the GPNC was provided in both English and Spanish. Additional strengths of our study include the large sample size (>2000 participants), the racially and ethnically diverse population, and the rich measures of sociodemographic, psychosocial, behavioral, reproductive, and clinical factors at baseline and over pregnancy. | PMC10466168 |
Limitations | SECONDARY | Our study had several limitations. First, the early termination of the trial due to the COVID-19 pandemic resulted in a smaller sample size than originally planned, limiting the power for our secondary analysis. According to our previously published observational study, | PMC10466168 | |
Conclusions | In this RCT among pregnant individuals, participants receiving GPNC had similar risk of developing GD, compared with participants receiving IPNC, suggesting that GPNC could be a feasible care option for some patients. Future studies should explore additional strategies to enhance participant engagement with GPNC. Moreover, research is needed to assess the effect of GPNC on GD progression among pregnant individuals with GD. | PMC10466168 | ||
1. Introduction | hypertension | HYPERTENSION | The use of garlic (A wealth of evidence exists to demonstrate that lowering blood pressure can substantially reduce premature morbidity and mortality [Several studies have shown that garlic can help lower blood pressure in individuals with hypertension [Aged black garlic (ABG) is a type of modified garlic that contains a unique composition of organosulfur compounds and polyphenols compared to fresh garlic [In this sense, this study aimed to evaluate the antihypertensive effects of a daily intake of a low-dose SAC-optimized ABG extract for 12 weeks in individuals with Grade I hypertension following blood-pressure-reducing drug therapy. For that purpose, a randomized, triple-blind, placebo-controlled parallel trial was developed, where the primary outcome was the reduction in office and home blood pressure. Secondary outcomes such as endothelial function, nitric oxide, inflammatory cytokines, angiotensin-converting enzyme activity, and antioxidant capacity levels in blood were determined to explain the antihypertensive effect of ABG. | PMC10490347 |
2. Materials and Methods | PMC10490347 | |||
2.1. Experimental Design | hypertension | HYPERTENSION | The study was designed as a triple-blind, placebo-controlled, randomized parallel study to determine whether an optimized aged black garlic (ABG) extract could reduce systolic and diastolic blood pressure in subjects with Grade I hypertension. The study consisted of two periods. An initial period called the “Run-in phase”, two weeks in duration, involved all volunteers being treated with a placebo, and blood pressure was monitored daily and served as the basis for the evaluation of future changes in blood pressure. At least five consecutive days of home blood pressure monitoring are required for a reliable diagnosis of home hypertension [Volunteers were randomly assigned to each group by sequential number assignment, and they were divided by sex after their acceptance to participate in the study. The study was carried out under the ethical principles established in the latest version of the Declaration of Helsinki and Tokyo for human investigation and following Regulation (EU) 2016/679 of the European Parliament of the Council of 27 April 2016 on Data Protection (RGPD); Law 14/2007 on biomedical research; and Organic Law 3/2018 on the Protection of Personal Data and Guarantee of Digital Rights. Participants provided informed consent before they participated in the study. The study protocol was approved by Hospital Universitari Arnau de Vilanova (CEIC-2435), Lleida, Spain, and the trial is registered at ClinicalTrials.gov NCT04915053. No changes to methods after trial commencement were introduced. | PMC10490347 |
2.2. Intervention | DEL | The intervention consisted of a daily intake of one tablet after wake-up and before breakfast. Group L received an optimized ABG10+ -extract tablet manufactured by Pharmactive Biotech Products, S.L.U. (Madrid, Spain), according to a proprietary process. The extract was from garlic harvested in the area of Las Pedroñeras (Castilla la Mancha, Spain), and the tablets were manufactured at Instant Procès (La Roca del Vallès, Spain). Each ABG tablet contained 250 mg of ABG extract, which provided 0.25 mg of SAC per tablet plus 300 mg of the excipients shown in | PMC10490347 | |
2.3. Study Population | hypertension | DISEASE, MORBID OBESITY, HYPERTENSION | Volunteers were recruited in collaboration with the Atherothrombotic Disease Detection and Treatment Unit (UDETMA) of the Hospital Universitari Arnau de Vilanova (Lleida, Spain) from the database of patients with Grade I hypertension. The inclusion criteria included: men and women over 18 years of age with diagnosed hypertension that were under treatment with one or more antihypertensive drugs, excluding ACE inhibitors. Exclusion criteria included suffering from morbid obesity (body mass index > 35 kg/m | PMC10490347 |
2.4. Sample Size Determination | The sample size was calculated based on the study published by Rothwell et al. [ | PMC10490347 | ||
2.5. Outcomes | PMC10490347 | |||
2.5.1. Blood Pressure | Office and home blood pressure were determined by the same oscillometric automatic sphygmomanometers (Medisana BU 512, Medisana GmbH, Neuss, Germany), with a maximum error tolerance for static pressure of ±3 mmHg. Volunteers were seated comfortably in a quiet environment for 5 min before blood pressure measurements. Office and home blood pressure were determined by the average of three recordings of systolic and diastolic blood pressure, obtained at 3 min intervals after subjects had been seated on a chair with their feet on the floor and arms supported at the heart level. For home blood pressure measurements, volunteers were instructed to take measurements in the morning, 15 min after getting up and urinating (if applicable); to sit comfortably; and to take blood pressure three times at 5 min intervals. They were provided with a notebook where they had to record the measurements daily, including the exact time. Additionally, at the time of the appointments, the measurements provided by the volunteer were verified by consulting the memory of the sphygmomanometer and, if necessary, corrected in their notebook based on the time and date of measurement. | PMC10490347 | ||
2.5.2. Endothelial Function | REACTIVE HYPEREMIA | The EndoPAT™ parameters reactive hyperemia index (RHI) and augmentation index (AI | PMC10490347 | |
2.5.3. Nitric Oxide | Nitric oxide was determined by nitrate/nitrite concentration using a fluorometric assay kit (Abcam ab65327, Cambridge, UK) following manufacturer instructions. Serum samples were filtered with a 10 kDa Spin column (Abcam ab93349, Cambridge, UK) to deproteinize the samples before the analysis. The analysis consisted of a two-step process: first, nitrate is converted to nitrite by nitrate reductase, and then nitrite reacts with the fluorescent probe 2,3 diaminonaphthalene. A nitrite standard calibration curve was used to compare the fluorescence intensity of samples. The analysis was performed in triplicate in each sample. | PMC10490347 | ||
2.5.4. Antioxidant Capacity | Antioxidant capacity was measured by the FRAP (ferric reducing antioxidant power) assay. Briefly, 900 μL of the FRAP reagent containing 2,4,6-tri(2-pyridyl)-s-triazine, FeCl | PMC10490347 | ||
2.5.5. Inflammatory Cytokines | The simultaneous assessment of serum concentrations of IL-2, IL-4, IL-5, IL-8, INF-γ, inducible protein 10 (IP-10), and soluble CD40 ligand (sCD40L) was performed using commercially available multiplex bead-based immunoassay kits (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, HCYTOMAG-60K, Millipore, Billerica, MA, USA) following manufacturer’s instructions. Briefly, plasma samples (25 μL/well) or standards (25 μL well) were incubated with 25 μL of the pre-mixed bead sets in pre-wetted 96-well microtiter plates at 4 °C overnight. After washing, 25 μL of the fluorescent detection antibody mixture was added for 30 min, and 25 μL of streptavidin-phycoerythrin was added to each well for 30 min at room temperature. A range of 3.2–10,000 pg/mL recombinant cytokines was used to establish standard curves and maximize the assay’s sensitivity and dynamic range. Cytokine levels were determined using a Luminex IS 100 (Luminex, Austin, TX, USA). | PMC10490347 | ||
2.5.6. Angiotensin-Converting Enzyme (ACE) Activity | ACE activity was determined following the manufacturer’s instruction of Spinreact’s (41205, Sant Esteve de Bas, Spain) quantitative determination kit. Briefly, in this method, the direct substrate | PMC10490347 | ||
2.5.7. Statistical Analysis | SECONDARY, REGRESSIONS | Statistical analysis was performed as per protocol. Primary and secondary parameters were measured at baseline and after 12 weeks of intervention. Data are presented as mean ± standard deviation of the mean. Two-way ANOVA and multiple comparisons, used to analyze the treatment effect, were performed using Sidak’s test. A statistical analysis of initial differences between Groups A and L was performed by a two-tailed unpaired Student’s t-test. A Chi-square test was performed for categorical variables. Correlation analysis between the change in blood pressure and confounding variables was performed by Pearson’s correlation analysis. To determine the evolution in home blood pressure measurements, linear regressions were conducted between the days of treatment (0–84 days) and the mean of the blood pressure taken daily. Differences in slopes were monitored by a two-tailed t-test analysis. In all cases, the cut-off to determine significant differences between groups was set at a | PMC10490347 | |
3. Results | PMC10490347 | |||
3.1. Study Design | RECRUITMENT, GASTROESOPHAGEAL REFLUX | The recruitment phase included creating a database of potential volunteers according to the inclusion and exclusion criteria. Of the 303 patients in the database, 89 volunteers showed interest in participating in the study and entered the run-in phase. Eight volunteers did not complete the run-in phase due to placebo intolerances, personal issues, and non-response to the next appointment. Eighty-one volunteers were randomized to participate in one of the two groups of the present study (Group A: Placebo and Group L: Active compound) and started the experimental phase. Finally, 38 and 39 volunteers from Groups A and L completed the experimental phase. The leading causes of withdrawal from the study were non-response to appointments in Groups A and L and intolerance to treatment in Group L, mainly due to gastroesophageal reflux. A flowchart of the study is depicted in | PMC10490347 | |
3.2. Compliance and Reported Adverse Events | muscular cramps | ADVERSE EVENTS | Treatment compliance was determined from the number of pills taken divided by the total days of the treatment period. Some volunteers took extra treatment days due to volunteer availability adjustments in appointments. The mean treatment days in both groups were 87 ± 5 and 88 ± 5 for groups L and A, respectively. The mean compliance in both groups was above 96%, where no difference in compliance was observed between groups (Four volunteers reported treatment adverse events. Two volunteers from Group L (active compound) and one from Group A (placebo group) reported mild gastric discomfort, while one volunteer from Group A reported muscular cramps.The treatment blinding of volunteers was executed by asking each participant in the last appointment if they believed there where in the active or placebo group. Moreover, 23% and 45% of volunteers in Groups L and A, respectively, thought they were in the active group. Therefore, it was determined that volunteer treatment blinding was appropriately conducted. Regarding the researcher blinding, none of the researchers were aware of which group the active compound belonged to until the finalization of the statistical analysis. | PMC10490347 |
3.3. Blood Pressure, Endothelial Function, and Related Variables | Changes in blood pressure were determined through two methods: the measurements in the office at baseline and 12 weeks and the daily measurement performed by the volunteers at home. The results of the office pressure measurements are shown in No changes in endothelial function parameters (RHI and AIRegarding the variables that could explain ABG-extract effects on blood pressure, except for IL-2 levels, there were no significant changes due to treatment in the variables included in | PMC10490347 | ||
3.4. Confounding Variables Analysis | No differences in response to the treatment were observed due to sex ( | PMC10490347 | ||
4. Discussion | inflammation, reduction in blood pressure, hypercholesterolemia | HYPERCHOLESTEROLEMIA, INFLAMMATION, CARDIOVASCULAR MORBIDITY, ADVERSE EFFECTS, HYPERTENSION | This study aimed to validate whether daily supplementation with an optimized black-garlic extract could help to control blood pressure in medicated people with Grade I hypertension. The results of this study suggest a drop in systolic and diastolic blood pressure of 1.8 and 1.5 mmHg, respectively, at values measured at home, not observing significant changes in the measurements taken in the office.Garlic has repeatedly shown a beneficial effect in lowering blood pressure [On the other hand, it has also been shown that a daily ABG-extract supplementation, even at low doses of SAC (0.25 mg/day), induces significant effects on blood pressure control. This last point is critical to highlight since it demonstrates garlic extracts at low doses that are effective without inducing commonly reported side effects [The reduction in blood pressure measured at home is considered even more relevant than the measurement in the office since recent meta-analyses have indicated that home blood pressure monitoring better predicts cardiovascular morbidity and mortality than office blood pressure [The changes in blood pressure observed in this study are consistent with previous observations of the effect of the same ABG extract on cardiovascular physiology. A clinical trial in subjects with moderate hypercholesterolemia reported reduced diastolic blood pressure, particularly in men with diastolic blood pressure above 75 mmHg [Regarding inflammation markers, previous studies suggest that components of ABG extract present anti-inflammatory properties in models of lipopolysaccharide toxin inflammation induction [It is suggested that combination therapy is more effective than increasing doses of a single blood-pressure-reducing drug [This study has some limitations. Although a significant reduction in blood pressure was observed, the time of the day of administration can be optimized. Treatment-time differences affect the beneficial and adverse effects of different blood pressure-reducing drugs [ | PMC10490347 |
5. Conclusions | hypertension, reductions in blood pressure | HYPERTENSION | Based on the results obtained in this study, it can be concluded that daily supplementation with ABG extracts with low doses of SAC (0.25 mg/day) can induce significant reductions in blood pressure in individuals with Grade I hypertension and antihypertensive drug therapy. | PMC10490347 |
Author Contributions | CRediT author statement: J.C.E.S.: Conceptualization, Methodology, Validation, Formal analysis, Writing, Review and Editing. E.C.-B.: Investigation. A.G.-C.: Investigation. M.I.M.-V.: Funding acquisition, Resources, Review and Editing. D.G.-H.: Funding acquisition, Resources, Review and Editing. M.B.-L.: Investigation. J.M.V.: Methodology, Resources. A.E.E.: Methodology, Resources, Funding Acquisition, Review and Editing. M.P.-O.: Conceptualization, Methodology, Validation, Writing, Review and Editing. All authors have read and agreed to the published version of the manuscript. | PMC10490347 | ||
Institutional Review Board Statement | The study was conducted by the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Hospital Universitari Arnau de Vilanova (CEIC-2435, 25 March 2021) for studies involving humans. | PMC10490347 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10490347 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. | PMC10490347 | ||
Conflicts of Interest | A García-Carrasco, J.M. Valdivielso, and M. Portero-Otin do not declare any potential competing interests. Jose CE Serrano reports that Pharmactive Biotech Products S.L.U. provided financial support for study development. Maria Ines Moran Valero, Alberto E. Espinel, and Daniel Gonzalez Hedstrom report a relationship with Pharmactive Biotech Products SL that includes the employment of Pharmactive S.L., the company that produces and distributes the garlic extract used in this study. | PMC10490347 | ||
Background | intraoperative blood loss, knee arthroplasty, blood loss, TKA | BLOOD LOSS, INTRAOPERATIVE BLOOD LOSS | The use of a tourniquet in combination with tranexamic acid (TXA) not only ensures clear vision, reduces intraoperative blood loss and shortens operative time but also improves cement-bone inter-digitation in total knee arthroplasty (TKA). However, there is no proof whether the blood flow blocking effect of tourniquet affects the antifibrinolytic effect of TXA, and the optimal timing of TXA administration is still unclear. Therefore, this study aims to investigate the effect of the first dose of TXA administered intravenously before tourniquet compression and release in TKA on perioperative blood loss and therapeutic efficacy in patients. | PMC10655351 |
Methods | blood loss, petechiae | BLOOD LOSS, PETECHIAE, GROUP B, COMPLICATIONS | In this double-blind trial, 90 patients undergoing primary TKA were randomised into 2 groups: Group A, patients received intravenous TXA 10 min before tourniquet compression (20 mg/kg) and 3, 6 and 24 h later (10 mg/kg), and Group B, patients were treated the same as those in Group A but received intravenous TXA before tourniquet release. The primary outcomes were changes in blood loss, haemoglobin and haematocrit. Secondary outcomes included operation and tourniquet times, blood transfusion rate, subcutaneous petechiae and circumferential changes in the operated limb, visual analogue scale (VAS) score, hospital for special surgery (HSS) score, length of stay (LOS) postoperatively, complications and patient satisfaction. | PMC10655351 |
Results | No statistically significant difference was found between the 2 groups with regard to age, sex, weight, body mass index (BMI), Kellgren-Lawrence class, preoperative blood volume, preoperative laboratory values, operation and tourniquet times, transfusion rate, knee circumference, preoperative HSS, or VAS score ( | PMC10655351 | ||
Conclusion | swelling, blood loss, knee arthroplasty, petechiae, bruising | BLOOD LOSS, PETECHIAE, COMPLICATION | TXA was administered intravenously prior to tourniquet compression could effectively reduce blood loss in patients who had undergone total knee arthroplasty. However, there was no significant difference in knee swelling rate, subcutaneous bruising and petechiae incidence, knee function, complication rate or satisfaction between patients who TXA was given intravenously before tourniquet compression and release in primary TKA. | PMC10655351 |
Keywords | PMC10655351 | |||
Introduction | bleeding, TKAs, pain, knee arthroplasty, TKA | OSTEOARTHRITIS OF THE KNEE, BLEEDING | Total knee arthroplasty (TKA) has become a routine procedure to reduce pain and improve the quality of life of patients with osteoarthritis of the knee, and the number of TKAs performed is increasing annually worldwide [Reducing perioperative bleeding and transfusion rates in patients undergoing TKA is a key measure to accelerate postoperative recovery, shorten hospital stays and reduce health care costs. The application of intraoperative tourniquets and tranexamic acid (TXA) [TXA, one of the commonly used antifibrinolytic drugs in clinical practice, is a lysine synthetic derivative that reversibly blocks the lysine binding site on fibrinolytic enzymes and fibrinogen, resulting in the inability of fibrinogen to bind to fibrin molecules, thus achieving antifibrinolytic effects [Some scholars currently apply the first dose of intravenous TXA 5 to 30 min prior to skin incision, but a tourniquet in TKA blocks blood circulation to the lower extremity while also affecting blood levels in the operative area [ | PMC10655351 |
Methods | PMC10655351 | |||
Patients and design | anaemia, varus-valgus, cardiovascular disease, end-stage osteoarthritis, lower limb arterial occlusion, flexion deformity, venous thrombosis | ANAEMIA, OSTEOARTHRITIS OF THE KNEE, CARDIOVASCULAR DISEASE, DISEASE, LIVER DISEASE, HAEMATOLOGICAL DISORDERS, VENOUS THROMBOSIS | This prospective, double-blind randomised study was approved by The Institutional Review Board of Panzhihua Central Hospital (no. pzhszxyyll-2022-10) and registered in the Chinese Clinical Trial Registry (ChiCRT-2100053885). Informed consent was obtained before participation in the study. Ninety patients with osteoarthritis of the knee who underwent primary TKA from 01/2022 to 07/2022 in our hospital were selected. All patients 18 years of age or older who were scheduled for primary unilateral TKA for end-stage osteoarthritis were eligible for inclusion. Exclusion criteria: (1) preoperative anaemia or other haematological disorders; (2) preoperative history of severe cardiovascular disease and/or still taking oral anticoagulants; (3) preoperative unilateral lower limb arterial occlusion, venous thrombosis or history of disease; (4) preoperative preexisting autologous blood transfusion or request for blood return device; (5) contraindication for the use of TXA or low molecular weight heparin; (6) perioperative use of erythropoietin, iron, antiplatelet therapy or blood transfusion; (7) preoperative diagnosis of liver disease; (8) BMI > 35; (9) flexion deformity of ≥ 30°, varus-valgus deformity of ≥ 30° (10) inability to cooperate with the trial. | PMC10655351 |
Treatment groups | GROUP B | In total, 90 patients were randomised to 1 of 2 groups. Group A received intravenous TXA 10 min before tourniquet compression (20 mg/kg) and 3, 6 and 24 h later (10 mg/kg); Group B was treated the same as Group A but received intravenous TXA before tourniquet release. The included patients were randomised into Groups A and B in a 1:1 ratio using the random number table method. The random numbers generated were sealed in opaque envelopes and kept by staff who were not involved in the study and did not measure outcomes. Preoperative, intraoperative and postoperative data were collected and recorded by one researcher without the surgeon being involved in the collection. Throughout the study, the surgeon, patient, and data collector and analyst were unaware of the intervention. | PMC10655351 | |
Surgical procedure | bleeding, postoperative pain | BLEEDING, CAVITY | All of the operations were performed by the same team of senior surgeons, all under general anaesthesia. We performed all operations through a midline skin incision and medial parapatellar approach. Intramedullary guides were used for all femoral preparations, and extramedullary guides were used for the tibial preparation. A tourniquet was used throughout the operation to stop bleeding, with a tourniquet pressure of (systolic + 100) mmHg (1 mmHg = 0.133 kPa). A surgeon-selected cemented posterior-stabilised prosthesis (The Legion system (Smith & Nephew, London, UK) was used. The tourniquet was loosened, the bleeding had completely stopped, the wound was flushed with saline and TXA 3 g (30 ml) was injected into the joint cavity, followed by a 60 ml cocktail of 200 mg Ropivacaine (10 ml, 100 mg, Naropin; AstraZeneca AB, Sodertalje, Sweden) and 0.1 ml Betamethasone (1 ml, Diprospan; Merck Sharp & Dohme, Luzern, Switzerland) to reduce postoperative pain prior to capsule closing [ | PMC10655351 |
Postoperative management | All patients were managed using the same Postoperative protocols. One gram of TXA (5 ml, 0.5 g; Salvage Pharmaceutical CO.,LTD., Guizhou, China) was given intravenously at 3 and 6 h and on day 2 postoperatively; 1.5 g of Cefuroxime Sodium (1.5 g, Axetine; Medochemie Ltd., Limassol, Cyprus)was given as prophylaxis once every 8 h for a day), Perioperative oral analgesia [ | PMC10655351 | ||
Outcome measurements | bleeding | BLEEDING | Intraoperatively, the amount of bleeding, need for blood transfusion, duration of the operation and duration of tourniquet use were recorded, and the total blood volume was calculated according to the Nadler equation [ | PMC10655351 |
Statistical analysis | blood loss | BLOOD LOSS | The sample size was calculated on the basis of the difference in the primary outcome, namely, total blood loss. Based on pilot data from 24 patients who received unilateral primary TKA with TXA was given intravenously before tourniquet compression between December 2020 and September 2021, the mean total blood loss was 421 ml (SD 272). In the study of TXA was given intravenously before tourniquet release, the mean total blood loss was 642 ml (SD 242) [ | PMC10655351 |
Results | PMC10655351 | |||
Intraoperative and postoperative blood loss, haemoglobin and red blood cell count drop values | blood loss, HBL Hidden blood loss | BLOOD LOSS, INTRAOPERATIVE BLOOD LOSS, TOTAL BLOOD LOSS | There was no significant difference in IBL (52.7 ml vs. 63.4 ml,
Box plots of blood loss, Hb and RBC postoperatively between two groups. IBL Intraoperative blood loss, HBL Hidden blood loss, TBL Total blood loss, Hb Haemoglobin, RBC Red blood cell, ns No significant difference, *P < 0.05 | PMC10655351 |
Changes in haemoglobin, haematocrit and red blood cell count (RBC) | Preoperative haemoglobin, haematocrit and RBC were in the normal range in both groups (Table
Changes of hemoglobin, hematocrit and RBC in 2 groups | PMC10655351 | ||
Incidence of petechiae and knee circumference changes | petechiae | PETECHIAE, GROUP B | The incidence of petechiae, mean petechiae area and maximum petechiae area were not significantly different between the 2 groups, with the mean incidence of petechiae remaining at 23.5% and 25.0% and the mean petechiae area being approximately 1.0%, with the maximum petechiae area being 4.0% in Group A and 3.0% in Group B (Table
Incidence and size of petechiae
Knee circumference changes of the 2 groups of patients | PMC10655351 |
Postoperative VAS scores, HSS scores and patient satisfaction | The preoperative VAS scores were 5.1 ± 1.4 and 4.9 ± 1.5 in Groups A and B, respectively, which started to drop postoperatively and gradually decreased to 1.3 ± 0.3 and 1.3 ± 0.6 at 3 months postoperatively. The HSS score decreased from 51.2 ± 7.3 and 51.0 ± 9.4 preoperatively to 48.0 ± 8.3 and 45.7 ± 9.0 on postoperative day 1, began to improve on postoperative day 3 and improved to 81.8 ± 7.5 and 82.4 ± 8.1 at follow-up until 3 months after surgery. However, there was no significant difference in the VAS and HSS scores between the 2 groups at each time point. Patient satisfaction was 97.6% and 95.4% in the 2 groups, respectively ( | PMC10655351 | ||
Discussion | thrombosis, nonhealing, postoperative pain, blood loss, intraoperative and postoperative blood loss, pain, knee arthroplasty, thrombus, ’ postoperative hypoproteinaemia, cardiovascular or cerebrovascular accidents, coagulation abnormalities, postoperative knee swelling | THROMBOSIS, DEEP VEIN THROMBOSIS, BLOOD LOSS, WOUND INFECTION, ACUTE RENAL FAILURE, THROMBUS, ASYMPTOMATIC PULMONARY EMBOLISM, COMPLICATIONS | TXA administered intravenously prior to tourniquet compression could effectively reduce blood loss in patients who had undergone total knee arthroplasty. There was no statistical significance in the comparison of intraoperative and postoperative blood loss, postoperative haemoglobin, haematocrit or red blood cell count between the two groups of patients in this study, but the data demonstrated that applying TXA before tourniquet pressurisation had a better haemostatic effect. However, the use of an intraoperative tourniquet and the effect of repelling the blood will have a negative impact on the TXA blood concentration in the tissues of the operated area while blocking the blood circulation of the affected limb [Multimodal analgesia was strictly applied to both groups, and active and passive functional exercises of the knee joint were strictly performed in the postoperative period. The results showed that there was no difference in the effect of the two regimens on the postoperative pain and function of the patients. During the follow-up period, the pain of the affected limbs was reduced compared with that in the preoperative period, and the improvement in pain was obvious over time; however, due to the influence of postoperative knee swelling, pain and other comprehensive factors, the knee function score decreased first and then increased later, and the improvement in knee function was satisfactory at 3 months after the operation. There was no significant difference in the incidence of complications between the two groups of patients. In this study, some patients had thrombosis of the intermuscular vein of the calf, but there were no obvious clinical symptoms, and the thrombus disappeared after intensive anticoagulation treatment. There was no deep vein thrombosis of the lower extremities or symptomatic pulmonary embolism. Some patients’ wounds showed oozing blood and fluid, which was related to the patients’ postoperative hypoproteinaemia and slow wound healing factors; the state of the wounds improved after dressing changes. None of the patients had complications such as wound infection, nonhealing, acute renal failure, cardiovascular or cerebrovascular accidents, or coagulation abnormalities.Although this study was well designed, it still has some limitations. First, the study was a single-centre study and the sample size was small. Haemoglobin and blood loss indicators reflected less blood loss and more stable haemoglobin levels in the group of patients who received TXA before loosening the tourniquet, but there was no significant difference in the statistical analysis. Because of the strict inclusion criteria, the sample size may not have been large enough to determine significance for all variables. Second, venography was not used as a standard method to screen for postoperative lower extremity deep vein thrombosis, and Doppler ultrasonography may affect the accuracy of the diagnosis of lower extremity deep vein thrombosis, but the occurrence of lower extremity deep vein thrombosis and symptomatic pulmonary embolism can be determined according to the clinical signs and symptoms at the 1-month postoperative follow-up, and the safety of TXA has been well supported by evidence. | PMC10655351 |
Acknowledgements | This study adheres to CONSORT guidelines. We are thankful for the support of the nursing staffs from the Department of Orthopaedics, Panzhihua Central Hospital and the patients enrolled in this study. | PMC10655351 | ||
Author Contributions | Mingyou Wang and Yuping Lan were responsible for research, collect and analyse data, and wrote the main manuscript text; Qifeng Tao is responsible for research guidance, article review; Wang Hongping, Chen Chunyu and Mei zhu are responsible for research guidance, data collection and statistical analysis; All authors reviewed the manuscript. | PMC10655351 | ||
Funding | This research was funded by The Primary Health Development Research Center of Sichuan Province Program (SWFZ21-C-111), who is not involved in study design, data collection, analysis and interpretation or manuscript preparation. | PMC10655351 | ||
Data Availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. | PMC10655351 | ||
Declarations | PMC10655351 | |||
Ethics approval and consent to participate | This study was approved by The Institutional Review Board of Panzhihua Central Hospital (no. pzhszxyyll-2022-27) and written informed consent to participate was obtained from all of the individual participants included in the study. All methods were carried out in accordance with relevant guidelines and regulations. | PMC10655351 | ||
Consent for publication | Not applicable. | PMC10655351 | ||
Competing interests | The authors declare no competing interests. | PMC10655351 | ||
Abbreviations | venous thrombosisPulmonary embolism | Intraoperative blood lossHidden blood lossTotal blood lossHemoglobinRed blood cellTotal knee arthroplastyTranexamic acidVisual analog scaleHospital for Special SurgeryLength of stayRange of motionDeep venous thrombosisPulmonary embolism | PMC10655351 | |
References | PMC10655351 | |||
1. Introduction | OMIM 264800, calcification of the skin, calcification, PXE | RARE DISEASE, DISEASES, PSEUDOXANTHOMA ELASTICUM | Both authors contributed as senior authors.Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM (Pseudoxanthoma elasticum (PXE, OMIM 264800, ORPHA 758) is a rare disease caused by biallelic variants of the ABCC6 gene, which encodes an ABC transporter primarily found in the hepatic and renal tissues [In addition to the ABC proteins, PPi levels are regulated by two enzymes: tissue-nonspecific alkaline phosphatase (TNAP), which transforms PPi into two molecules of Pi, and the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) that produces PPi from ATP. We and others have shown that TNAP activity is increased and PPi is reduced in PXE subjects compared with controls [There is no specific treatment to stop progressive calcification in PXE. PPi supplementation has been tested in animal models through its addition to drinking water [There have been few clinical trials in PXE. One trial in PXE patients with oral magnesium supplementation for 2 years was not able to show benefit in terms of reducing calcification of the skin and there were no changes in retinal signs [Lansoprazole is a proton-pump inhibitor licensed to treat diseases related to gastric acid output. Lansoprazole has been shown to partially inhibit the effects of TNAP [ | PMC10003519 |
3. Discussion | calcification, PXE, gastrointestinal intolerance | DISEASE, OSTEOPOROTIC FRACTURE, PATHOGENESIS, MINERALIZATION | Our trial shows that administration of lansoprazole 30 mg increased PPi levels in patients with PXE compared with the placebo in a short period of 8 weeks. Because PPi is recognized as a molecule directly involved in the pathogenesis of calcification in these patients, lansoprazole might be considered for new clinical trials with clinical outcomes.Of note, PPi levels were similar at visits one and three (The rationale for our trial relies on the fact that TNAP activity is higher and PPi is lower in PXE patients compared with non-PXE subjects [Another interesting point concerning lansoprazole and PXE is the effect of the drug on PHOSPHO1, a cytosolic phosphatase highly expressed in osteoblasts and essential for bone mineralization [There were very few adverse side effects, with six in the placebo phase and three in the lansoprazole phase, mainly gastrointestinal intolerance, and in only one case causing the patient to drop out of the study (in the placebo phase). Putting this into perspective, we should take into account the long-term side effects of lansoprazole: on the one hand, it has been shown to increase the risk of osteoporotic fractures under long-term use and a high dose [In our study, lansoprazole elevated PPi more than the placebo by an average of 18%, partially compensating for the 30% deficit the patients with PXE had relative to the controls, but without normalizing levels [We do not know if the observed 18% increase might provide a clinical benefit to patients, such as delaying the progression of the disease. Only a long-term trial with clinical end points might answer this question, or a mid-term trial with the deposition of Na18F in the neck skin as the end point [Our trial has several limitations that should be taken into account: the low number of participants, the short-term follow-up (only 8 weeks of therapy), the fact we do not know how many days it took for PPi to be increased after lansoprazole was taken, the absence of clinical values as end points, as well the heterogeneous response in some patients.In conclusion, our trial supports the establishment of a new clinical trial with lansoprazole in PXE patients, with clinical outcomes as the major end points. It might be considered as monotherapy or as an adjuvant with a second medication, such as oral PPi ingestion. | PMC10003519 |
4. Materials and Methods | PXE symptoms, cardiovascular or cerebrovascular disease, diabetes | RENAL LITHIASIS, ADVERSE EVENTS, DISEASE, ADVERSE EVENT, DYSLIPIDEMIA, INTERMITTENT CLAUDICATION, BLOOD, HYPERTENSION, DIABETES | Capsules of lansoprazole 30 mg or a placebo were provided by the Pharmacy Service of Hospital Virgen de la Macarena, Sevilla, Spain. The random sequence was created using the software Random Integer Generator (Patients who consented to participate in the trial had 4 visits to the hospital, just before and after the two 8-week periods. At each visit, demographics, clinical and anthropometric data, and the presence of any adverse event were obtained. At the beginning of each 8-week period, a bottle containing 59 capsules of lansoprazole 30 mg or a placebo was given to each patient; the bottle was returned at the end of each period and the capsules were counted.At the first visit, age, sex, date of the first PXE symptoms, skin, vascular and eye stage of the disease, and comorbidities (hypertension, diabetes, dyslipidemia, renal lithiasis, cardiovascular or cerebrovascular disease, intermittent claudication, and any concomitant therapy) were recorded. Body weight, stature, body mass index, blood pressure, and the ankle–brachial index were registered. At each visit, the physical examination, medication, adverse events, and returned pills were recorded.At each visit, after an overnight fast, blood samples were drawn and collected into serum, K2-EDTA, citrate, and citrate-theophylline-adenosine-dipyridamole (CTAD) vacuum tubes (BD Vacutainer; Plymouth, UK). Blood samples were kept on ice and then the K2-EDTA tubes were centrifuged for 15 min at 1750× PPi, TNAP and ENPP1 activities, CXCL4, Osteocalcin, and ENPP1 concentrations were measured as described previously [Hematological and basic biochemistry variables were collected through a clinical autoanalyzer and the Siemens Dimension Vista System Flex analysis system at the clinical laboratory of the Virgen de la Victoria University Hospital in Malaga, Spain.Statistical analyses: These were performed by a statistician not on the research team. The statistical package used was R 3.5.2. Data are shown as mean ± SD, median (IQR) or n (%). A generalized linear mixed-model approach was used to estimate differences between periods of lansoprazole and placebo while accounting for within-subject correlations arising from the crossover design. Study data were collected and managed using REDCap electronic data capture tools hosted at Hospital Regional Universitario de Málaga, Spain [ | PMC10003519 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10003519 | ||
Author Contributions | M.G.F., J.L.C.L. and P.V. contributed to conception and study design; B.M.C., I.B.A., J.R.V., M.Á.R.C., R.B. and M.Á.S.C. contributed to data collection and data analysis. A.G.J. performed statistical analyses. V.M.B. prepared the drug and placebo capsules and blinded them. P.V. prepared the manuscript. All authors maintained full editorial control over the content of the manuscript and were responsible for all final decisions on the manuscript content, for final approval of the version for submission, and publication. All authors have read and agreed to the published version of the manuscript. | PMC10003519 | ||
Institutional Review Board Statement | This clinical trial was approved by the Ethics Committee of Málaga on 23 March 2017, as well for the Spanish Medicinal Products on 31 October 2018. The investigations were carried out following the rules of the Declaration of Helsinki of 1975 ( | PMC10003519 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10003519 | ||
Data Availability Statement | Data will be provided upon reasonable request. | PMC10003519 | ||
Conflicts of Interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. | PMC10003519 |
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