Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and ß-amyloid (Aß) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aß or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aß PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aß in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aß (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aß differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets.

Inflammatory, Metabolic and Endothelial Biomarkers Before and After Pregnancy Complications.

Women with gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and preterm birth (PTB) have excess cardiovascular disease compared to those with uncomplicated births, perhaps related to pre-pregnancy inflammation, dysmetabolism or endothelial dysfunction. We included 1238 women in the Coronary Artery Risk Development in Young Adults Study (1985-2011) with 2215 births classified according to outcomes (term, uncomplicated births were the referent). Repeated measures ANOVA estimated pre-pregnancy, post-pregnancy and biomarker change according to pregnancy outcomes, adjusted for confounders. GDM and HDP groups had higher pre-pregnancy hsCRP (+0.37 [0.08, 0.65]; +0.29 [0.04, 0.55] log mg/L), leptin (+0.29 [0.09, 0.50]; +0.37 [0.17, 0.56] log ng/ml), and lower adiponectin (-0.25 [-0.36, -0.13); -0.11 [-0.22, -0.01] log ng/ml) than those with uncomplicated births and these profiles persisted in magnitude post-pregnancy. Controlling for BMI attenuated most profiles, except lower pre-pregnancy adiponectin remained associated with GDM. PTB without HDP or GDM was related to lower pre-pregnancy hsCRP and sICAM-1 (-0.31 [-0.56, -0.06] log mg/L; -0.05 [-0.09, - 0.01] log ng/ml) and a larger leptin increase from pre- to post-pregnancy, (+0.20 [0.02, 0.37] log ng/ml). Pre-pregnancy inflammation and metabolic dysfunction contributed to GDM and HDP, perhaps due to higher BMI. PTB may be related to adverse metabolic changes post-pregnancy, though the unexpected endothelial biomarker profile warrants further study.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

Longitudinal Associations Between Higher Self-Reported Energy, Gait Speed, and Cognition in Older Adults With Fatigue.

BACKGROUND: Older adults reporting higher energy levels have better physical function. It is not known if these associations persist among older adults reporting fatigue or if higher energy is associated with cognitive function. We examined longitudinal associations between self-reported energy, gait speed, and cognition, stratified by fatigue, in 2 613 participants (aged 74.6 ±â€…2.87 years) in the Health, Aging and Body Composition Study. METHODS: Self-reported energy (0-10, dichotomized at median) and fatigue (present/absent) were measured at baseline. Usual and rapid-paced gait speed (m/s), modified Mini-Mental State Examination (3MS), and Digit Symbol Substitution Test (DSST) were measured at baseline and annually over 8 years. Linear mixed effect models compared changes in gait speed, 3MS, and DSST between higher and lower energy groups within fatigue strata. RESULTS: At baseline, 724 participants (27%) were fatigued; 240 (33%) coreported higher energy (9% of total). The remaining 1 889 participants were fatigue-free (73%); 1 221 (65%) coreported higher energy (47% of total). Those with fatigue and higher energy had average rapid gait declines of 0.007 m/s per year (p = .04) after adjustment for demographics, comorbidities, depressive symptoms, and exercise. DSST declines were found among only fatigue-free participants (ß = 0.17, p = .01). No statistically significant associations with energy were found for fatigue-free participants, or for usual gait or 3MS. CONCLUSIONS: Asking about older adults' energy levels as well as fatigue may identify a subgroup of older adults protected against physical and cognitive decline, even among those with fatigue.

Prepregnancy obesity and risk of placental inflammation at term: a selection bias analysis.

PURPOSE: Placental histopathology is a resource for investigating obesity-associated pregnancy conditions. However, studies oversample adverse pregnancies, biasing findings. We examine the association between prepregnancy obesity (risk factor for inflammation) and histologic placental inflammation (correlated with impaired infant neurodevelopment) and how selection bias may influence the association. METHODS: Singleton term deliveries between 2008 and 2012 from the Magee Obstetric Maternal and Infant database were analyzed. Prepregnancy body mass index (BMI) was categorized as underweight, lean (referent), overweight, and obese. Outcomes were diagnoses of acute (acute chorioamnionitis and fetal inflammation) and chronic placental inflammation (chronic villitis). Risk ratios for associations between BMI and placental inflammation were estimated using selection bias approaches: complete case, exclusion of pregnancy complications, multiple imputation, and inverse probability weighting. E-values approximated how susceptible estimates were to residual selection bias. RESULTS: Across methods, obesity was associated with an 8-15% lower risk of acute chorioamnionitis, a 7%-14% lower risk of acute fetal inflammation, and a 12%-30% higher risk of chronic villitis relative to lean women. E-values indicated modest residual selection bias could explain away associations, though few measured indications of placental evaluations met this threshold. CONCLUSIONS: Obesity may contribute to placental inflammation, and we highlight robust methods to analyze clinical data susceptible to selection bias.

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion.

Objective: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. Methods: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as > 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. Results: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. Conclusion: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

Latent class analysis of placental histopathology: a novel approach to classifying early and late preterm births.

BACKGROUND: Neonatal morbidity attributable to prematurity predominantly occurs among early preterm births (<32 weeks) rather than late preterm births (32 to <37 weeks). Methods to distinguish early and late preterm births are lacking given the heterogeneity in pathophysiology and risk factors, including maternal obesity. Although preterm births are often characterized by clinical presentation (spontaneous or clinically indicated), classifying deliveries by placental features detected on histopathology reports may help identify subgroups of preterm births with similar etiology and risk factors. Latent class analysis is an empirical approach to characterize preterm births on the basis of observed combinations of placental features. OBJECTIVE: To identify histopathologic markers that can distinguish early (<32 weeks) and late preterm births (32 to <37 weeks) that are also associated with maternal obesity and neonatal outcomes. STUDY DESIGN: Women with a singleton preterm birth at University of Pittsburgh Medical Center Magee-Womens Hospital (Pittsburgh, PA) from 2008 to 2012 and a placental evaluation (89% of preterm births) were stratified into early (n=900, 61% spontaneous) and late preterm births (n=3362, 57% spontaneous). Prepregnancy body mass index was self-reported at first prenatal visit and 16 abstracted placental features were analyzed. Placental subgroups (ie, latent classes) of early and late preterm births were determined separately by latent class analysis of placental features. The optimal number of latent classes was selected by comparing fit statistics. The probability of latent class membership across prepregnancy body mass indexes was estimated in early preterm births and in late preterm births by an extension of multinomial regression called pseudo-class regression, adjusting for race, smoking, education, and parity. The frequencies of severe neonatal morbidity (composite outcome: respiratory distress, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, patent ductus arteriosus, and retinopathy of prematurity), small-for-gestational-age, and length of neonatal intensive care unit stay were compared across latent classes by chi-square and Kruskal-Wallis tests. RESULTS: Early preterm births were grouped into 4 latent classes based on placental histopathologic features: acute inflammation (38% of cases), maternal vascular malperfusion with inflammation (29%), maternal vascular malperfusion (25%), and fetal vascular thrombosis with hemorrhage (8%). As body mass index increased from 20 to 50kg/m2, the probability of maternal vascular malperfusion and fetal vascular thrombosis with hemorrhage increased, whereas the probability of maternal vascular malperfusion with inflammation decreased. There was minimal change in the probability of acute inflammation with increasing body mass index. Late preterm births also had 4 latent classes: maternal vascular malperfusion (22%), acute inflammation (12%), fetal vascular thrombosis with hemorrhage (9%), and low-risk pathology (58%). Body mass index was not associated with major changes in likelihood of the latent classes in late preterm births. Associations between body mass index and likelihood of the latent classes were not modified by type of delivery (spontaneous or indicated) in early or late preterm births. Maternal malperfusion and fetal vascular thrombosis with hemorrhage were associated with greater neonatal morbidity than the other latent classes in early and late preterm births. CONCLUSION: Obesity may predispose women to early but not late preterm birth through placental vascular impairment. Latent class analysis of placental histopathologic data provides an evidence-based approach to group preterm births with shared underlying etiology and risk factors.

Prepregnancy weight change associated with high gestational weight gain.

OBJECTIVE: Gestational weight gain (GWG) above recommendations is a risk factor for adverse maternal, perinatal, and long-term outcomes. This study hypothesized that prepregnancy weight gain may portend excess GWG. METHODS: Among 1,126 women (51% of whom were of Black race) in the Coronary Artery Risk Development in Young Adults (CARDIA) study with post-baseline births, the prepregnancy annual rate of BMI change per woman was estimated (slope; 5 years before pregnancy) and was related to the risk of GWG above Institute of Medicine recommendations using mixed-effects models (binary) and GWG z score (continuous), adjusting for confounders, and stratified by prepregnancy overweight/obesity status. RESULTS: A total of 626 women (56%) had excess GWG. Each standard deviation increase in prepregnancy BMI (0.16 kg/m2 per year) was associated with an 18% increased risk of excess GWG (95% CI: 1.13-1.23), adjusted for covariates. Stratified results showed an association for women without overweight or obesity (adjusted relative risk = 1.71 [95% CI: 1.38-2.13]) but not among those with overweight or obesity (adjusted relative risk = 0.98 [95% CI: 0.91-1.05]). When evaluated as a z score, prepregnancy weight gain was associated with higher GWG among women with and without overweight or obesity (mean = 0.24 [0.10] and 0.28 [0.12] z score, respectively). CONCLUSIONS: Weight gain before pregnancy is associated with higher GWG during pregnancy. Assessment of prepregnancy weight changes may identify those at risk for high GWG.

Quality of periprocedural care in patients with von Willebrand disease.

INTRODUCTION: While it has been shown that haemophilia patients receiving care at Haemophilia Treatment Centres (HTCs) experience decreased morbidity and mortality, little research has been done on the outcomes of patients with von Willebrand disease (VWD). AIM: To compare the quality of periprocedural care received by patients with VWD at HTCs and non-HTCs. METHODS: We performed a retrospective chart review on all adult VWD patients undergoing an invasive procedure from 2015 to 2017. Quality of periprocedural care was measured using the following surrogate outcomes: periprocedural VWD-specific therapy use per 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines, procedural estimated blood loss (EBL), and post-procedure bleeding. Comparisons were performed according to the setting of care at the time of the invasive procedure, HTC versus non-HTC. RESULTS: There were 668 invasive procedures performed on 305 patients, of which 8.2% were HTC cases. Non-type 1 VWD was more likely in HTC cases. VWD-specific therapy was used per NHLBI guidelines in 100% of HTC cases compared with 10.6% of non-HTC cases. Procedural EBL > = 100 ml was more likely to occur in HTC differences cases (OR = 2.34; 95% CI, 1.05 to 5.25). There was no difference in post-procedure bleeding between the two groups (OR = 1.26, 95% CI, .20- 7.86). CONCLUSION: Despite widespread periprocedural use of VWD-specific therapy outside established guidelines at non-HTCs, there was no difference in periprocedural bleeding. Possible explanations include diagnostic error, in disease severity and procedure types, and dataset limitations. Additional studies are needed to investigate this further and compare other patient care outcomes between HTCs and non-HTCs.

The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia.

Among individuals with the rare congenital bleeding disorder hemophilia A, the major challenge is inhibitor formation, which is associated with significant morbidity and cost. Yet, as the optimal approach to prevent and eradicate inhibitors is not known, we are at equipoise. Because classic trial design is not practical in a rare disease setting, we designed 2 48-week randomized trials comparing ELOCTATE and emicizumab to prevent and eradicate inhibitors. To achieve statistical efficiency, we incorporated historic data (Bayesian priors) on inhibitor formation to allow preferential randomization to emicizumab, piecewise exponential survival models to determine mean and 95% confidence interval for inhibitor formation in each arm, and simulations to determine the best model design to optimize power. To achieve administrative efficiency, the trials will be performed with the same sites, staff, visit frequency, blood sampling, laboratories, and laboratory assays, with streamlined enrollment so patients developing inhibitors in the first trial may be enrolled on the second trial. The primary end point is the probability of inhibitor formation or inhibitor eradication, respectively. The design indicates early stopping rules for overwhelming evidence of superiority of the emicizumab arms. Simulations indicate that, with 66 subjects, the Prevention Trial will have 84% power to detect noninferiority of emicizumab to ELOCTATE with a margin of 10% if emicizumab is truly 10% superior to ELOCTATE; with 90 subjects, the Eradication Trial will have 80% power to detect 15% superiority of ELOCTATE immune tolerance induction with vs without emicizumab. Thus, a platform design provides statistical and administrative efficiency to conduct INHIBIT trials.

Changes in Cardiometabolic Risk Factors Before and After Gestational Diabetes: A Prospective Life-Course Analysis in CARDIA Women.

OBJECTIVE: This study hypothesized that both preconception and postchildbearing patterns of cardiometabolic risk factors may be different for women with gestational diabetes mellitus (GDM) compared with women without GDM. METHODS: Among 1,302 (51% black) women in the Coronary Artery Risk Development in Young Adults (CARDIA) study with births and followed for 30 years, this study evaluated changes in cardiometabolic factors (BMI, waist circumference [WC], lipids, blood pressure) during prechildbearing (prior to the first postbaseline birth) and postchildbearing periods (after the last birth) by GDM status using piecewise linear mixed models adjusted for sociodemographics, parity, and time-varying covariates. RESULTS: Compared with women who did not develop GDM, weight and WC increases in women who developed GDM (n = 152, 12%) were faster (BMI difference: +0.12 kg/m2 /y, P = 0.04; WC difference: +0.28 cm/y, P = 0.04) during the prechildbearing period, accounting for covariates. This translated to an average of 1.3 kg of excess weight gain across 4 years among women with subsequent GDM versus non-GDM births. In contrast, slopes after childbearing did not differ by GDM status, nor were there other cardiometabolic differences. CONCLUSIONS: Women with GDM exhibited an increasing prepregnancy pattern of weight gain and central adiposity. Absolute postchildbearing weight was also higher in GDM-affected women, but the slope of gain after GDM was not.

Life Course Changes in Cardiometabolic Risk Factors Associated With Preterm Delivery: The 30-Year CARDIA Study.

Background Women who deliver preterm infants (<37 weeks) have excess cardiovascular risk; however, it is unclear whether the unfavorable changes in the cardiometabolic profile associated with preterm delivery initiate before, during, or after childbearing. Methods and Results We identified 1306 women (51% Black) with births between baseline (1985-1986) and year 30 in the CARDIA (Coronary Artery Risk Development in Young Adults) study. We compared life course changes in blood pressure, body mass index, waist circumference, and lipids in women with preterm deliveries (n=318) with those with all term deliveries (n=988), using piecewise linear mixed-effects models. Specifically, we evaluated group differences in rates of change before and after the childbearing period and change in level across the childbearing period. After adjusting for the covariates, women with preterm deliveries had a higher change in diastolic blood pressure across the childbearing period than those with all term deliveries (1.59 versus -0.73 mm Hg, P<0.01); the rates of change did not differ by group, both prechildbearing and postchildbearing. Women with preterm deliveries had a larger body mass index increase across the childbearing period (1.66 versus 1.22 kg/m2, P=0.03) compared with those with all term deliveries, followed by a steeper increase after the childbearing period (0.22 versus 0.17 kg/m2 per year, P=0.02). Conclusions Preterm delivery was associated with unfavorable patterns of change in diastolic blood pressure and adiposity that originate during the childbearing years and persist or exacerbate later in life. These adverse changes may contribute to the elevated cardiovascular risk among women with preterm delivery.

D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: a systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to determine whether D-mannose reduces urinary tract infection recurrence (ie, cumulative incidence) in adult women with recurrent urinary tract infection compared with other prevention agents. Secondary outcomes included side effects and compliance with D-mannose use. DATA SOURCES: Ovid Medline 1946-, Embase 1947-, Scopus 1823-, Cochrane Library, Web of Science 1900-, and ClinicalTrials.gov were searched through 4/15/2020. STUDY ELIGIBILITY CRITERIA: Systematic review inclusion: randomized controlled trials, prospective cohorts, and retrospective cohorts written in English of women ≥18 years old with recurrent urinary tract infection in which D-mannose was utilized as an outpatient prevention regimen. Systematic review exclusion: lab or animal-based research, study protocols only, and conference abstracts. Meta-analysis inclusion: stated D-mannose dose, follow-up time ≥6 months, a comparison arm to D-mannose, and data available from women ≥18 years of age. STUDY APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers made abstract, full text, and data extraction decisions. Study methodologic quality was assessed using the Cochrane Risk of Bias tool. Relative risks, confidence intervals, and heterogeneity were computed. RESULTS: Searches identified 776 unique citations. Eight publications met eligibility: 2 using D-mannose only; 6 using D-mannose combined with another treatment. Seven studies were prospective: 2 randomized controlled trials, 1 randomized cross-over trial, and 4 prospective cohort studies. One retrospective cohort study was included. Three studies met meta-analysis eligibility (1 randomized controlled trial, 1 randomized cross-over trial, and 1 prospective cohort). Pooled relative risk of urinary tract infection recurrence comparing D-mannose to placebo was 0.23 (95% confidence interval, 0.14-0.37; heterogeneity=0%; D-mannose n=125, placebo n=123). Pooled relative risk of urinary tract infection recurrence comparing D-mannose to preventative antibiotics was 0.39 (95% confidence interval, 0.12-1.25; heterogeneity=88%; D-mannose n=163, antibiotics n=163). Adverse side effects were reported in 2 studies assessing D-mannose only (1 study (n=10) reported none; the other reported a low incidence (8/103 participants) of diarrhea). Two studies reported compliance, which was high. CONCLUSION: D-mannose appears protective for recurrent urinary tract infection (vs placebo) with possibly similar effectiveness as antibiotics. Overall, D-mannose appears well tolerated with minimal side effects-only a small percentage experiencing diarrhea. Meta-analysis interpretation must consider the small number of studies with varied study design and quality and the overall small sample size.

Early pregnancy immune profile and preterm birth classified according to uteroplacental lesions.

INTRODUCTION: Preterm birth is a heterogeneous phenotype, with placental abnormalities underlying many cases. The etiology of preterm births that occur in the absence of placental abnormalities, however, remain enigmatic and we considered that early pregnancy biomarkers may provide clues. METHODS: Women from a hospital-based cohort (2008-2012, n = 397) were randomly selected within 6 strata of term and preterm birth with and without placental decidual vasculopathy (arteriopathy), intrauterine inflammation/infection (acute chorioamnionitis), or no lesions. Lipids and inflammatory markers were analyzed in first trimester samples (12.5 ± 0.6 weeks) and related to outcome groups (referent, term births with no lesions). Factor analysis then clustered analytes and related these to preterm birth groups, adjusted for covariates and stratified by pre-pregnancy obesity. RESULTS: Three biomarker patterns were identified. Immune activation cytokines (33% of the variance) were associated with preterm birth with no lesions (aOR 1.5, 95%CI 1.1-2.1), particularly among obese women. In contrast, inflammatory chemokines (9% of variance) were associated with term and preterm vasculopathy among non-obese women (aOR 2.6 [1.3, 4.7] and 2.0 [1.1, 3.0], respectively). DISCUSSION: The early pregnancy maternal immune profile is related to preterm births classified according to placental lesions, and these associations vary according to obesity status.

Utility and safety of adenosine challenge for subtle ventricular pre-excitation in the pediatric population.

INTRODUCTION: Adenosine challenge (AC) can be used to evaluate possible Wolff-Parkinson-White (WPW) pattern on an electrocardiogram (ECG). Despite the use of this technique, there is a paucity of studies in the pediatric population evaluating the efficacy, safety, and outcomes of this testing modality. METHODS AND RESULTS: All ACs performed from January 2009 to June 2017 were retrospectively reviewed. Patient demographics, adenosine dosing, results, adverse effects, and outcomes including results of electrophysiology studies (EPS) were reviewed. Analysis was conducted between AC positive and negative cohorts. ECG criteria of shortest PR interval, longest QRS duration, and the number of suspected pre-excited leads were evaluated for inter-rater reliability and correlation to positive AC. Fifty-six AC (n = 51) were performed (median age, 13.8; range, 0.3-20 years). Forty-one AC were pre-EPS and 15 post-EPS due to concern for recurrent WPW. Thirty-one (76%) pre-EPS AC were negative, 9 (22%) positive, and 1 (2%) equivocal. EPS was performed following seven positive AC revealing 5 (71%) left posterior and 2 (29%) right posteroseptal AP. The 15 post-EPS AC were all found to be negative. Mean effective adenosine dose was 0.2 ± 0.11 mg/kg. No adverse events were reported. Mean follow up duration after AC was 314 ± 482 days with no documented arrhythmias. CONCLUSION: Adenosine challenge is an effective and safe testing modality for subtle WPW in the pediatric population. In our population, there were no adverse events or documented arrhythmias in patients following a negative study.

Breastfeeding Greater Than 6 Months Is Associated with Smaller Maternal Waist Circumference Up to One Decade After Delivery.

BACKGROUND: Abdominal obesity is an important indicator of cardiometabolic dysfunction in later life. Prior studies have observed an inverse association between breastfeeding and maternal waist circumference (WC) in the years after pregnancy, but this may be due to bias resulting from systematic differences in women who do and do not breastfeed. MATERIALS AND METHODS: A total of 678 women enrolled in the Pregnancy Outcomes and Community Health (POUCH) cohort also participated in the POUCHmoms Study 7-15 years after delivery. Multivariable linear regression models and propensity scores were used to assess the relationship between WC measured at follow-up and self-reported history of breastfeeding duration of >6 months versus ≤6 months. RESULTS: After a mean follow-up period of 11.0 (standard deviation = 1.4) years, breastfeeding was significantly associated with smaller WC. A threshold effect was detected for women who reported breastfeeding >6 months; their adjusted mean WC was 3.5 cm (95% confidence interval [CI]: -5.7 to -1.2) smaller compared with women who breastfed ≤6 months. The use of two propensity score approaches, weighted and matched, produced similar results; adjusted mean WC difference was -3.6 cm (95% CI: -5.6 to -1.6) and -3.1 cm (95% CI: -5.5 to -0.7), respectively. CONCLUSIONS: This study extends conventional observational study methods to incorporate propensity score approaches that make it possible to separate the study design from the study analysis to account for systematic differences in women who did and did not breastfeed. After reducing potential bias, breastfeeding for greater than 6 months was independently associated with smaller WC in the decade after delivery.

A Randomized Clinical Trial of Wheeled Mobility for Pressure Injury Prevention and Better Function.

OBJECTIVES: To evaluate the effectiveness of wheelchair assessment and configuration on pressure injury incidence, mobility, and functioning in a wheelchair. DESIGN: Randomized controlled trial with participants individually randomized into intervention and control groups. SETTING: Nursing home. PARTICIPANTS: Nursing home residents aged 60 and older who used wheelchairs and were at risk for pressure injuries (N=258). INTERVENTION: Treatment and evaluation, individually configured wheelchair and skin protection cushion; control and evaluation, facility-provided wheelchair and skin protection cushion. MEASUREMENTS: Pressure injury incidence, Nursing Home Life Space Diameter score, Functioning Every Day in a Wheelchair-Capacity (FEW-C) score, and Wheelchair Skills Test (WST) score. RESULTS: No differences in pressure injuries (p=.77) were found. Pelvic rotation (odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.70, p=.02) and Day 14 WST skill score (OR=0.74, 95% CI=0.60-0.91, p=.004) were significant predictors of pressure injuries. Significant differences were observed between groups in change in FEW-C independence scores between before randomization and endpoint (p=.03) and before randomization and 14 days (p=.04). CONCLUSION: Participants with individually configured wheelchairs improved more in the safe and effective use of their wheelchairs than residents with facility-provided wheelchairs. The outcomes indicated that nursing home residents functioned safely at a higher level in their wheelchairs if their devices were individually configured using a comprehensive wheelchair and seating assessment process. There was no difference in the incidence of pressure injuries between the two groups. TRIAL REGISTRATION: NCT01275313.