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Background: Bacterial vaginosis is believed to be a risk factor for preterm delivery. We undertook a study of the association between bacterial vaginosis and the preterm delivery of infants with low birth weight after accounting for other known risk factors.Methods: In this cohort study, we enrolled 10,397 pregnant women from seven medical centers who had no known medical risk factors for preterm delivery. At 23 to 26 weeks' gestation, bacterial vaginosis was determined to be present or absent on the basis of the vaginal pH and the results of Gram's staining. The principal outcome variable was the delivery at less than 37 weeks' gestation of an infant with a birth weight below 2500 g.Results: Bacterial vaginosis was detected in 16 percent of the 10,397 women. The women with bacterial vaginosis were more likely to be unmarried, to be black, to have low incomes, and to have previously delivered low-birth-weight infants. In a multivariate analysis, the presence of bacterial vaginosis was related to preterm delivery of a low-birth-weight infant (odds ratio, 1.4; 95 percent confidence interval, 1.1 to 1.8). Other risk factors that were significantly associated with such a delivery in this population were the previous delivery of a low-birth-weight infant (odds ratio, 6.2; 95 percent confidence interval, 4.6 to 8.4), the loss of an earlier pregnancy (odds ratio, 1.7; 1.3 to 2.2), primigravidity (odds ratio, 1.6; 1.1 to 1.9), smoking (odds ratio, 1.4; 1.1 to 1.7); and black race (odds ratio, 1.4; 1.1 to 1.7). Among women with bacterial vaginosis, the highest risk of preterm delivery of a low-birth-weight infant was found among those with both vaginal bacteroides and Mycoplasma hominis (odds ratio, 2.1; 95 percent confidence interval, 1.5 to 3.0).Conclusions: Bacterial vaginosis was associated with the preterm delivery of low-birth-weight infants independently of other recognized risk factors. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosures MGK reports institutional research support from Pfizer, BridgeBio Pharma, Alnylam Pharmaceuticals, and Ionis Pharmaceuticals, consulting/advisory board support from BridgeBio Pharma and Alnylam Pharmaceuticals, and is a member of Alnylam Pharmaceuticals Speaker's Bureau. OAO receives research support from National Institute on Minority Health and Health Disparities (5R01-MD016401) KMA has received an investigator-initiated research grant from Alnylam and consulting fees from Arbor Biotechnologies, Attralus, Intellia, and Prothena. SHS reports research funding through sponsored research agreements to Duke University from Astra Zeneca, Lilly, and Verily and is a coinventor of unlicensed patents held by Duke University. SS receives research support from the National Heart, Lung, and Blood Institute (K23HL161348), Doris Duke Charitable Foundation (#2020061), American Heart Association (#935275), the Mandel Foundation, Duke Heart Center Leadership Council, the Institute for Translational Medicine and Therapeutics, and Foundation for Sarcoidosis Research and has participated in advisory boards for AstraZeneca. All other authors report no relevant disclosures.

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Background: Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures., Methods: We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach., Results: PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065)., Conclusions: Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks., (© 2022. The Author(s).)

There is increasing evidence that HFpEF is a heterogeneous clinical entity and distinct molecular pathways may contribute to pathophysiology. Leveraging unbiased proteomics to identify novel biomarkers, this study seeks to understand the underlying molecular mechanisms of HFpEF. The discovery cohort consisted of HFpEF cases and non-HF controls from the CATHGEN study (N = 176); the validation cohort consisted of participants from the TECOS trial of patients with diabetes (N = 109). Proteins associated with HFpEF were included in a LASSO model to create a discriminative multi-protein model and assessed in the validation cohort. Survival models and meta-analysis were used to test the association of proteins with incident clinical outcomes, including HF hospitalization, mortality and HFpEF hospitalization in CATHGEN, TECOS and the Jackson Heart Study. In the derivation set, 190 proteins were associated with HFpEF in univariate analysis, of which 65 remained significant in the multivariate model. Twenty (30.8%) of these proteins validated in TECOS, including LCN2, U-PAR, IL-1ra, KIM1, CSTB and Gal-9 (OR 1.93-2.77, p < 0.01). LASSO regression yielded a 13-protein model which, when added to a clinical model inclusive of NT-proBNP, improved the AUC from 0.82 to 0.92 (p = 1.5 × 10 -4 ). Five proteins were associated with incident HF hospitalization, four with HFpEF hospitalization and eleven with mortality (p < 0.05). We identified and validated multiple circulating biomarkers associated with HFpEF as well as HF outcomes. These biomarkers added incremental discriminative capabilities beyond clinical factors and NT-proBNP., (© 2022. The Author(s).)

Background: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM., Methods: Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed., Results: A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p  =  2 × 10 -7 , and were differentially associated in participants with and without DM (beta 1.58, p  =  8  ×  10 -8 vs. 0.67, p  =  9  ×  10 -4 , respectively; p value for interaction  =  0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p  =  0.24) than in those without DM (mean ∆ 0.16, p  =  0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p  =  2.74  ×  10 -8 ), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p  =  3.21  ×  10 -9 v. HR 0.90, p  =  0.104, p value for interaction  =  0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study., Conclusions: LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437., (© 2021. The Author(s).)

Introduction: One Health (OH) is an important concept to design appropriate public health responses to emerging diseases such as COVID-19. How trainee health professionals understand this concept is important to its implementation. In this study, we explored how medical (MD), veterinary (DVM), and dual degree MD and DVM Master of Public Health (MPH) students define OH and its relevance to practice. Methods: Students participated in a survey that included the Readiness for Interprofessional Learning Scale (RIPLS), and two questions requiring them to define and explain the relevance of OH. The transcripts of the OH responses underwent thematic analysis. Role theory was used to explain the variation in how students from these different programmes viewed the concept. Results: The responses of the MD and DVM students in contrast to the dual degree MPH students reflected gaps in their understanding of the concept that pertained to the specific health impacts of global warming; antimicrobial resistance, food security; social, cultural and environmental determinants of zoonoses occurrence, and health policy formation. Discussion: Mitigation of the global risks to public health require a collaborative approach by health professionals. Our findings suggest that MD and DVM students are unaware of many factors that impact patient health outside of their own discipline. The inclusion of dual degree students revealed novel insights that undertaking an MPH may have enabled them to be more aware about the interdisciplinary relevance of OH to their professional practice. We recommend that structured incorporation of OH should inform future medical and veterinary curricula., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BK declared a past collaboration with one of the authors RR., (Copyright © 2021 Roopnarine, Boeren and Regan.)

Introduction: The conceptual framework of One Health (OH) provides a strategy for promoting collaboration across the nexus of animal, human, and environmental health, which is essential for tackling emerging disease threats, such as COVID-19. However, there is no accreditation requirement for OH to prepare students across the professions for collaborative practice. This study aimed to explore the perspectives of faculty across the medical, veterinary, and public health programs about the need, opportunities, and challenges of developing OH in the curricula., Methods: In this qualitative study, faculty across the three disciplines were invited to participate in audio-recorded, focus group interviews. Recordings were transcribed verbatim and analyzed using inductive and deductive thematic analysis., Results: All participants recognized the need for OH as a critical concept for preparing students for collaborative practice. Opportunities were identified for shared learning and research across the disciplines, particularly through the use of interprofessional education. The lack of an accreditation mandate for OH in the medical curriculum was perceived to be the greatest challenge, leading to an anticipation of significant resistance among medical educators and students., Discussion: Successful development of OH in all three curricula is vital to prepare students for current and future threats to global health. The role of accreditation bodies in ensuring medical, veterinary, and public health curricula prepare students for these threats is crucial. Implications for practice include strategies for persuading medical educators and medical students to embrace OH in the curriculum and promote a culture of shared learning., Competing Interests: Disclosures: The authors declare no conflict of interest. Ethical approval: This research was approved by the St. George's University Institutional Research Board (IRB): ID no. 18051 and also by the Virtual Program Research Ethics Committee (VPREC) at the University of Liverpool., (Copyright © 2020 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Purpose of Review: Obesity is a significant international public health epidemic with major downstream consequences on morbidity and mortality. While lifestyle factors contribute, there is an evolving understanding of genomic and metabolomic pathways involved with obesity and its relationship with cardiometabolic risk. This review will provide an overview of some of these important findings from both a biologic and clinical perspective., Recent Findings: Recent studies have identified polygenic risk scores and metabolomic biomarkers of obesity and related outcomes, which have also highlighted biological pathways, such as the branched-chain amino acid (BCAA) pathway that is dysregulated in this disease. These biomarkers may help in personalizing obesity interventions and for mitigation of future cardiometabolic risk. A multifaceted approach is necessary to impact the growing epidemic of obesity and related diseases. This will likely include incorporating precision medicine approaches with genomic and metabolomic biomarkers to personalize interventions and improve risk prediction.

There is a sharp rise in cardiovascular disease (CVD) risk and progression with the onset of menopause. The 4-vinylcyclohexene diepoxide (VCD) model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. We hypothesized that menopausal female mice were more susceptible to CVD than pre- or perimenopausal females. Female mice were treated with VCD or vehicle for 20 consecutive days. Premenopausal, perimenopausal, and menopausal mice were administered angiotensin II (ANG II) or subjected to ischemia-reperfusion (I/R). Menopausal females were more susceptible to pathological ANG II-induced cardiac remodeling and cardiac injury from a myocardial infarction (MI), while perimenopausal, like premenopausal, females remained protected. Specifically, ANG II significantly elevated diastolic (130.9 ± 6.0 vs. 114.7 ± 6.2 mmHg) and systolic (156.9 ± 4.8 vs. 141.7 ± 5.0 mmHg) blood pressure and normalized cardiac mass (15.9 ± 1.0 vs. 7.7 ± 1.5%) to a greater extent in menopausal females compared with controls, whereas perimenopausal females demonstrated a similar elevation of diastolic (93.7 ± 2.9 vs. 100.5 ± 4.1 mmHg) and systolic (155.9 ± 7.3 vs. 152.3 ± 6.5 mmHg) blood pressure and normalized cardiac mass (8.3 ± 2.1 vs. 7.5 ± 1.4%) compared with controls. Similarly, menopausal females demonstrated a threefold increase in fibrosis measured by Picrosirus red staining. Finally, hearts of menopausal females (41 ± 5%) showed larger infarct sizes following I/R injury than perimenopausal (18.0 ± 5.6%) and premenopausal (16.2 ± 3.3, 20.1 ± 4.8%) groups. Using the VCD model of menopause, we provide evidence that menopausal females were more susceptible to pathological cardiac remodeling. We suggest that the VCD model of menopause may be critical to better elucidate cellular and molecular mechanisms underlying the transition to CVD susceptibility in menopausal women. NEW & NOTEWORTHY Before menopause, women are protected against cardiovascular disease (CVD) compared with age-matched men; this protection is gradually lost after menopause. We present the first evidence that demonstrates menopausal females are more susceptible to pathological cardiac remodeling while perimenopausal and cycling females are not. The VCD model permits appropriate examination of how increased susceptibility to the pathological process of cardiac remodeling accelerates from pre- to perimenopause to menopause.

Objectives: This study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF)., Background: Comorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood., Methods: Cox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF., Results: Age did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m 2 corresponded to 17.6%; a BMI of 30 kg/m 2 corresponded to 7.0%; and a BMI of 40 kg/m 2 corresponded to 11%. For patients <60 years of age, mortality increased nonsignificantly from 3.2% to 3.7% with increasing BMI. Age also modified the effect of depressive symptoms on all-cause mortality (interaction p = 0.03). Among patients ≥70 years of age, a 1-year mortality rate significantly increased from 7.8% for a Beck Depression Inventory (BDI) score of 5% to 15.6% for BDI of 20. For patients <60 years of age, mortality was nonsignificantly related to BDI. Cumulative comorbidity scores were stronger predictors than age for mortality/hospitalization., Conclusions: In chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The number of vaginal breech and twin deliveries may be insufficient for adequate training., Objective: To determine whether advanced trainees and new Fellows in obstetrics are gaining adequate experience and confidence in vaginal breech and twin deliveries., Methods: An online survey was emailed to registered Royal Australia and New Zealand College of Obstetrics and Gynaecology (RANZCOG) advanced trainees and new Fellows (Years 1-5). This survey asked about their experience, confidence and whether they intend to perform vaginal breech and twin deliveries as specialists., Results: The survey was sent to 703 advanced trainees (162) and Fellows (541) and answered by 217 (31.7%). Experience and confidence in vaginal breech and twin deliveries increased with the number of procedures performed (P < 0.001) in both groups and were significantly higher among Fellows. Despite the level of experience, 100% of respondents felt confident in managing vaginal twin deliveries with or without supervision, whereas 14.9% of respondents did not feel confident in managing vaginal breech deliveries. Intention to offer these procedures in their practice depended on confidence levels, and there was a significant difference between twins and breech. Overall, 87.3% of respondents intended to offer vaginal twin deliveries in their practice, while only 32.7% intended to offer vaginal breech deliveries., Conclusion: Confidence in complex vaginal deliveries increases with increasing number of procedures performed and a significant proportion of trainees and Fellows consider they do not have sufficient experience. The association between confidence and intention to offer these procedures is stronger in twins than in breech deliveries., (© 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

The origin of the supermassive black holes that inhabit the centres of massive galaxies remains unclear 1,2 . Direct-collapse black holes-remnants of supermassive stars, with masses around 10,000 times that of the Sun-are ideal seed candidates 3-6 . However, their very existence and their formation environment in the early Universe are still under debate, and their supposed rarity makes modelling their formation difficult 7,8 . Models have shown that rapid collapse of pre-galactic gas (with a mass infall rate above some critical value) in metal-free haloes is a requirement for the formation of a protostellar core that will then form a supermassive star 9,10 . Here we report a radiation hydrodynamics simulation of early galaxy formation 11,12 that produces metal-free haloes massive enough and with sufficiently high mass infall rates to form supermassive stars. We find that pre-galactic haloes and their associated gas clouds that are exposed to a Lyman-Werner intensity roughly three times the intensity of the background radiation and that undergo at least one period of rapid mass growth early in their evolution are ideal environments for the formation of supermassive stars. The rapid growth induces substantial dynamical heating 13,14 , amplifying the Lyman-Werner suppression that originates from a group of young galaxies 20 kiloparsecs away. Our results strongly indicate that the dynamics of structure formation, rather than a critical Lyman-Werner flux, is the main driver of the formation of massive black holes in the early Universe. We find that the seeds of massive black holes may be much more common than previously considered in overdense regions of the early Universe, with a co-moving number density up to 10 -3 per cubic megaparsec.

Background: Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance., Methods: We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment., Results: LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients., Conclusions: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Background: One of the first clinically detectable alterations in heart function in hypertrophic cardiomyopathy (HCM) is a decline in diastolic function. Diastolic dysfunction is caused by changes in intrinsic properties of cardiomyocytes or an increase in fibrosis. We investigated whether clinical and cellular parameters of diastolic function are different between male and female patients with HCM at the time of myectomy., Methods and Results: Cardiac tissue from the interventricular septum of patients with HCM (27 women and 44 men) was obtained during myectomy preceded by echocardiography. At myectomy, female patients were 7 years older than male patients and showed more advanced diastolic dysfunction than men evident from significantly higher values for E/e' ratio, left ventricular filling pattern, tricuspid regurgitation velocity, and left atrial diameter indexed for body surface. Whereas most male patients (56%) showed mild (grade I) diastolic dysfunction, 50% of female patients showed grade III diastolic dysfunction. Passive tension in HCM cardiomyocytes was comparable with controls, and myofilament calcium sensitivity was higher in HCM compared with controls, but no sex differences were observed in myofilament function. In female patients with HCM, titin was more compliant, and more fibrosis was present compared with men. Differences between female and male patients with HCM remained significant after correction for age., Conclusions: Female patients with HCM are older at the time of myectomy and show greater impairment of diastolic function. Furthermore, left ventricular and left atrial remodeling is increased in women when corrected for body surface area. At a cellular level, HCM women showed increased compliant titin and a larger degree of interstitial fibrosis., (© 2018 American Heart Association, Inc.)

There is a growing appreciation that our microbial environment in the gut plays a critical role in the maintenance of health and the pathogenesis of disease. Probiotic, beneficial gut microbes, administration can directly attenuate cardiac injury and post-myocardial infarction (MI) remodelling, yet the mechanisms of cardioprotection are unknown. We hypothesised that administration of Bifidobacterium animalis subsp. lactis 420 (B420), a probiotic with known anti-inflammatory properties, to mice will mitigate the pathological impact of MI, and that anti-inflammatory T regulatory (T reg ) immune cells are necessary to impart protection against MI as a result of B420 administration. Wild-type male mice were administered B420, saline or Lactobacillus salivarius 33 (Ls-33) by gavage daily for 14 or 35 days, and underwent ischemia/reperfusion (I/R). Pretreatment with B420 for 10 or 28 days attenuated cardiac injury from I/R and reduced levels of inflammatory markers. Depletion of T reg cells by administration of anti-CD25 monoclonal antibodies eliminated B420-mediated cardio-protection. Further cytokine analysis revealed a shift from a pro-inflammatory to an anti-inflammatory environment in the probiotic treated post-MI hearts compared to controls. To summarise, B420 administration mitigates the pathological impact of MI. Next, we show that T reg immune cells are necessary to mediate B420-mediated protection against MI. Finally, we identify putative cellular, epigenetic and/or post-translational mechanisms of B420-mediated protection against MI.

Background: Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients., Methods: Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland. Recipients were cross-referenced with the National Cancer Registry to determine incidence of PTLD. Kaplan-Meier analysis was performed for PTLD-free survival, allograft survival, and patient survival after PTLD. Cox proportional hazards models were used to identify independent risk factors for PTLD in our population., Results: We identified 31 cases of PTLD during the study period. Histological subgroups included: early lesions (n = 1); polymorphic PTLD (n = 1); monomorphic PTLD (n = 27), Hodgkin disease (n = 2). Median time to PTLD diagnosis was 8.3 (range, 1.2-13.9) years. Cumulative incidence (95% CI) of PTLD at 1, 2, 3, 5, 10, and 15 years was 0%, 0.16% (0.05-0.5%), 0.21% (0.08-0.57%), 0.21% (0.08-0.57%), 1.76% (1.15-2.69%), and 3.07% (2.1-4.43%), respectively. Allograft survival after PTLD diagnosis was 94.4% (66.6-99.2%) at 5 years. Patient survival after PTLD diagnosis was 64% at 1 year, 53% at 2 years, 48% at 5 years, and 37% at 10 years. No risk factors for PTLD were identified., Conclusions: We found a paucity of early onset PTLD in our cohort with no cases in the first posttransplant year. Potential contributing factors included a high prevalence of previous Epstein-Barr virus exposure and a relatively low immunological risk profile in our recipient cohort compared with prior studies. Further studies are required to reevaluate the epidemiology of PTLD in the modern era of transplant immunosuppression.

Aims: Hypertrophic cardiomyopathy (HCM) has been associated with reduced β-adrenergic receptor (β-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished β-AR signalling in HCM. We aimed to investigate the role of β-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G > A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C., Methods and Results: Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca²⁺sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force-sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values., Conclusion: These data provide evidence that in the KI HCM mouse model, β-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

The photodissociation of H 2 by a nearby anisotropic source of radiation is seen as a critical component in creating an environment in which a direct collapse black hole may form. Employing radiative transfer we model the effect of multifrequency (0.76-60 eV) radiation on a collapsing halo at high redshift. We vary both the shape of the spectrum which emits the radiation and the distance to the emitting galaxy. We use blackbody spectra with temperatures of T = 10 4  K and 10 5  K and a realistic stellar spectrum. We find that an optimal zone exists between 1 and 4 kpc from the emitting galaxy. If the halo resides too close to the emitting galaxy the photoionizing radiation creates a large H ii region which effectively disrupts the collapsing halo, too far from the source and the radiation flux drops below the level of the expected background and the H 2 fraction remains too high. When the emitting galaxy is initially placed between 1 and 2 kpc from the collapsing halo, with a spectral shape consistent with a star-forming high-redshift galaxy, then a large central core forms. The mass of the central core is between 5000 and 10 000 M ⊙ at a temperature of approximately 1000 K. This core is however surrounded by a reservoir of hotter gas at approximately 8000 K, which leads to mass inflow rates of the order of ∼0.1 M ⊙  yr -1 .

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg(-1)·day(-1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF., (Copyright © 2015 the American Physiological Society.)

Background: As exemptions to school-entry requirements rise, vaccination rates in Arizona school children are approaching levels that may threaten public health. Understanding the interactions physicians have with vaccine-hesitant parents, as well as the opinions physicians hold regarding vaccination, exemption, and exemption policies, are critical to our understanding of, and ability to affect, vaccination exemption rates among children., Methods: Survey responses were elicited from practitioners listed in The Arizona Partnership for Immunization and the Arizona Medical Association databases using a multi-pronged recruitment approach. Respondents provided data regarding their practice, comfort with parental refusal of individual vaccines, opinions about the beliefs held by parents that seek exemptions, parent education strategies, issues regarding providing care to unvaccinated children, and potential changes to Arizona policy., Results: A total of 152 practitioners providing care to a wide geographic and economic population of Arizona responded to the survey. Respondents were generally strong advocates of all immunizations but were more accepting of parents' desires to refuse hepatitis B and rotavirus vaccines. Almost all providers indicated that they see patients whose parents request to refuse or delay from vaccinations at least occasionally (88% and 97%, respectively). Only 37% of respondents indicated that they would be supportive of a policy requiring them to sign off on a parent's decision to refuse vaccination., Conclusions: Vaccination providers in Arizona are generally very supportive of childhood immunizations but have varying comfort with exemption from individual vaccines. Responding providers tended to not support a requirement for a physician's signature for vaccine exemptions due to varying concerns regarding the implementation of such a practice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cardiac muscle cells are equipped with specialized biochemical machineries for the rapid generation of force and movement central to the work generated by the heart. During each heart beat cardiac muscle cells perceive and experience changes in length and load, which reflect one of the fundamental principles of physiology known as the Frank-Starling law of the heart. Cardiac muscle cells are unique mechanical stretch sensors that allow the heart to increase cardiac output, and adjust it to new physiological and pathological situations. In the present review we discuss the mechano-sensory role of the cytoskeletal proteins with respect to their tight interaction with the sarcolemma and extracellular matrix. The role of contractile thick and thin filament proteins, the elastic protein titin, and their anchorage at the Z-disc and M-band, with associated proteins are reviewed in physiologic and pathologic conditions leading to heart failure. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé, (© 2013.)

Although familial hypertrophic cardiomyopathy (FHC) is characterized as cardiac disease in the absence of overt stressors, disease penetrance, and pathological progression largely depend on modifying factors. Accordingly, pressure overload by transverse aortic constriction (TAC) was induced in 2-month-old, male mice with and without a FHC (R403Q) mutation in α-myosin heavy chain. A significantly greater number of FHC mice (n = 8) than wild-type (WT) mice (n = 5) died during the 9-week study period. TAC induced a significant increase in cardiac mass whether measured at 2 or 9 weeks post-TAC in both WT and FHC mice, albeit to a different extent. However, the temporal and morphological trajectory of ventricular remodeling was impacted by the FHC transgene. Both WT and FHC hearts responded to TAC with an early (2 weeks post-TAC) and significant augmentation of the relative wall thickness (RWT) indicative of concentric hypertrophy. By 9 weeks post-TAC, RWT decreased in WT hearts (eccentric hypertrophy) but remained elevated in FHC hearts. WT hearts following TAC demonstrated enhanced cardiac function as measured by the end-systolic pressure-volume relationship, pre-load recruitable stroke work (PRSW), and myocardial relaxation indicative of compensatory hypertrophy. Similarly, TAC induced differential histological and cellular remodeling; TAC reduced expression of the sarcoplasmic reticulum Ca(2+)-ATPase (2a) (SERCA2a; 2 and 9 weeks) and phospholamban (PLN; 2 weeks) but increased PLN phosphorylation (2 weeks) and β-myosin heavy chain (β-MyHC; 9 weeks) in WT hearts. FHC-TAC hearts showed increased β-MyHC (2 and 9 weeks) and a late (9 weeks) decrease in PLN expression concomitant with a significant increase in PLN phosphorylation. We conclude that FHC hearts respond to TAC induced pressure overload with increased premature death, severe concentric hypertrophy, and a differential ability to undergo morphological, functional, or cellular remodeling compared to WT hearts.

The pathological progression of hypertrophic cardiomyopathy (HCM) is sexually dimorphic such that male HCM mice develop phenotypic indicators of cardiac disease well before female HCM mice. Here, we hypothesized that alterations in myofilament function underlies, in part, this sex dimorphism in HCM disease development. Firstly, 10-12month female HCM (harboring a mutant [R403Q] myosin heavy chain) mice presented with proportionately larger hearts than male HCM mice. Next, we determined Ca(2+)-sensitive tension development in demembranated cardiac trabeculae excised from 10-12month female and male HCM mice. Whereas HCM did not impact Ca(2+)-sensitive tension development in male trabeculae, female HCM trabeculae were more sensitive to Ca(2+) than wild-type (WT) counterparts and both WT and HCM males. We hypothesized that the underlying cause of this sex difference in Ca(2+)-sensitive tension development was due to changes in Ca(2+) handling and sarcomeric proteins, including expression of SR Ca(2+) ATPase (2a) (SERCA2a), β-myosin heavy chain (β-MyHC) and post-translational modifications of myofilament proteins. Female HCM hearts showed an elevation of SERCA2a and β-MyHC protein whereas male HCM hearts showed a similar elevation of β-MyHC protein but a reduced level of cardiac troponin T (cTnT) phosphorylation. We also measured the distribution of cardiac troponin I (cTnI) phosphospecies using phosphate-affinity SDS-PAGE. The distribution of cTnI phosphospecies depended on sex and HCM. In conclusion, female and male HCM mice display sex dimorphic myofilament function that is accompanied by a sex- and HCM-dependent distribution of sarcomeric proteins and cTnI phosphospecies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has not been studied sufficiently. Accordingly, we investigated the effect of voluntary wheel-running and forced treadmill exercise on cardiac adaptation in mice treated with 4-vinylcyclohexine diepoxide (VCD), which selectively accelerates the loss of primary and primordial follicles and results in a state that closely mimics human menopause. Two-month-old female C57BL/6 mice injected with VCD (160 mg/kg) for 20 consecutive days underwent ovarian failure by 60 to 90 d after injection. Responses to voluntary wheel running and treadmill exercise did not differ between VCD- and vehicle-treated 7-mo-old C57BL/6 or outbred B6C3F1 mice. Moreover, adaptive cardiac hypertrophy, hypertrophic marker expression, and skeletal muscle characteristics after voluntary cage-wheel exercise did not differ between VCD- and vehicle-treated mice. Because 5' AMP-activated protein kinase (AMPK) is a key component for the maintenance of cardiac energy balance during exercise, we determined the effect of exercise and VCD-induced ovarian failure on the AMPK signaling axis in the heart. According to Western blotting, VCD treatment followed by voluntary cage-wheel exercise differently affected the upstream AMPK regulatory components AMPKα1 and AMPKα2. In addition, net downstream AMPK signaling was reduced after VCD treatment and exercise. Our data suggest that VCD did not affect exercise-induced cardiac hypertrophy but did alter cellular cardiac adaptation in a mouse model of menopause.

Rationale: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce., Objective: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins., Methods and Results: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values., Conclusions: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

Approximately 18% of human cancers have a viral etiology and the majority of these involve transformation of epithelial cells. Viral proteins transform epithelia by inducing alterations in the normal cell growth and differentiation pathways through the targeting of host proteins. Among the DNA viruses responsible for causing carcinomas are the human papillomaviruses as well as several members of the herpes and polyomavirus families. A number of techniques have been developed to study the mechanisms by which viruses immortalize epithelial cells and alter differentiation properties. These methods include the generation of immortalized lines by transfection or infection as well as the use of organotypic raft cultures, suspension in methylcellulose, and treatment with high calcium levels to examine how differentiation is altered.

The E5 proteins of human papillomaviruses (HPVs) are small hydrophobic proteins that are expressed in the early and late stages of the viral life cycle; however, their role in HPV pathogenesis is not clearly understood. In this study, a split-ubiquitin yeast (Saccharomyces cerevisiae) two-hybrid system was used to identify B-cell-associated protein 31 (Bap31) as a binding partner of HPV E5 proteins. The association of these proteins was confirmed by coimmunoprecipitation of complexes of Bap31 with either HPV type 16 (HPV16) or HPV31 E5. In addition, Bap31 and E5 were found to colocalize in perinuclear patterns consistent with localization to the endoplasmic reticulum. Mutational analysis of E5 identified amino acids in the extreme C terminus as important for stabilizing the interaction with Bap31. Deletion of these C-terminal amino acids of E5 in the context of complete HPV31 genomes resulted in impaired proliferative capacity of HPV-positive keratinocytes following differentiation. When small interfering RNAs were used to reduce the levels of Bap31, the proliferative ability of HPV-positive keratinocytes upon differentiation was also reduced, implicating Bap31 as a regulator of this process. These studies identify a novel binding partner of the high-risk HPV E5 proteins and provide insight into how the E5 proteins may modulate the life cycle in differentiating cells.

This article examines what motivates students towards self-directed learning (SDL). The results discussed are taken from a larger study examining students' perceptions of SDL, a concept that is increasingly evident in nurse education. The study focuses on the views of pre-registration students and their tutors. The study was conducted in two phases, firstly using focus groups, followed by a questionnaire to test the views of the focus group participants amongst a wider audience. A total of 12 students and 8 tutors took part in the focus groups, There were 97 student responses to the questionnaire and 18 tutor responses. The results indicated a wide range of motivational factors, with a good level of agreement between the two groups for most factors. The results also highlighted the importance of lectures in motivating students towards SDL. This link between teacher-led activities and the development of independent learners is not readily acknowledged in literature on adult learning. The study also indicated that students need specific guidance and feedback to motivate them towards SDL, which is not consistent with the philosophical basis of SDL and may lead to inconsistency amongst tutors in the facilitation of this process. Implications for practice are discussed within this article.

There are many factors that are associated with preterm labor and delivery. These include maternal conditions such as medical illness, anemia and uterine malformation. They may be related to past events such as prior obstetric complication, previous preterm labor, cervical surgery or induced abortion. They may be intrinsic to the current pregnancy, such as reproductive tract infection, multifetal gestation, maternal age, short interpregnancy interval or prolonged menstrual conception interval. Maternal behaviors such as smoking and substance abuse can be risk factors for a short gestation. Demographic variables such as race, employment and socioeconomic status can also be associated with preterm labor. This article briefly reviews these subjects.

Objective: Our purpose was to evaluate the effectiveness of a risk-based intrapartum antibiotic prophylaxis strategy for the prevention of early-onset neonatal group B streptococcal disease., Study Design: Cases and controls were selected from infants born to women with one or more risk factors: preterm labor or rupture of membranes, prolonged rupture of membranes (>18 hours), fever during labor, or previous child with group B streptococcal disease. Cases were matched with controls by birth hospital and gestational age. Data abstracted from medical records were analyzed to estimate the effectiveness of intrapartum antibiotic prophylaxis., Results: We analyzed data from 109 cases and 207 controls. Nineteen (17%) case versus 69 (33%) control mothers received an acceptable regimen of intrapartum antibiotic prophylaxis. In adjusted analyses, the effectiveness of intrapartum antibiotic prophylaxis was 86% (95% confidence interval, 66%-94%). When the first dose of antibiotics was given > or =2 hours before delivery, the effectiveness increased to 89% (95% confidence interval, 70%-96%); when it was given within 2 hours of delivery, the effectiveness was 71% (95% confidence interval, -8%-92%). Effectiveness was lowest in mothers with intrapartum fever (72%, 95% confidence interval, -9%-93%). On the basis of a 70% prevalence of maternal risk factors expected among cases in the absence of intrapartum antibiotic prophylaxis, we estimate that the risk-based strategy could reduce early-onset group B streptococcal disease by 60%., Conclusions: The risk-based approach to intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease. To achieve the maximum preventive effect, the first dose of antibiotics should be administered at least 2 hours before delivery.

1996 saw the implementation of Clinical Effectiveness Initiatives by the NHS Executive and the Royal College of Nursing to promote the use of evidence-based care. This paper examines whether or not nurses will be encouraged and facilitated by these initiatives to provide evidence-based care for their clients. Both initiatives appear to assume that the use of evidence-based care leads to improved client care, but several issues are raised which still need to be resolved before this assumption can be made. The NHS Executive advocates the use of randomized controlled trials as the method of choice for providing evidence of clinical effectiveness. However, this may not necessarily be the best methodology for some areas of nursing practice. The paper concludes that the Royal College of Nursing's Clinical Effectiveness Initiative has great potential to provide the necessary motivation and facilitation, providing other professional issues are resolved.

The distribution of serotypes of group B streptococci (GBS) isolated from 67 infants with early-onset sepsis are described. Case-infants were assembled from 13 hospitals across the United States from 15 July 1995 to 5 February 1997 through prospective active surveillance. The distribution of GBS serotypes was Ia, 40%; Ib, 9%; II, 6%; III, 27%; V, 15%; and nontypeable, 3%. Type V occurred more frequently in the northeast region (New York and New Jersey) than in other regions (29% vs. 9%, P = .06). Conversely, type III occurred significantly less frequently in the northeast region than other regions (10% vs. 35%, P = .04). GBS types Ia, III, and V accounted for 82% of the isolates. This report supports previous observations about the emergence of GBS type V, but our data caution that conclusions about serotype distributions based on one geographic location or on a small number of patients may not be generally applicable. Continued monitoring seems necessary for the design of a GBS vaccine.

Objective: The purpose of this study was to determine if treatment of pregnant women with Chlamydia trachomatis infection would lower the incidence of preterm delivery and/or low birth weight., Methods: Pregnant women between the 23rd and 29th weeks of gestation were randomized in double-blind fashion to receive either erythromycin 333 mg three times daily or an identical placebo. The trial continued until the end of the 35th week of gestation., Results: When the results were examined without regard to study site, erythromycin had little impact on reducing low birth weight (8% vs. 11%, P = 0.4) or preterm delivery (13% vs. 15%, P = 0.7). At the sites with high persistence of C. trachomatis in the placebo-treated women, low birth weight infants occurred in 9 (8%) of 114 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.04) and delivery <37 weeks occurred in 15 (13%) of 115 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.4)., Conclusions: The results of this trial suggest that the risk of low birth weight can be decreased by giving erythromycin to some women with C. trachomatis. Due to the high clearance rate of C. trachomatis in the placebo group, these data do not provide unequivocal evidence that erythromycin use in all C. trachomatis-infected women prevents low birth weight.

Objective: Our purpose was to study the association of cervicovaginal colonization with group B streptococci with pregnancy and neonatal outcome., Study Design: A prospective study was conducted at seven medical centers between 1984 and 1989. Genital tract cultures were obtained at 23 to 26 weeks' gestation and at delivery. Prematurity and neonatal sepsis rates were compared between group B streptococci positive and negative women., Results: Group B streptococci was recovered from 2877 (21%) of 13,646 women at enrollment. Heavy colonization was associated with a significant risk of delivering a preterm infant who had a low birth weight (odds ratio = 1.5, 95% confidence interval 1.1 to 1.9). Heavily colonized women given antibiotics effective against group B streptococci had little increased risk of a preterm, low-birth-weight birth. Women with light colonization were at the same risk of adverse outcome as the uncolonized women. Neonatal group B streptococci sepsis occurred in 2.6 of 1000 live births in women with and 1.6 of 1000 live births in women without group B streptococci at 23 to 26 weeks' gestation (p = 0.11). However, sepsis occurred in 16 of 1000 live births to women with and 0.4 of 1000 live births to women without group B streptococci at delivery (p < 0.001)., Conclusions: Heavy group B streptococci colonization of 23 to 26 weeks' gestation was associated with an increased risk of delivering a preterm, low-birth-weight infant. Cervicovaginal colonization with group B streptococci at 23 to 26 weeks' gestation was not a reliable predictor of neonatal group B streptococci sepsis. Colonization at delivery was associated with sepsis.

Objective: Our purpose was to determine whether erythromycin treatment of pregnant women colonized with group B streptococci would reduce the occurrence of low birth weight (< 2500 gm) and preterm (< 37 completed weeks) birth., Study Design: In a double-blind clinical trial, 938 carriers of group B streptococci were randomized to receive erythromycin base (333 mg three times a day) or matching placebo beginning during the third trimester and before 30 weeks and continuing for 10 weeks or until 35 weeks 6 days of pregnancy., Results: Pregnancy outcomes were available for 97% of randomized women; 14% of subjects withdrew from the trial. Birth weight < 2500 gm occurred in 8.6% of the erythromycin and 6.1% of the placebo recipients (relative risk 1.4, 0.9 to 2.2, p = 0.16). Preterm delivery occurred in 11.4% of women randomized to erythromycin and in 12.3% randomized to placebo (relative risk 0.9, 95% confidence limits 0.6 to 1.3, p = 0.65). Greater benefit of erythromycin in reducing these outcomes was not observed among women reporting the best compliance., Conclusions: In this study of pregnant women colonized with group B streptococci treatment with erythromycin was not shown to be effective at prolonging gestation or reducing low birth weight. Greater than anticipated complicating factors, including spontaneous clearance of the organism, use of nontrial antibiotics, and density of colonization, may have resulted in population sizes too small to detect a benefit of treatment. Future studies should take these factors into account in determining sample sizes.

A critical appraisal of four cohort studies examining the relationship between Ureaplasma urealyticum and chronic lung disease (CLD) of prematurity is presented. Three studies were concurrently conducted, but the fourth was conducted 4 years later when surfactant replacement was a widespread practice. Although infants were enrolled in all studies soon after birth before they had developed CLD, there were differences in patients population, the definition of colonization with U. urealyticum, neonatal management, and the definition of CLD of prematurity. Despite the differences, all four studies found an association between colonization and development of CLD of prematurity. A combined estimate of relative risk for the four studies was 1.91 (95% confidence interval, 1.54-2.37). When infants were categorized into groups by birth weight, the association was not observed in infants who weighed > 1,250 g. The association was also not observed in infants who weighed < 750 g, but the risk of CLD of prematurity in the uncolonized control group was already 82%. Because the cohort study design allows for the possibility that one or more additional factors associated with U. urealyticum may be the true cause(s) of CLD of prematurity, there is strong but not definitive evidence that U. urealyticum causes CLD of prematurity.

Coarctation of the aorta is usually caused by a congenital narrowing of the aorta. This report describes two children who developed hypertension secondary to an acquired coarctation of the aorta. In one patient the coarctation was temporally related to umbilical artery catheterization and was associated with thrombosis and aneurysmal dilatation of the aorta. In the second patient, the coarctation occurred after surgical aortotomy during the removal of an intrathoracic neuroblastoma. Patients who have interventional damage to the aorta should be periodically examined for the appearance of a coarctation. Although an acquired coarctation of the aorta is an infrequent complication of invasive or surgical procedures, it should be identified since it represents a remediable cause of hypertension in children.