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Systematic reviews and meta-analyses are methods increasingly used in biomedical research since their introduction in the 1970s. They serve to replace other non-systematic and cherry-picked narrative reviews, which are highly variable in their approach, structure and content. Their increase in popularity parallels the increase in overall scientific output, and when properly conducted, systematic reviews can contribute highly impactful summaries of a fast-growing evidence base. Meta-analyses offer statistical summaries, called forest plots, which similarly provide a powerful synopsis unachievable by individual studies. Thus, it is not difficult to imagine why systematic reviews are published more often. Should scientists be concerned by the accelerated output of research, from systematic reviews or other? If quantity comes at the expense of quality, then yes, of course; but should important manuscripts be rationed out otherwise? A new scientific technique can seem scary at first, especially to the researcher who is unfamiliar with its application or uncertain of its validity. In that case, we should become familiar with new and popular methods, and understand their strengths and limitations. There is a rightful place for systematic reviews and meta-analyses among respectable research tools. Importantly, however, despite standard operating procedures and best practices, the quality of systematic reviews today is highly variable, warranting serious concerns for quantity exceeding quality. Therefore, the appropriate response should be to instil researchers with an appreciation for the complexity of conducting and interpreting a systematic review and meta-analysis, to create more knowledgeable authors, reviewers and editors, who collectively will improve, rather than dismiss, these important scientific contributions.

Dietary diversity scores (DDS) are considered as metrics for monitoring the implementation of the UN's Sustainable Development Goals, but they need to be rigorously evaluated. To examine two DDS, the Food Groups Index (FGI), and the Minimum Dietary Diversity-Women (MDD-W), alongside two dietary quality scores, the Alternate Healthy Eating Index (AHEI-2010) and the Prime Diet Quality Score (PDQS), with risks of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDPs). The analysis included 21,312 (GDM) and 19,917 (HDPs) singleton births reported in the Nurses' Health Study II cohort (1991-2001), among women without major chronic disease or GDM/HDPs. Scores were derived using prepregnancy diet collected by a comprehensive food frequency questionnaire. Multivariable models were utilized to calculate relative risks (RR) and confidence intervals (95%CIs). Incident GDM (n = 916) and HDPs (n = 1,421) were reported. The MDD-W and FGI were not associated with risk of GDM or HDPs, but the AHEI-2010 and PDQS were associated with a lower risk of GDM and marginally lower risk of HDP. The RR's of GDM comparing the highest vs. lowest quintiles were 1.00 (95%CI: 0.79, 1.27; p-trend = 0.82) for MDD-W, 0.96 (95%CI: 0.76, 1.22; p-trend = 0.88) for FGI, 0.63 (95%CI: 0.50, 0.81; p-trend <0.0001) for the AHEI-2010 and 0.68 (95%CI: 0.54, 0.86; p-trend = 0.003) for the PDQS. Similarly, the RR's of HDPs were 0.92 (95%CI: 0.75, 1.12, p-trend = 0.94) for MDD-W, 0.97 (95%CI: 0.79, 1.17; p-trend = 0.83) for FGI, 0.84 (95%CI: 0.70, 1.02; p-trend = 0.07) for AHEI-2010 and 0.89 (95%CI: 0.74, 1.09; p-trend = 0.07) for PDQS. MDD-W and FGI did not predict the risk of GDM and HDPs. These DDS should not be widely used as metrics for achieving dietary goals in their present form. The Prime Diet Quality Score warrants further testing as a promising measure of a sustainable and healthy diet on a global scale.

Experimental studies reported biochemical actions underpinning aging processes and mortality, but the relevant metabolic alterations in humans are not well understood. Here we examine the associations of 243 plasma metabolites with mortality and longevity (attaining age 85 years) in 11,634 US (median follow-up of 22.6 years, with 4288 deaths) and 1878 Spanish participants (median follow-up of 14.5 years, with 525 deaths). We find that, higher levels of N2,N2-dimethylguanosine, pseudouridine, N4-acetylcytidine, 4-acetamidobutanoic acid, N1-acetylspermidine, and lipids with fewer double bonds are associated with increased risk of all-cause mortality and reduced odds of longevity; whereas L-serine and lipids with more double bonds are associated with lower mortality risk and a higher likelihood of longevity. We further develop a multi-metabolite profile score that is associated with higher mortality risk. Our findings suggest that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality. The underlying mechanisms remain to be determined. The metabolic alterations underpinning aging processes and mortality in humans are not well understood. Here, the authors show that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality and longevity.

Observational and experimental evidence suggests that vitamin D plays a role in type 2 diabetes (T2D). However, prior randomized supplementation trials are limited to high-risk patients with prediabetes. Here we aim to evaluate whether vitamin D supplementation reduces risk of T2D in a general population of older US adults. The study design is an ancillary analysis (VITAL-T2D) of The Vitamin D and Omega-3 Trial (VITAL), a completed randomized, double-blind, placebo-controlled 2 × 2 trial of daily vitamin D 3 (cholecalciferol; 2000 IU/day) and omega-3 fatty acids (1 g/day) for the primary prevention of cancer and cardiovascular disease. We also conducted a systematic review and meta-analysis of vitamin D trial (≥1000 IU/d cholecalciferol) vs. placebo and T2D risk. We analyzed 22,220 adults with mean age 67.2 years (SD = 7.1) without T2D at enrollment (2011 to 2014), randomized to vitamin D 3 or placebo. Mean body mass index (BMI) was 27.5 kg/m 2 (SD = 5.3), with 51% female and 17% Black race/ethnicity. A subcohort ( n  = 911) attended in-person visits at baseline and 2 years for glycemic trait analyses. Our meta-analysis included 3 additional trials (5205 participants; 936 T2D cases). The primary outcome for the VITAL-T2D is intention-to-treat effect of vitamin D vs. placebo for incident T2D. T2D incidence (cases/1000py) at median follow-up of 5.3 y was 3.98 for vitamin D and 4.37 for placebo (hazard ratio [HR] = 0.91; 95% confidence interval [CI] = 0.76, 1.09). Results did not differ by age, sex, BMI, or baseline 25-hydroxyvitamin D, and vitamin D had no effect on glycemic traits at 2 years. Meta-analysis of 4 trials ( n  = 5205; 936 T2D cases) obtained HR = 0.89 (CI = 0.80, 0.99). In conclusion, Vitamin D supplementation did not reduce T2D in older US adults, but a modest reduction was observed when meta-analyzed with prior trials. Trial Registration : ClinicalTrials.gov #NCT01633177. Systematic Review Registration : PROSPERO #CRD42019147562. Observational and experimental evidence suggests that vitamin D plays a role in glycemic control. Here, the authors report that in an ancillary study of the placebo-controlled randomized VITAL trial there is no effect of 2000 IU/day of vitamin D supplementation over 5 years on the prevention of type 2 diabetes in 22,220 older US adults.

Backgroud Gestational diabetes mellitus (GDM) is associated with various short-term and long-term adverse health outcomes for both mothers and offspring. It is critical to identify modifiable factors that may inform the prevention of GDM. We, therefore, examined whether pre-pregnancy pro-inflammatory and hyperinsulinemic dietary patterns are associated with increased risk of GDM. Methods We included 14,674 women in the Nurses’ Health Study II who reported at least one singleton pregnancy between 1991 and 2001. We derived pre-pregnancy dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) from validated food frequency questionnaires collected before pregnancy. Incident first-time GDM was ascertained from self-report of a physician diagnosis with high validity. We used log-binomial models with generalized estimating equations to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the associations of pre-pregnancy EDIP and EDIH scores with GDM risk, adjusting for pre-pregnancy body mass index and other potential confounders. Results Participants reported 20,337 pregnancies over 10 years of follow-up, with 831 complicated by GDM. Women with higher pre-pregnancy EDIP and EDIH scores had a greater risk of GDM: adjusted RRs (95% CIs) for EDIP increasing quintiles were 1.00 (reference), 1.22 (0.97, 1.53), 1.19 (0.94, 1.49), 1.40 (1.13, 1.75), and 1.41 (1.13, 1.75); for EDIH were 1.00, 1.19 (0.94, 1.52), 1.21 (0.95, 1.54), 1.29 (1.02, 1.64), and 1.58 (1.26, 1.98) (both P -trend: <0.001). The observed associations were generally consistent across stratum of major risk factors of GDM such as pre-pregnancy overweight or obesity status, family history of diabetes, and genetic susceptibility of GDM. Conclusions In a large US cohort of predominantly White women, higher intake of pro-inflammatory and hyperinsulinemic diets was associated with increased risk of GDM. Further studies are warranted to confirm our findings, to provide evidence promoting anti-inflammatory and anti-hyperinsulinemic diets as a preventive measure for gestational diabetes in women planning pregnancy.

Objectives To prospectively assess the joint association of birth weight and established lifestyle risk factors in adulthood with incident type 2 diabetes and to quantitatively decompose the attributing effects to birth weight only, to adulthood lifestyle only, and to their interaction.Design Prospective cohort study.Setting Health Professionals Follow-up Study (1986-2010), Nurses’ Health Study (1980-2010), and Nurses’ Health Study II (1991-2011).Participants 149 794 men and women without diabetes, cardiovascular disease, or cancer at baseline.Main outcome measure Incident cases of type 2 diabetes, identified through self report and validated by a supplementary questionnaire. Unhealthy lifestyle was defined on the basis of body mass index, smoking, physical activity, alcohol consumption, and the alternate healthy eating index.Results During 20-30 years of follow-up, 11 709 new cases of type 2 diabetes were documented. The multivariate adjusted relative risk of type 2 diabetes was 1.45 (95% confidence interval 1.32 to 1.59) per kg lower birth weight and 2.10 (1.71 to 2.58) per unhealthy lifestyle factor. The relative risk of type 2 diabetes associated with a combination of per kg lower birth weight and per unhealthy lifestyle factor was 2.86 (2.26 to 3.63), which was more than the addition of the risk associated with each individual factor, indicating a significant interaction on an additive scale (P for interaction<0.001). The attributable proportions of joint effect were 22% (95% confidence interval 18.3% to 26.4%) to lower birth weight alone, 59% (57.1% to 61.5%) to unhealthy lifestyle alone, and 18% (13.9% to 21.3%) to their interaction.Conclusion Most cases of type 2 diabetes could be prevented by the adoption of a healthier lifestyle, but simultaneous improvement of both prenatal and postnatal factors could further prevent additional cases.

Obesity is a risk factor for > 13 cancer sites, although it is unknown whether there is a common mechanism across sites. Evidence suggests a role for impaired branched-chain amino acid (BCAAs; isoleucine, leucine, valine) metabolism in obesity, insulin resistance, and immunity; thus, we hypothesized circulating BCAAs may be associated with incident obesity-related cancers. We analyzed participants in the prospective Women’s Health Study without a history of cancer at baseline blood collection (N = 26,711, mean age = 54.6 years [SD = 7.1]). BCAAs were quantified via NMR spectroscopy, log-transformed, and standardized. We used Cox proportional regression models adjusted for age, race, smoking, diet, alcohol, physical activity, menopausal hormone use, Body Mass Index (BMI), diabetes, and other risk factors. The endpoint was a composite of obesity-related cancers, defined per the International Agency for Research on Cancer 2016 report, over a median 24 years follow-up. Baseline BMI ≥ 30 kg/m 2 compared with BMI 18.5–25.0 kg/m 2 was associated with 23% greater risk of obesity-related cancers (n = 2751 events; multivariable HR 1.23, 95% CI 1.11–1.37). However, BCAAs were not associated with obesity-related cancers (multivariable HR per SD = 1.01 [0.97–1.05]). Results for individual BCAA metabolites suggested a modest association for leucine with obesity-related cancers (1.04 [1.00–1.08]), and no association for isoleucine or valine (0.99 [0.95–1.03] and 1.00 [0.96–1.04], respectively). Exploratory analyses of BCAAs with individual sites included positive associations between leucine and postmenopausal breast cancer, and isoleucine with pancreatic cancer. Total circulating BCAAs were unrelated to obesity-related cancer incidence although an association was observed for leucine with incident obesity-related cancer.

Objectives. To review the contribution of the Nurses’ Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. Methods. We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. Results. The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene–environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. Conclusions. Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes.

Abstract Context Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship. Objective To determine whether vitamin D3 supplementation lowers weight or improves body composition. Design The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention). Setting Harvard Clinical and Translational Science Center in Boston. Participants 771 participants (men ≥ 50 and women ≥ 55 years). Interventions 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day). Main Outcome Measures Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored. Results There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04). Conclusions Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study.

Healthy maternal diets during pregnancy are an important protective factor for pregnancy‐related outcomes, including gestational weight gain (GWG) and birth outcomes. We prospectively examined the associations of maternal dietary diversity and diet quality, using Minimum Dietary Diversity for Women (MDD‐W) and Prime Diet Quality Score (PDQS), with GWG and birth outcomes among women enrolled in a trial in Tanzania (n = 1190). MDD‐W and PDQS were derived from a baseline food frequency questionnaire. Women were monthly followed until delivery, during which weight was measured. GWG was classified based on the 2009 Institute of Medicine guidelines. Adverse birth outcomes were classified as low birth weight (LBW), small for gestational age, large for gestational age, and preterm birth. 46.2% participants had MDD‐W ≥ 5. Mean score of PDQS was 23.3. Maternal intakes of nuts, poultry, and eggs were low, whereas intakes of sugar‐sweetened beverages and refined grains were high. MDD‐W was not associated with GWG or birth outcomes. For PDQS, compared to the lowest tertile, women in the highest tertile had lower risk of inappropriate GWG (risk ratio [RR] = 0.93, 95% confidence interval [CI]: 0.87–1.00). Women in the middle tertile group of PDQS (RR = 0.72, 95% CI: 0.51–1.00) had lower risk of preterm birth. After excluding women with prior complications, higher PDQS was associated with lower risk of LBW (middle tertile: RR = 0.55, 95% CI: 0.31–0.99, highest tertile: RR = 0.52, 95% CI: 0.29–0.94; continuous per SD: RR = 0.77, 95% CI: 0.60–0.99). Our findings support continuing efforts to improve maternal diet quality for optimal GWG and infant outcomes among Tanzanian women. Key messages •Maternal diets are a key modifiable determinant of gestational weight gain (GWG) and birth outcomes. •We observed suboptimal intakes of healthy proteins and fats and high intakes of refined grains and sugar‐containing foods among well‐nourished pregnant women in urban Tanzania. •This study found that higher‐quality maternal diets were associated with lower risks of inappropriate GWG, low birth weight, and preterm birth. •This study supports the importance of high maternal diet quality and continuing efforts to promote well‐balanced maternal diets with avoiding both under‐ and over‐nutrition for optimal pregnancy outcomes among Tanzanian populations.