Random-effects Dose-response Meta-analysis Research Articles

Vortioxetine for depression in adults: A systematic review and dose-response meta-analysis of randomized controlled trials.

Major depressive disorder (MDD) is a prevalent psychiatric condition and vortioxetine offers promising antidepressant effects due to its unique pharmacological profile. However, the dose-response relationships of vortioxetine for MDD is not well established. We aimed to conduct dose-response meta-analyses to fill this gap. We systematically searched multiple electronic databases for randomized controlled trials of vortioxetine for MDD, with the last search conducted on 08 February, 2024. The dose-response relationship was evaluated using a one-stage random-effects dose-response meta-analysis with restricted cubic spline model. The primary outcome was efficacy (mean change in depression scale score), with secondary outcomes including response, dropout for any reasons (acceptability), dropout for adverse events (tolerability), and any adverse events (safety). The dose-response meta-analysis comprised 16 studies, with 4,294 participants allocated to the vortioxetine group and 2,299 participants allocated to the placebo group. The estimated 50% effective dose was 4.37 mg/day, and the near-maximal effective dose (95% effective dose) was 17.93 mg/day. Visual inspection of the dose-efficacy curve suggests that a plateau possibly had not been reached yet at 20 mg/day. Acceptability, tolerability and safety decreased as the dose increased. Subgroup analysis indicated that no significant differences were observed in acceptability, tolerability and safety among the dosage groups. Vortioxetine may potentially provide additional therapeutic benefits when exceeding the current licensed dosage without significantly impacting safety. Conducting clinical trials exceeding the current approved dosage appears necessary to fully comprehend its efficacy and risk.

Efficacy and safety of omega-3 fatty acids supplementation for anxiety symptoms: a systematic review and dose-response meta-analysis of randomized controlled trials

Background/ObjectivesThere is uncertainty about the optimum dose of omega-3 fatty acids for anxiety symptoms. We aimed to find the dose-dependent effect of omega-3 supplementation on anxiety symptoms.MethodsWe systematically reviewed PubMed, Scopus, and Web of Science until December 2022 to find randomized trials that assessed the effects of omega-3 fatty acids supplementation on anxiety symptoms in adults. Investigators performed the literature search and screened the titles/abstracts and full-texts and between-reviewer agreement was assessed as Cohen’s kappa coefficient. We conducted a random-effects dose-response meta-analysis to estimate standardized mean differences (SMD) and 95% confidence intervals (CIs) and assessed the certainty of evidence using the GRADE framework.ResultsA total of 23 trials with 2189 participants were included. Each 1 gram per day supplementation with omega-3 fatty acids resulted in a moderate decrease in anxiety symptoms (SMD: -0.70, 95%CI: -1.17, -0.22; GRADE = low). The non-linear dose-response analysis indicated the greatest improvement at 2 g/d (SMD: -0.93, 95%CI: -1.85, -0.01), and that supplementation in a dose lower than 2 g/d did not affect anxiety symptoms. Omega-3 fatty acids did not increase adverse events (odds ratio: 1.20, 95%CI: 0.89, 1.61; GRADE = moderate).ConclusionsThe present dose-response meta-analysis suggested evidence of very low certainty that supplementation with omega-3 fatty acids may significantly improve anxiety symptoms, with the greatest improvements at 2 g/d. More trials with better methodological quality are needed to reach more robust evidence.Protocol registrationPROSPERO (CRD42022309636).

Impact of hormone replacement therapy on all-cause and cancer-specific mortality in colorectal cancer: A systematic review and dose‒response meta-analysis of observational studies.

The effect of hormone replacement therapy (HRT) on colorectal cancer (CRC) mortality and all-cause mortality remains unclear. We conducted a systematic review and dose-response meta-analysis to determine the effects of HRT on CRC mortality and all-cause mortality. We searched the electronic databases of PubMed, Embase, and The Cochrane Library for all relevant studies published until January 2024 to investigate the effects of HRT exposure on survival rates for patients with CRC. Two reviewers independently extracted individual study data and evaluated the risk of bias between the studies using the Newcastle‒Ottawa Scale. We performed a two-stage random-effects dose-response meta-analysis to examine a possible nonlinear relationship between the year of HRT use and CRC mortality. Ten cohort studies with 480,628 individuals were included. HRT was inversely associated with the risk of CRC mortality (hazard ratios (HR)=0.77, 95% CI (0.68, 0.87), I2=69.5%, p<0.05). The pooled results of seven cohort studies revealed a significant association between HRT and the risk of all-cause mortality (HR=0.71, 95% CI (0.54, 0.92), I2=89.6%, p<0.05). A linear dose-response analysis (p for nonlinearity=0.34) showed a 3% decrease in the risk of CRC for each additional year of HRT use; this decrease was significant (HR=0.97, 95% CI (0.94, 0.99), p<0.05). An additional linear (p for nonlinearity=0.88) dose-response analysis showed a nonsignificant decrease in the risk of all-cause mortality for each additional year of HRT use. This study suggests that the use of HRT is inversely associated with all-cause and colorectal cancer mortality, thus causing a significant decrease in mortality rates over time. More studies are warranted to confirm this association.

Abstract MP61: Independent, Joint-Aerobic, and Dose-Response Associations of Resistance Exercise With Cardiovascular Disease Mortality: A Living Meta-Analysis

Introduction: Cardiovascular diseases (CVDs) account for ~33% of all deaths globally. Aerobic exercise (AE) is a well-established modifiable risk factor for lowering the risk of CVD mortality, but the global prevalence of meeting the World Health Organization’s (WHO’s) recommendation for weekly AE in adults is only ~25%. Given the rapidly growing body of evidence indicating resistance exercise (RE) confers numerous health benefits independent of AE, and may also lower the risk of CVD mortality, we conducted a living meta-analysis (PROSPERO ID: CRD42022356528) to determine: 1) if RE is associated with lower CVD mortality risk independent of, and jointly with, AE; and 2) whether there is a dose-response pattern of CVD mortality by amount of RE. Methods: We searched MEDLINE, Embase, SPORTDiscus, The Cochrane Library, and SCOPUS from inception to October 10, 2023. We included prospective cohort studies in which: 1) AE and RE were the exposures and CVD mortality the outcome; and 2) nonclinical adult populations (aged ≥18 years) were sampled. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were pooled using random effects meta-analysis models. The independent effect of RE from AE was based on models with AE as a covariate. A random effects dose-response meta-analysis characterized the association between the RE dose (sessions/week) and CVD mortality risk. Results: Ten cohort studies from 5 countries (Mean follow-up time = 10.1 years) were included (9, 8, and 5 examined independent, joint, and dose-response associations, respectively). Relative to no RE, meeting the WHO guideline for RE (1-2 sessions/week), independent of meeting the AE guideline (≥150 minutes/week at moderate to vigorous intensities), was associated with a lower risk of CVD mortality (HR: 0.90, 95% CI: 0.85-0.95). A sensitivity analysis removing a highly weighted study (53%) yielded consistent results. Compared to meeting neither guideline, meeting the joint AE-RE guideline was associated with a larger difference in CVD mortality risk (HR: 0.60, 95% CI: 0.45-0.81). The dose-response meta-analysis showed evidence of a non-linear, U-shaped relationship between the amount of RE (independent of AE) and risk of CVD mortality. In detail, relative to no RE, participating in 1-2 sessions/week of RE was associated with a lower risk of CVD mortality (HR: 0.81; 95% CI: 0.72, 0.91), but there was no difference in CVD mortality risk between those who exceeded the guideline and those who participated in no RE (HR: 1.00, 95% CI: 0.89, 1.12). Conclusion: With the increasing global prevalence of obesity and physical inactivity, RE—a more movement-varied, lower-impact exercise modality—should receive more attention in public health policy to help alleviate the global burden of CVD mortality. Public health surveillance instruments capturing RE volume (sets, repetitions) are needed to improve prescription.

The origin of vitamin B12 levels and risk of all-cause, cardiovascular and cancer specific mortality: A systematic review and dose-response meta-analysis

BackgroundVitamin B12 is essential to human but the implications of serum vitamin B12 level for mortality in clinical practice remain unclear. We conducted a systematic review and dose-response meta-analysis to quantify the relationship between vitamin B12 levels and the risk of all-cause, cardiovascular, and cancer mortality. MethodsElectronic databases of PubMed, Embase, and the Cochrane Library Central Register of Controlled Trials were searched from inception through May 2023. Two reviewers independently extracted individual study data and evaluated the risk of bias among the studies using the Newcastle‒Ottawa Scale. To examine a potential nonlinear relationship between the vitamin B12 levels and all-cause mortality, we performed a two-stage random effects dose‒response meta-analysis. ResultsTwenty-two cohort studies (92,346 individuals with 10,704 all-cause deaths) were included. A linear trend dose-response analysis showed that each 100 pmol/L increase in serum vitamin B12 concentration was associated with a 4 % higher risk of all-cause mortality in the general population (adjusted HR 1.04, 95 % confidence interval CI 1.01 to 1.08; n = 8; P non-linearity = 0.11) and a 6 % higher risk for all-cause mortality in older adults (adjusted HR 1.06, 95 % CI 1.01 to 1.13; n = 4; P non-linearity = 0.78). Current evidence was mixed for the association between serum vitamin B12 concentration and cardiovascular mortality and was limited for cancer mortality. The meta-analysis of cohort studies showed a positive association between a high serum vitamin B12 concentration (>600 pmol/L) and all-cause mortality (adjusted HR 1.50, 95 % CI 1.29 to 1.74; n = 10; p < 0.01), CVD mortality (adjusted HR 2.04, 95 % CI 0.99 to 4.19; n = 2; p = 0.02), except cancer mortality (adjusted HR 1.56, 95 % CI 0.82 to 2.95; n = 3). Similarly, serum vitamin B12 concentrations (400–600 pmol/L) were associated with increased all-cause mortality (adjusted HR 1.34, 95 % CI 1.10 to 1.64; n = 9; p < 0.01). ConclusionsSerum vitamin B12 concentration was positively associated with the risk of all-cause mortality, especially among older adults, with a linear increasing trend. These findings suggested the primary cause of elevated level of serum vitamin B12 concentration should be timely identified and effectively managed in clinical practice.

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough

Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough. MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023. Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID). Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events. Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]). Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects

BackgroundThe follow-up effect after acute repetitive transcranial magnetic stimulation (rTMS) for major depressive episodes remains unclear. Furthermore, the benefits of maintenance rTMS are poorly understood. AimTo investigate the trajectory of changes in depressive symptoms after acute rTMS and effects of maintenance rTMS during this period. MethodThis meta-analysis (PROSPERO: CRD42022374077) searched major databases up to October 1, 2022. Treatment outcome was depressive scores collected at least 3 months after the end of an acute rTMS course for depression. We extracted data at different time points after acute rTMS and categorized by whether maintenance rTMS was performed. A single-stage random-effects dose-response meta-analysis was undertaken to model the nonlinear relationships. Effect sizes were calculated as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results24 eligible studies comprising 911 total patients—225 of whom received maintenance rTMS—were included. Maintenance rTMS contributed to relative stability in patients' mood symptoms during the first 5 months (SMD [95% CI]: 3rd month, −0.10 [−0.30 to 0.10]; 5th month, 0.00 [−0.55 to 0.55]), with heterogeneity characterized as low to moderate. Further analysis revealed that maintenance rTMS performed monthly or more frequently provided sustained benefits for up to 6–12 months. Conversely, patients without maintenance rTMS had moderate to high heterogeneity, although the change in mean mood symptom scores during the 12-month follow-up was also minor (6th month, 0.03 [−0.51 to 0.56]; 12th month, 0.10 [−0.59 to 0.79]). ConclusionMaintenance rTMS might keep patients' mood relatively stable for up to 5 months after acute rTMS. Monthly or more frequent maintenance rTMS offers greater benefits.

Mobility and balance rehabilitation in multiple sclerosis: A systematic review and dose-response meta-analysis.

To assess the benefits of neurological rehabilitation and the dose-response relationship for the treatment of mobility and balance in multiple sclerosis. We included studies investigating the effects of neurological rehabilitation on mobility and balance with the following eligibility criteria for inclusion: Population, People with Multiple Sclerosis (PwMS); Intervention, method of rehabilitation interventions; Comparison, experimental (specific balance intervention) vs control (no intervention/no specific balance intervention); Outcome, balance clinical scales; Study Design, randomised controlled trials. We conducted a random effects dose-response meta-analysis to assess linear trend estimations and a one stage linear mixed effects meta-regression for estimating dose-response curves. We retrieved 196 studies from a list of 5020 for full text review and 71 studies (n subjects=3306) were included. One study was a cross-over and 70 studies were randomized controlled trials and the mean sample size per study was 46.5±28.6 (mean±SD) with a mean age of 48.3±7.8years, disease duration of 11.6±6.1years, and EDSS of 4.4±1.4points. Twenty-nine studies (40.8%) had the balance outcome as the primary outcome, while 42 studies (59.1%) had balance as secondary outcome or did not specify primary and secondary outcomes. Thirty-three trials (46.5%) had no active intervention as comparator and 38 trials (53.5%) had an active control group. Individual level data from 20 studies (n subjects=1016) were analyzed showing a medium pooled effect size for balance interventions (SMD=0.41; 95% CIs 0.22 to 0.59). Moreover, we analyzed 14 studies (n subjects=696) having balance as primary outcome and BBS as primary endpoint yielding a mean difference of 3.58 points (95% CIs 1.79 to 5.38, p<0.0001). Finally, we performed meta regression of the 20 studies showing an association between better outcome, log of intensity defined as minutes per session (β=1.26; SEβ=0.51; p=0.02) and task-oriented intervention (β=0.38; SEβ=0.17; p=0.05). Our analyses provide level 1 evidence on the effect of balance intervention to improve mobility. Furthermore, according to principles of neurological rehabilitation, high intensity and task-specific interventions are associated with better treatment outcomes.

Investigation of the Utility of Multivariate Meta-Analysis Methods in Estimating the Summary Dose Response Curve.

Traditional meta-analyses often assess the effectiveness of different doses of the same intervention separately or examine the overall differences between intervention and placebo groups. The present study aimed to model the effect sizes obtained from different doses in multiple studies using a two-stage dose-response meta-analytic approach while taking dose variations into account. Different dose-response meta-analysis models using linear, quadratic, and restricted cubic spline (RCS) functions were fitted. A two-stage approach utilizing multivariate meta-analysis was performed and the obtained results were compared with those of the univariate meta-analysis. A random effect dose-response meta-analysis was performed using data from an existing systematic review on combination therapy with zonisamide and anti-Parkinson drugs for Parkinson's disease. The effective or optimum dose for producing maximum response was also investigated. Moreover, a sensitivity analysis was performed by changing the knots of the RCS model. Dose-response meta-analysis was performed using data from four double-blinded randomized controlled trials with 724 and 309 patients with Parkinson's disease in dose and placebo arms, respectively. The quadratic model yielded the smallest Akaike information criterion (AIC), compared to the linear and RCS models, indicating it to be the best fit for the data. Compared to the traditional approach, the two-stage approach could model the dose-dependent effect of zonisamide on the Unified Parkinson's Disease Rating Scale (UPRDS) part III score and predict the outcome for different doses through a single analysis.

Dietary Potassium Intake and Risk of Diabetes: A Systematic Review and Meta-Analysis of Prospective Studies.

(1) Background: Dietary potassium intake is positively associated with reduction of cardiovascular risk. Several data are available on the relationship between dietary potassium intake, diabetes risk and glucose metabolism, but with inconsistent results. Therefore, we performed a meta-analysis of the prospective studies that explored the effect of dietary potassium intake on the risk of diabetes to overcome these limitations. (2) Methods: A random-effects dose-response meta-analysis was carried out for prospective studies. A potential non-linear relation was investigated using restricted cubic splines. (3) Results: A total of seven prospective studies met the inclusion criteria. Dose-response analysis detected a non-linear relationship between dietary potassium intake and diabetes risk, with significant inverse association starting from 2900 mg/day by questionnaire and between 2000 and 5000 mg/day by urinary excretion. There was high heterogeneity among studies, but no evidence of publication bias was found. (4) Conclusions: The results of this meta-analysis indicate that habitual dietary potassium consumption is associated with risk of diabetes by a non-linear dose-response relationship. The beneficial threshold found supports the campaigns in favour of an increase in dietary potassium intake to reduce the risk of morbidity and mortality. Further studies should be carried out to explore this topic.

Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized trials.

ObjectiveTo examine the dose-dependent influence of oral alpha-lipoic acid (ALA) supplementation on cardiometabolic risk factors in patients with type 2 diabetes (T2D).DesignWe followed the instructions outlined in the Cochrane Handbook for Systematic Reviews of Interventions and the Grading of Recommendations, Assessment, Development, and Evaluation Handbook to conduct our systematic review. The protocol of the study was registered in PROSPERO (CRD42021260587).MethodWe searched PubMed, Scopus, and Web of Science to May 2021 for trials of oral ALA supplementation in adults with T2D. The primary outcomes were HbA1c, weight loss, and LDL cholesterol (LDL-C). Secondary outcomes included fasting plasma glucose (FPG), triglyceride (TG), C-reactive protein (CRP), and blood pressure. We conducted a random-effects dose–response meta-analysis to calculate the mean difference (MD) and 95% CI for each 500 mg/day oral ALA supplementation. We performed a nonlinear dose–response meta-analysis using a restricted cubic spline.ResultsWe included 16 trials with 1035 patients. Each 500 mg/day increase in oral ALA supplementation significantly reduced HbA1c, body weight, CRP, FPG, and TG. Dose–response meta-analyses indicated a linear decrement in body weight at ALA supplementation of more than 600 mg/day (MD600 mg/day: −0.30 kg, 95% CI: −0.04, −0.57). A relatively J-shaped effect was seen for HbA1c (MD: −0.32%, 95% CI: −0.45, −0.18). Levels of FPG and LDL-C decreased up to 600 mg/day ALA intake. The point estimates were below minimal clinically important difference thresholds for all outcomes.ConclusionDespite significant improvements, the effects of oral ALA supplementation on cardiometabolic risk factors in patients with T2D were not clinically important.

Association Between Physical Activity and Risk of Depression

Depression is the leading cause of mental health-related disease burden and may be reduced by physical activity, but the dose-response relationship between activity and depression is uncertain. To systematically review and meta-analyze the dose-response association between physical activity and incident depression from published prospective studies of adults. PubMed, SCOPUS, Web of Science, PsycINFO, and the reference lists of systematic reviews retrieved by a systematic search up to December 11, 2020, with no language limits. The date of the search was November 12, 2020. We included prospective cohort studies reporting physical activity at 3 or more exposure levels and risk estimates for depression with 3000 or more adults and 3 years or longer of follow-up. Data extraction was completed independently by 2 extractors and cross-checked for errors. A 2-stage random-effects dose-response meta-analysis was used to synthesize data. Study-specific associations were estimated using generalized least-squares regression and the pooled association was estimated by combining the study-specific coefficients using restricted maximum likelihood. The outcome of interest was depression, including (1) presence of major depressive disorder indicated by self-report of physician diagnosis, registry data, or diagnostic interviews and (2) elevated depressive symptoms established using validated cutoffs for a depressive screening instrument. Fifteen studies comprising 191 130 participants and 2 110 588 person-years were included. An inverse curvilinear dose-response association between physical activity and depression was observed, with steeper association gradients at lower activity volumes; heterogeneity was large and significant (I2 = 74%; P < .001). Relative to adults not reporting any activity, those accumulating half the recommended volume of physical activity (4.4 marginal metabolic equivalent task hours per week [mMET-h/wk]) had 18% (95% CI, 13%-23%) lower risk of depression. Adults accumulating the recommended volume of 8.8 mMET hours per week had 25% (95% CI, 18%-32%) lower risk with diminishing potential benefits and higher uncertainty observed beyond that exposure level. There were diminishing additional potential benefits and greater uncertainty at higher volumes of physical activity. Based on an estimate of exposure prevalences among included cohorts, if less active adults had achieved the current physical activity recommendations, 11.5% (95% CI, 7.7%-15.4%) of depression cases could have been prevented. This systematic review and meta-analysis of associations between physical activity and depression suggests significant mental health benefits from being physically active, even at levels below the public health recommendations. Health practitioners should therefore encourage any increase in physical activity to improve mental health.

Dose-Dependent Effect of Supervised Aerobic Exercise on HbA1c in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials.

Previous meta-analyses indicated that aerobic exercise can improve glycemic control. However, the optimum dose of exercise is still being discussed. The aim of this study was to examine the dose-dependent effect of supervised aerobic training (SAT) on glycated hemoglobin (HbA1c). We searched PubMed, Scopus, and Web of Science to May 2021 for randomized trials with an intervention period of 12weeks or longer evaluating the effect of SAT on HbA1c in adults with type 2 diabetes mellitus. Secondary outcomes included quality of life, change in hypoglycemic medications, and adverse events. A random-effects dose-response meta-analysis was conducted. The analysis of 26 trials with 1253 participants indicated that each 30-min/week SAT reduced HbA1c by - 0.22 percentage point (95% CI - 0.29 to - 0.15; GRADE = strong). Levels of HbA1c decreased proportionally with the increase in the duration of moderate to vigorous-intensity SAT to 100min/week (mean difference100min/week: - 0.96 percentage point, 95% CI - 1.25 to - 0.67), with flattening of the curve at higher duration. Aerobic exercise decreased antidiabetic medications by 13 per 100 patients (risk difference 0.13, 95% CI 0.02-0.23; 7 trials, n = 375; GRADE = moderate), and increased hypoglycemic reactions by 10 per 100 patients (risk difference: 0.10, 95% CI 0.03-0.17; 4 trials, n = 263; GRADE = low) and adverse events by 4 per 100 patients (risk difference: 0.04, 95% CI - 0.02 to 0.11; 2 trials, n = 236; GRADE = low). Limited evidence is available for quality of life. Every 30min/week of moderate to vigorous aerobic exercise can exert a significant effect on HbA1c, with the highest effect observed from 100min/week and above. However, exercise durations above 100min/week seem ineffective for further reductions. PROSPERO (CRD42021257251).

Mediterranean dietary pattern and bone mineral density: a systematic review and dose-response meta-analysis of observational studies.

We aimed to systematically review the literature and test the dose-response relationship between adherence to the Mediterranean diet (MedDiet) and values of bone mineral density (BMD) in adults. Relevant observational studies were selected through searching PubMed, Scopus, and Web of Science databases up to March 4, 2021. A random-effects dose-response meta-analysis was performed to estimate the change in total and regional-specific BMD for a 2-point increment in the score of adherence to the MedDiet, and to clarify the shape of these associations. Seven cross-sectional and one cohort studies with a total number of 13,209 participants were included in the final analyses. Each 2-point increment in the score of adherence to the MedDiet was associated with 0.009 (95% CI: 0.002, 0.016; I2 = 34%, n = 7), 0.006 (95% CI: 0.001, 0.012; I2 = 34%, n = 7), 0.005 (95% CI: 0.003, 0.007; I2 = 1%, n = 4), 0.005 (95% CI: 0.002, 0.008; I2 = 0%, n = 3), and 0.007 (95% CI: 0.005, 0.009; I2 = 0%, n = 4) gr/cm2 higher BMD of lumbar spine, femoral neck, hip, trochanter, and whole body, respectively. There was a positive linear relationship between the MedDiet adherence score and BMD of hip and trochanter. A nonlinear relationship was seen for lumbar spine, femoral neck, and whole body, with sharper increase in the BMD at lower MedDiet scores. The associations remained significant after controlling for important confounders including body weight, physical activity, smoking status, and energy intake. Greater adherence to the MedDiet was associated with a small but important increase in BMD at the lumbar spine, femoral neck, hip, trochanter, and whole body. Adopting a Mediterranean-style eating pattern may have modest beneficial effects on bone health.

Dietary carbohydrate and the risk of type 2 diabetes: an updated systematic review and dose\u2013response meta-analysis of prospective cohort studies

We did this study to clarify the association between carbohydrate intake and the risk of type 2 diabetes (T2D) and potential effect modification by geographical location. PubMed, Scopus and Web of Science were searched to find prospective cohort studies of dietary carbohydrate intake and T2D risk. A random-effects dose–response meta-analysis was performed to calculate the summary hazard ratios (HRs) and 95%CIs. The quality of cohort studies and the certainty of evidence was rated using the Newcastle–Ottawa Scale and GRADE tool, respectively. Eighteen prospective cohort studies with 29,229 cases among 607,882 participants were included. Thirteen studies were rated to have high quality, and five as moderate quality. The HR for the highest compared with the lowest category of carbohydrate intake was 1.02 (95%CI: 0.91, 1.15; I2 = 67%, GRADE = low certainty). The HRs were 0.93 (95%CI: 0.82, 1.05; I2 = 58%, n = 7) and 1.26 (95%CI: 1.11, 1.44; I2 = 6%, n = 6) in Western and Asian countries, respectively. Dose–response analysis indicated a J shaped association, with the lowest risk at 50% carbohydrate intake (HR50%: 0.95, 95%CI: 0.90, 0.99) and with risk increasing significantly at 70% carbohydrate intake (HR70%: 1.18, 95%CI: 1.03, 1.35). There was no association between low carbohydrate diet score and the risk of T2D (HR: 1.14, 95%CI: 0.89, 1.47; I2 = 90%, n = 5). Carbohydrate intake within the recommended 45–65% of calorie intake was not associated with an increased risk of T2D. Carbohydrate intake more than 70% calorie intake might be associated with a higher risk.

The J-Shaped Relationship Between Body Mass Index and Mortality in Patients With Covid-19: A Systematic Review and Dose-Response Meta-Analysis

Introduction: Several studies have linked obesity to more severe illness and higher mortality in COVID-19 patients. However, the relationship between being underweight and COVID-19 mortality remains inconclusive. Previous dose-response meta-analyses did not enroll or specifically analyze the underweight population. Herein, we conducted a systematic review and dose-response meta-analysis to investigate the relationship between body mass index (BMI) and mortality in both obese and underweight patients with COVID-19. Methods: We searched PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases from inception until August 12, 2020 using the keywords “COVID-19,” “body mass index,” “obesity,” “overweight”, and “underweight.” Three reviewers independently assessed the relevant articles, including the title, abstract, and full text, to identify eligible studies. We performed a two-stage random-effects dose-response meta-analysis, including only studies with at least three quantitative classifications for BMI. The nonlinear trend was evaluated using a restricted cubic splines model with three-knots at the 10th, 50th, and 90th percentiles. A sensitivity analysis was conducted by pooling only those studies which specifically evaluated underweight patients (BMI<18.5 kg/m2). Results: Thirteen studies comprising 25,828 patients were included in the analysis. In the linear model, the mortality of patients with COVID-19 increased by 1.5% for each 1-kg/m2 increase in BMI (pooled relative risk [RR] =1.015, 95% confidence interval [CI] =1.004−1.027). However, a significant non-linear relationship between BMI and mortality was observed (Wald test: Pnon-linearity<0.001). We demonstrated a J-shaped curve, indicating that both underweight and obese patients had a higher mortality than those with normal weight. Interestingly, overweight patients (BMI, 25−30 kg/m2) seemed to have the lowest mortality risk. Using a BMI of 15 kg/m2 as the reference, the RRs of mortality decreased with BMI, and this trend continued until BMI of approximately 28 kg/m2 (RR=0.743, 95% CI=0.576−0.959). The relationship between BMI and mortality was then reversed, and an upward trend was observed when BMI exceeded 30 kg/m2; the RRs (95% CI) at BMIs 30, 35, 40, and 45 kg/m2 were 0.745 (0.570−0.974), 0.841 (0.643−1.100), 1.082 (0.850−1.377), and 1.457 (1.129−1.879), respectively. Conclusion: This study is the first dose-response meta-analysis that showed both underweight and obese COVID-19 patients are at higher risk of increased mortality. A J-curve relationship was demonstrated between BMI and COVID-19 mortality.

Storage Time of Cryopreserved Embryos and Pregnancy Outcomes: A Dose-Response Meta-Analysis.

Purpose Cryopreservation techniques have become an essential part of assisted reproduction technology. Embryos may be cryopreserved for several years before transfer, and the safety of long-term cryopreservation needs to be considered. This dose-response meta-analysis was conducted to evaluate whether there were dose-response relationships between the storage time of cryopreserved embryos and pregnancy outcomes such as survival rate, implantation rate, miscarriage rate, clinical pregnancy rate, and congenital malformation rate. Methods After searching the databases PubMed, Embase, MEDLINE, CCRT and related reviews up until June 4, 2020, seven studies were included for analysis. Two reviewers extracted the relevant information and independently assessed the study quality using the Newcastle-Ottawa scale. Potential linear or non-linear dose-response relationships were assessed with a random-effect dose-response meta-analysis. Results No dose-response association was found between duration of embryo cryostorage and survival rate, implantation rate, miscarriage rate, clinical pregnancy rate or congenital malformation rate. Conclusion The interval between the start of embryo cryopreservation and frozen/thawed embryo transfer does not influence pregnancy outcomes.

Impact of Body Mass Index on the Development of Inflammatory Bowel Disease: A Systematic Review and Dose-Response Analysis of 15.6 Million Participants.

Background: A growing trove of literature describes the effect of malnutrition and underweight on the incidence of inflammatory bowel disease (IBD). However, evidence regarding the association between underweight or obesity and IBD is limited. The study aimed to assess the association of body mass index (BMI) with a risk of IBD (Crohn’s disease (CD) and ulcerative colitis (U.C.)) incidence. Methods: We systematically searched PubMed/Medline, Cochrane, Web of Science, and Scopus for observational studies assessing the association between BMI and IBD that were published up to 30 June 2020. We estimated pooled hazard ratios (HR) with corresponding 95% confidence intervals (CI). Random effect dose-response meta-analysis was performed using the variance weighted least-squares regression (VWLS) models to identify non-linear associations. Results: A total of ten studies involving 15.6 million individuals and 23,371 cases of IBD were included. Overall, obesity was associated with an increased IBD risk (HR: 1.20, 95% CI: 1.08–1.34, I2 = 0%). Compared to normal weight, underweight (BMI < 18.5 kg/m2) and obesity (BMI ≥ 30 kg/m2) were associated with a higher risk of CD, and there was no difference in the risk of U.C. among those with BMI < 18.5 kg/m2 and BMI ≥ 30 kg/m2. There was a significant non-linear association between being underweight and obesity and the risk of development of CD (Coef1 = −0.0902, p1 < 0.001 Coef2 = 0.0713, p2 < 0.001). Conclusions: Obesity increases the risk of IBD development. Underweight and obesity are independently associated with an increased risk of CD, yet there is no evident association between BMI and the risk of U.C. Further studies are needed to clarify the underlying mechanism for these findings, particularly in CD.

High admission blood glucose independently predicts poor prognosis in COVID-19 patients: A systematic review and dose-response meta-analysis

AimsTo investigate the prognostic value of admission blood glucose (BG) in predicting COVID-19 outcomes, including poor composite outcomes (mortality/severity), mortality, and severity. MethodsEligible studies evaluating the association between admission fasting BG (FBG) and random BG (RBG) levels with COVID-19 outcomes were included and assessed for risk of bias with the Quality in Prognosis Studies tool. Random-effects dose-response meta-analysis was conducted to investigate potential linear or non-linear exposure-response gradient. ResultsThe search yielded 35 studies involving a total of 14,502 patients. We discovered independent association between admission FBG and poor COVID-19 prognosis. Furthermore, we demonstrated non-linear relationship between admission FBG and severity (Pnon-linearity < 0.001), where each 1 mmol/L increase augmented the risk of severity by 33% (risk ratio 1.33 [95% CI: 1.26–1.40]). Albeit exhibiting similar trends, study scarcity limited the evidence strength on the independent prognostic value of admission RBG. GRADE assessment yielded high-quality evidence for the association between admission FBG and COVID-19 severity, and moderate-quality evidence for its association with mortality and poor outcomes. ConclusionHigh admission FBG level independently predicted poor COVID-19 prognosis. Further research to confirm the prognostic value of admission RBG and to ascertain the estimated dose-response risk between admission FBG and COVID-19 severity are required.

Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies

ObjectiveTo quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index,...