Endoscopic Ultrasound-Guided Fine-Needle Biopsy Versus Aspiration for Tissue Sampling Adequacy for Molecular Testing in Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND AIMS: There is limited literature on sample adequacy for molecular testing in pancreatic ductal adenocarcinoma obtained via endoscopic ultrasound (EUS) fine-needle aspiration (FNA) versus EUS fine-needle biopsy (FNB). We aimed to compare these two modalities regarding sample adequacy for molecular and genomic sequencing. METHODS: We reviewed all patients with pancreatic ductal adenocarcinoma who underwent EUS at Saint Luke's Hospital from 2018 to 2021. The patients were categorized based on the method of EUS tissue acquisition, specifically FNA or FNB. A comprehensive evaluation was conducted for all cases by cytotechnologists. RESULTS: Out of 132 patients who underwent EUS-guided biopsies, 76 opted for FNA, 48 opted for FNB, and 8 opted for a combination of both. The average number of passes required for FNB and FNA was 2.58 ± 1.06 and 2.49 ± 1.07, respectively (p = 0.704), indicating no significant difference. Interestingly, 71.4% (35) of FNB-obtained samples were deemed adequate for molecular testing, surpassing the 32.1% (26) adequacy observed with FNA (p < 0.001). Additionally, 46.4% (26) of FNB-obtained samples were considered adequate for genomic testing, a notable improvement over the 23.8% (20) adequacy observed with FNA (p = 0.005). CONCLUSION: Although the number of passes required for cytologic diagnosis did not differ significantly between EUS-FNB and EUS-FNA, the former demonstrated superiority in obtaining samples adequate for molecular testing. Tumor surface area and cellularity were crucial parameters in determining sample adequacy for molecular testing, irrespective of the chosen tissue acquisition modality.

Validation of a noninvasive cardiac output monitor in maternal cardiac disease: comparison of NICOM and transthoracic echocardiogram.

BACKGROUND: The physiological changes to the cardiovascular system during pregnancy are considerable and are more pronounced in those with cardiac disease. In the general population, noninvasive hemodynamic monitoring is a valid alternative to pulmonary artery catheterization, which poses risk in the pregnant population. There is limited data on noninvasive cardiac output monitoring in pregnancy as an alternative to pulmonary artery catheterization. OBJECTIVE: We sought to compare transthoracic echocardiography with a noninvasive cardiac output monitor (NICOM, Cheetah Medical) in pregnant patients with and without cardiac disease. STUDY DESIGN: This was a prospective, open-label validation study that compared 2-dimensional transthoracic echocardiography with NICOM estimations of cardiac output in each trimester of pregnancy and the postpartum period. Participants with and without cardiac disease with a singleton gestation were included. NICOM estimations of cardiac output were derived from thoracic bioreactance and compared with 2-dimensional transthoracic echocardiography for both precision and accuracy. A mean percentage difference of ±30% between the 2 devices was considered acceptable agreement between the 2 measurement techniques. RESULTS: A total of 58 subjects were enrolled; 36 did not have cardiac disease and 22 had cardiac disease. Heart rate measurements between the 2 devices were strongly correlated in both groups, whereas stroke volume and cardiac output measurements showed weak correlation. When comparing the techniques, the NICOM device overestimated cardiac output in the control group in all trimesters and the postpartum period (mean percentage differences were 50.3%, 52.7%, 48.1%, and 51.0% in the first, second, and third trimesters and the postpartum period, respectively). In the group with cardiac disease, the mean percentage differences were 31.9%, 29.7%, 19.6%, and 35.2% for the respective timepoints. CONCLUSION: The NICOM device consistently overestimated cardiac output when compared with 2-dimensional transthoracic echocardiography at all timepoints in the control group and in the first trimester and postpartum period for the cardiovascular disease group. The physiological changes of pregnancy, specifically the mean chest circumference and total body water, may alter the accuracy of the cardiac output measurement by the NICOM device as they are currently estimated. Although NICOM has been validated for use in the critical care setting, there is insufficient data to support its use in pregnancy.

Baseline Health Status and its Association With Subsequent Cardiovascular Events in Patients With Atrial Fibrillation.

BACKGROUND: Clinical practice guidelines recommend optimizing the health status of patients with atrial fibrillation (AF) as a primary treatment goal. Whether disease-specific health status is associated with subsequent clinical events is unknown. OBJECTIVES: The aim of this study was to investigate the association between health status and subsequent clinical events among patients with AF. METHODS: Using a prospective cohort study of patients with new-onset AF referred to 11 hospitals (n = 3,313, 68.4% men, mean age 67.8 ± 11.6 years), data were extracted from 3,296 patients (99.4%) who completed the disease-specific Atrial Fibrillation Effects on Quality-of-Life (AFEQT) questionnaire between 2012 and 2018. Factors associated with baseline AFEQT overall summary (OS) score and associations between major adverse cardiovascular or neurologic events (MACNE; a composite of all-cause death, stroke, or new-onset heart failure hospitalization) over 2 years were investigated. RESULTS: Overall, 517 participants (15.6%) had poor to fair health status (AFEQT OS <60), and 1,035 (31.2%) had fair to good health status (AFEQT OS 60 to <80) at baseline. Female sex, younger age, family history of AF, higher baseline heart rate, paroxysmal AF, initial visit to the emergency department, and history of heart failure were associated with lower AFEQT OS scores. Of those, 226 participants (6.8%) experienced MACNE; restricted cubic spline analysis with adjustment for factors associated with baseline AFEQT score showed a nonlinear increase in the risk for MACNE with AFEQT OS score <80. The strongest associations were observed for baseline AFEQT daily activity scores (for AFEQT daily activity score of <80 vs ≥80, HR: 1.65; 95% CI: 1.21-2.25). CONCLUSIONS: Diminished health status in patients with AF is common and is independently associated with subsequent adverse cardiovascular events.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes.

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis-defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P<0.05 with false discovery rate-adjusted P<0.10 was used to determine statistical significance. RESULTS: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis-defined metabolite clusters compared with placebo (nominal P=0.01, false discovery rate-adjusted P=0.08 for both clusters). However, ketosis (ß-hydroxybutyrate levels >500 µmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. CONCLUSIONS: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02653482.

Lifetime ovulations and epithelial ovarian cancer risk and survival: A systematic review and meta-analysis.

OBJECTIVE: To assess the relationship between lifetime ovulatory years (LOY) and Epithelial ovarian cancer (EOC) risk and survival. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Relevant studies were identified from PubMed, MEDLINE, and Embase through December 31, 2021 combining the following search: [("ovulation" or "ovulation cycles" or "ovulatory age" or "ovulatory cycles") and ("ovarian cancer" or "ovarian neoplasms") and ("humans" and "female")]. Reference lists of identified articles were searched for additional studies. Studies were excluded from consideration if they were not a published, peer-review article; not in English; lacked data on effect sizes; had data included in another publication; or were a review article, cross-sectional study, or case report. Two independent investigators screened abstracts and full texts for eligibility, extracted study-level data, and assigned study quality. Disagreements between abstractors were discussed and resolved by consensus. RESULTS: Thirty-one reports were included in the qualitative review of LOY and EOC risk, inclusive of 24 studies with sufficient data to be included in the meta-analysis. Women with the highest level of LOY had 2.26 times higher odds of EOC than women with the lowest level of LOY (95% CI 1.94-2.83). LOY was associated with risk of serous (pooled OR 2.31, 95% CI 1.60-3.33) and endometrioid tumors (pooled OR 3.05, 95% CI 2.08-4.45) but not mucinous disease (pooled OR 1.52, 95% CI 0.87-2.64). There were only four studies examining the LOY-survival association, which precluded a quantitative assessment; however, three of the published studies reported worse outcome with greater LOY. CONCLUSION: LOY is a risk factor for specific EOC histotypes and may also influences EOC survival. Standard definitions of LOY, participant-level data, and larger sample size will enable more precise quantitation of the LOY-EOC association, which can inform EOC risk assessment models.

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. METHODS: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. RESULTS: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10-6). CONCLUSIONS: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. IMPACT: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Effects of garlic intake on cancer: a systematic review of randomized clinical trials and cohort studies.

BACKGROUND/OBJECTIVES: Due to the rapid increase of global cancer incidence and mortality and a high level of interest in cancer prevention, a systematic review of garlic intake and cancer risk is needed. SUBJECTS/METHODS: We implemented a systematic review to examine the effects of varying levels of garlic intake on cancer. We conducted comprehensive literature searches in three electronic databases (MEDLINE, Embase, and Web of Science) for studies published between database inception and July or September of 2018. Two investigators independently screened abstracts and full-texts, extracted data, and assessed risk of bias (RoB). A total of one medium-quality randomized controlled trial (RCT) and 13 cohort studies graded as high RoB were included. RESULTS: The 1-year follow-up results from a RCT showed that a significant decrease in the number and size of colorectal adenomas among participants with colorectal adenomas who received high-dose aged garlic extract (AGE) compared with those who received low-dose AGE (P < 0.05). The results of prospective observational studies provided inconsistent associations of colorectal cancer risk with garlic supplements and garlic intake as food. CONCLUSIONS: In summary, the AGE was effective in reducing the number and magnitude of colorectal adenomas in one RCT, but there were inconsistent associations between garlic intake and colorectal cancer in cohort studies. Therefore, we could not draw a firm conclusion regarding the effects of garlic on cancer, because the current strength of evidence is inadequate due to a lack of number of high-quality RCTs.

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

Gestational weight gain and risk of epithelial ovarian cancer.

OBJECTIVE: To examine the association between (GWG) and epithelial ovarian cancer (EOC). METHODS: We compared GWG between 670 incident EOC cases and 1,551 community controls from a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with GWG adjusting for potential confounders. To explore the potential effect of maternal long-term weight retention after childbearing, we restricted analyses to women who began their childbearing years as normal/underweight and examined differences in EOC risk between those who were normal/underweight versus those who were overweight/obese at study baseline reference date. RESULTS: Average GWG per full-term pregnancy did not differ between cases and controls. Among women who were normal/underweight at study baseline, greater average GWG was not associated with EOC (OR = 0.9, 0.8, 0.7 for quartiles 2, 3 and 4 of GWG gain, respectively, compared to quartile 1). In contrast, among women who were overweight/obese at study baseline, greater average GWG was positively associated with EOC (OR = 1.4, 1.8, 1.2, for quartiles 2, 3, and 4 compared to quartile 1; interaction p = 0.04). CONCLUSION: We posit that maternal post-partum weight retention and not gestational weight gain itself among normal/underweight women may impact subsequent risk of EOC. If our hypothesis is supported in other studies designed to assess this question directly, then counseling women on the importance of healthy weight management after a pregnancy could provide another means to help women reduce their risk of this often-fatal malignancy.

Offspring sex and risk of epithelial ovarian cancer: a multinational pooled analysis of 12 case-control studies.

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.

Effects of prenatal exposure to NO2 on children's neurodevelopment: a systematic review and meta-analysis.

The neurotoxicity of NO2 exposure is well-known and potentially causes impaired of neural functions. This review aimed to estimate associations between prenatal NO2 exposure and neurodevelopment for children. Articles published until May 2019 reported prenatal NO2 exposure and children's cognition, psychomotor, language, attention, IQ, and behavior function were searched according to all related terms. The main databases we retrieved included PubMed, Web of Science, Embase, and Cochrane Library. Coefficient was extracted, conversed, and synthesized by random effects meta-analysis. Meanwhile, qualitatively describe would be used for some studies which cannot be synthesized quantitatively for lack of quantity or methods inconsistency. Finally, a total of 3848 citations were searched, and only 10 studies were included. We estimated that per 10 µg/m3 increase of NO2 during pregnancy was associated with a - 0.76 point decrease in global psychomotor (95% CI, - 1.34, - 0.18) and a - 0.62 point decrease in fine psychomotor for children (95% CI, - 1.09, - 0.16). But no significant association found in general cognitive and language. In addition, through the literature review, it seemed that prenatal exposure to NO2 might cause adverse impacts on children's attention, IQ, and different behaviors, but this requires confirmation from further researches. Our study indicated that prenatal exposure to NO2 seems to be associated with impaired neural development for children, especially for fine psychomotor. However, further studies are needed for determining the effects of prenatal air pollution exposure on attention, IQ, and behavior.

The Effects of Irvingia gabonensis Seed Extract Supplementation on Anthropometric and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Background: It has been hypothesized that Irvingia gabonensis can promote weight loss by increasing fatty acid breakdown and inhibiting fatty acid synthesis.Objective: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Irvingia gabonensis seed extract supplementation on weight-related health outcomes.Methods: Literature searches were conducted in 4 databases from January 2018 to identify randomized controlled trials (RCTs) investigating the effects of Irvingia gabonensis seed extract supplementation on anthropometric measures and cardiovascular biomarkers. Two investigators independently performed abstract screenings, full-text screenings, data extraction, and risk of bias (ROB) assessments. Random effects meta-analyses were performed when 3 or more RCTs reported the same outcome.Results: Five RCTs met the eligibility criteria for this systematic review. Four of the 5 RCTs were rated as having a high ROB, and only one RCT was rated as having a low ROB. Random-effects meta-analysis of the 5 RCTs showed that a significant decrease in body weight, body fat, and waist circumference was observed in relation to Irvingia gabonensis seed extract supplementation. However, the only one low-ROB trial did not have significantly different outcomes. Meta-analysis also showed beneficial effects of Irvingia gabonensis seed extract supplementation on total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides. Only the low-ROB trial showed a trend of increasing HDL-cholesterol levels (net percent change = 11.61%; 95% confidence interval (CI: -6.12%, 29.34%) and decreasing triglyceride levels (net percent change = -29%; 95% CI: -76%, 19%). The reported adverse events were minor in these 5 RCTs.Conclusions: Overall efficacy of Irvingia gabonensis seed extract supplementation on weight loss seems positive but is limited due to poor methodological quality and the insufficient reporting of the clinical trials. Further high quality RCTs are needed to determine the effectiveness of Irvingia gabonensis seed extract supplement on the weight-related health outcomes.

Gender of offspring and risk of ovarian cancer: The HOPE study.

OBJECTIVE: To examine the association between gender of offspring and epithelial ovarian cancer (EOC). METHODS: We compared gender of offspring between 664 incident EOC cases and 1531 controls participating in a population-based study conducted in Pennsylvania, Ohio, and New York from 2003-2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) adjusting for potential confounders. RESULTS: Bearing a male offspring was associated with an 8 % lower EOC risk; bearing all boys was associated with an 11 % lower risk. Compared to bearing all girls, bearing all boys was associated with a 14 % decrease risk. Increasing number of male offspring increased the protective effect (adjusted-OR: 0.92, 0.91, 0.84, for 1, 2, and 3+ boys compared to all girls). Results where similar when limiting cases to invasive disease and to the high-grade serous histotype. CONCLUSION: Fetal sex, which influences maternal hormonal milieu, may impact EOC risk.

Role of milk and dairy intake in cognitive function in older adults: a systematic review and meta-analysis.

BACKGROUND: As aging populations increase across the globe, research on lifestyle factors that prevent cognitive decline and dementia is urgently needed. Therefore, a systematic review was conducted to examine the effects of varying levels of milk intake alone or in combination with other dairy products on the outcomes of cognitive function and disorders in adults. METHODS: A comprehensive search was conducted across 3 databases (PUBMED, CINAHL, and EMBASE) from their inception through October 2017. Prospective cohort studies and randomized controlled trials (RCTs) that enrolled adults were included. Studies with follow-up durations of less than 4 weeks and studies including schizophrenic patients were excluded. Two independent investigators conducted abstract and full-text screenings, data extractions, and risk-of-bias (ROB) assessments using validated tools. Studies were synthesized qualitatively using a strength of evidence (SoE) rating tool. A random-effects model for meta-analysis was conducted when at least 3 unique studies reported sufficient quantitative data for the same outcome. RESULTS: A total of 1 RCT and 7 cohort studies were included. One medium-quality small RCT (n = 38 participants) showed that only spatial working memory was marginally better in the high dairy diet group compared to the low dairy diet group. Two of the 7 cohort studies were rated as having a high ROB, and only 1 cohort study was rated as having a low ROB. There were large methodological and clinical heterogeneities, such as the methods used to assess milk or dairy intake and the characteristics of the study populations. It was impossible to conduct a dose-response meta-analysis because the studies utilized different categories of exposures (e.g., different frequencies of milk consumption or the amount of dairy intake). Thus, the overall SoE was rated as insufficient regarding the associations between milk intake and cognitive decline, dementia, and Alzheimer's disease outcomes. Our meta-analysis of 3 cohort studies showed no significant association between milk intake and cognitive decline outcome (pooled adjusted risk ratio = 1.21; 95% CI: 0.81, 1.82; for highest vs. lowest intake) with large statistical heterogeneity (I2 = 64.1%). CONCLUSIONS: The existing evidence (mostly observational) is too poor to draw a firm conclusion regarding the effect of milk or dairy intake on the risk of cognitive decline or disorders in adults.

Animal versus plant protein and adult bone health: A systematic review and meta-analysis from the National Osteoporosis Foundation.

BACKGROUND: Protein may have both beneficial and detrimental effects on bone health depending on a variety of factors, including protein source. OBJECTIVE: The aim was to conduct a systematic review and meta-analysis evaluating the effects of animal versus plant protein intake on bone mineral density (BMD), bone mineral content (BMC) and select bone biomarkers in healthy adults. METHODS: Searches across five databases were conducted through 10/31/16 for randomized controlled trials (RCTs) and prospective cohort studies in healthy adults that examined the effects of animal versus plant protein intake on 1) total body (TB), total hip (TH), lumbar spine (LS) or femoral neck (FN) BMD or TB BMC for at least one year, or 2) select bone formation and resorption biomarkers for at least six months. Strength of evidence (SOE) was assessed and random effect meta-analyses were performed. RESULTS: Seven RCTs examining animal vs. isoflavone-rich soy (Soy+) protein intake in 633 healthy peri-menopausal (n = 1) and post-menopausal (n = 6) women were included. Overall risk of bias was medium. Limited SOE suggests no significant difference between Soy+ vs. animal protein on LS, TH, FN and TB BMD, TB BMC, and bone turnover markers BSAP and NTX. Meta-analysis results showed on average, the differences between Soy+ and animal protein groups were close to zero and not significant for BMD outcomes (LS: n = 4, pooled net % change: 0.24%, 95% CI: -0.80%, 1.28%; TB: n = 3, -0.24%, 95% CI: -0.81%, 0.33%; FN: n = 3, 0.13%, 95% CI: -0.94%, 1.21%). All meta-analyses had no statistical heterogeneity. CONCLUSIONS: These results do not support soy protein consumption as more advantageous than animal protein, or vice versa. Future studies are needed examining the effects of different protein sources in different populations on BMD, BMC, and fracture.