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Background The Pharmacists’ Patient Care Process (PPCP) was developed to describe a consistent process in which pharmacists in any setting provide patient care. Faculty at a midwestern university developed and refined an assessment tool which provides an indirect approach to measure student confidence in performing skills essential to the PPCP. The objective of this paper is to conduct a stepwise factor analysis to refine the PPCP survey. Methods Assessing appropriateness of survey response data led to an exploratory factor analysis (EFA) on student confidence data to refine the survey instrument and examine the underlying constructs that influence student responses. Post EFA, the results were presented to the research team that collaboratively reached consensus on inclusion or exclusion of items. Results EFA factor loadings identified a 4-factor solution suggesting elimination of 30 items from the original 53 item survey. Team discussions led to eliminating 29 items, combining two items and generation of 5 new items in order to retain important concepts. The outcome was a well-conceptualized and refined 29 item-survey model assessing 4 constructs. Conclusion To potentially improve patient outcomes, it is imperative to utilize comprehensive yet concise survey instruments, like the PPCP Skills Self-Efficacy Survey, to prepare students to translate PPCP skills to practice.

Introduction: With the unprecedented expansion of women's roles in the U.S. military during recent (post-9/11) conflicts in Iraq and Afghanistan, the number of women seeking healthcare through the Veterans Health Administration (VHA) has increased substantially. Women Veterans often present as medically complex due to multiple medical, mental health, and psychosocial comorbidities, and consequently may be underserved. Thus, we conducted the nationwide Women Veterans Cohort Study (WVCS) to examine post-9/11 Veterans' unique healthcare needs and to identify potential disparities in health outcomes and care. Methods: We present baseline data from a comprehensive questionnaire battery that was administered from 2016 to 2019 to a national sample of post-9/11 men and women Veterans who enrolled in Veterans Affairs care (WVCS2). Data were analyzed for descriptives and to compare characteristics by gender, including demographics; health risk factors and symptoms of cardiovascular disease, chronic pain, and mental health; healthcare utilization, access, and insurance. Results: WVCS2 included 1,141 Veterans (51% women). Women were younger, more diverse, and with higher educational attainment than men. Women also endorsed lower traditional cardiovascular risk factors and comorbidities (e.g., weight, hypertension) and greater nontraditional cardiovascular risk factors (e.g., trauma, psychological symptoms). More women reported single-site pain (e.g., neck, stomach, pelvic) and multisite pain, but did not differ from men in posttraumatic stress disorder (PTSD) symptoms or treatment for PTSD. Women seek care at VHA medical centers more frequently, often combined with outside health services, but do not significantly differ from men in their insurance coverage. Conclusion: Overall, this investigation indicates substantial variation in risk factors, health outcomes, and healthcare utilization among post-9/11 men and women Veterans. Further research is needed to determine best practices for managing women Veterans in the VHA healthcare system.

Rationale CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of ...

Bone nonunions arising from large bone defects and composite injuries remain compelling challenges for orthopedic surgeons. Biological changes associated with nonunions, such as systemic immune dysregulation, can contribute to an adverse healing environment. Bone morphogenetic protein 2 (BMP-2), an osteoinductive and potentially immunomodulatory growth factor, is a promising strategy; however, burst release from the clinical standard collagen sponge delivery vehicle can result in adverse side effects such as heterotopic ossification (HO) and irregular bone structure, especially when using supraphysiological BMP-2 doses for complex injuries at high risk for nonunion. To address this challenge, biomaterials that strongly bind BMP-2, such as heparin methacrylamide microparticles (HMPs), may be used to limit exposure and spatially constrain proteins within the injury site. Here, we investigate moderately high dose BMP-2 delivered in HMPs within an injectable hydrogel system in two challenging nonunion models exhibiting characteristics of systemic immune dysregulation. The HMP delivery system increased total bone volume and decreased peak HO compared to collagen sponge delivery of the same BMP-2 dose. Multivariate analyses of systemic immune markers showed the collagen sponge group correlated with markers that are hallmarks of systemic immune dysregulation, including immunosuppressive myeloid-derived suppressor cells, whereas the HMP groups were associated with immune effector cells, including T cells, and cytokines linked to robust bone regeneration. Overall, our results demonstrate that HMP delivery of moderately high doses of BMP-2 promotes repair of complex bone nonunion injuries and that local delivery strategies for potent growth factors like BMP-2 may positively affect the systemic immune response to traumatic injury.

Developing working knowledge of integrated care models can guide pharmacists in operationalizing comprehensive medication management (CMM) alongside behavioral health services for holistic primary care integration. Over the last decade forces from both within and outside the pharmacy profession have culminated in trends toward an oversupply of pharmacists in the United States. In response, advocates of the profession have called for the materialization of long-awaited advancements in innovative, team-based, medication management roles. Although pharmacists are uniquely qualified to provide CMM services, the widespread integration to primary care teams has lagged behind that of other professions, such as behavioral health. Through the application of evidence-based integrated care models, behavioral health clinicians have become regular and routine contributors to primary care teams. To thrive in primary care roles, pharmacists must be able to navigate established teams practicing within existing integrated care models. Understanding how primary care physicians interact with other specialties, such as behavioral health, and the implications this has for pharmacy will play a role in meaningful adaptation of CMM services.

Preventing unintended pregnancy and sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) infection, among adolescents is a public health priority. This report presents prevalence estimates for condom and contraceptive use among sexually active U.S. high school students from the 2019 Youth Risk Behavior Survey. Behaviors examined included any condom use, primary contraceptive method use, and condom use with a more effective contraceptive method, all reported at last sexual intercourse. Analyses were limited to sexually active students (i.e., those who had sexual intercourse with one or more persons during the 3 months before the survey). Except for any condom use, students reporting only same-sex sexual contact were excluded from analyses. Weighted prevalence estimates were calculated, and bivariate differences in prevalence were examined by demographic characteristics (sex, race/ethnicity, and grade) and other sexual risk behaviors (age of sexual initiation, previous 3-month and lifetime number of sex partners, and substance use before last sexual intercourse). Nationwide, 27.4% of high school students reported being sexually active (n = 3,226). Among sexually active students who reported having had sexual contact with someone of the opposite sex (n = 2,698), most students (89.7%) had used a condom or a primary contraceptive method at last sexual intercourse. Prevalence of any condom use at last sexual intercourse was 54.3%, and condoms were the most prevalent primary contraceptive method (43.9% versus 23.3% for birth control pills; 4.8% for intrauterine device [IUD] or implant; and 3.3% for shot, patch, or ring). Approximately 9% had used condoms with an IUD, implant, shot, patch, ring, or birth control pills. Using no pregnancy prevention method was more common among non-Hispanic black (23.2%) and Hispanic (12.8%) students compared with non-Hispanic white students (6.8%); compared with Hispanic students, using no pregnancy prevention method was more common among non-Hispanic black students. Prevalence of condom use was consistently lower among students with other sexual risk behaviors. Results underscore the need for public health professionals to provide quality sexual and reproductive health education and clinical services for preventing unintended pregnancy and STDs/HIV and decreasing disparities among sexually active youths.

Initial microbial colonization and later succession in the gut of human infants are linked to health and disease later in life. The timing of the appearance of the first gut microbiome, and the consequences for the early life metabolome, are just starting to be defined. Here, we evaluated the gut microbiome, proteome and metabolome in 88 African-American newborns using faecal samples collected in the first few days of life. Gut bacteria became detectable using molecular methods by 16 h after birth. Detailed analysis of the three most common species, Escherichia coli, Enterococcus faecalis and Bacteroides vulgatus, did not suggest a genomic signature for neonatal gut colonization. The appearance of bacteria was associated with reduced abundance of approximately 50 human proteins, decreased levels of free amino acids and an increase in products of bacterial fermentation, including acetate and succinate. Using flux balance modelling and in vitro experiments, we provide evidence that fermentation of amino acids provides a mechanism for the initial growth of E. coli, the most common early colonizer, under anaerobic conditions. These results provide a deep characterization of the first microbes in the human gut and show how the biochemical environment is altered by their appearance. Using a multi-omics approach to analyse meconium and stool samples from babies during the first few days of life, the authors show that the gut is detectably colonized within 16 h of birth, with Escherichia coli dominating, and that this correlates with proteome and metabolome changes including the fermentation of amino acids.

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.

Yersinia pestis, the cause of plague, could be weaponized. Unfortunately, development of new vaccines is limited by lack of correlates of protection. We used pre- and post-vaccination sera and peripheral blood mononuclear cells from a flagellin adjuvanted F1/V vaccine trial to evaluate for protective markers. Here, we report for the first time in humans that inverse caspase-3 levels, which are measures of protective antibody, significantly increased by 29% and 75% on days 14 and 28 post-second vaccination, respectively. In addition, there were significant increases in T-cell responses on day 28 post-second vaccination. The strongest positive and negative correlations between protective antibody levels and gene expression signatures were identified for IFNG and ENSG00000225107 genes, respectively. Flagellin/F1/V subunit vaccine induced macrophage-protective antibody and significant CD4+ T-cell responses. Several genes associated with these responses were identified that could serve as potential correlates of protection.

Background The potential long-term effects of childhood fluoxetine therapy on brain serotonin systems were studied using a nonhuman primate model, the rhesus monkey. Methods Juvenile male rhesus (1–4 years of age, corresponding to 4–11 years of age in children) were treated orally with fluoxetine (2 mg/kg) or vehicle daily for 2 years and removed from treatment during the third year. Each treatment group was assigned an equal number of subjects with low and high transcription polymorphisms of MAOA. One year after discontinuation of treatment, positron emission tomography scans were conducted (n = 8 treated monkeys, n = 8 control monkeys) using [11C]DASB to quantify serotonin transporter in 16 cortical and subcortical regions. Results Fluoxetine-treated monkeys with MAOA low transcription polymorphism had significantly lower [11C]DASB binding potentials than control monkeys. This finding was seen throughout the brain but was strongest in prefrontal and cingulate cortices. The MAOA × fluoxetine interaction was enhanced by binding potentials that were nonsignificantly higher in monkeys with high transcription polymorphism. Conclusions Juvenile fluoxetine treatment has residual posttreatment effects on brain serotonin transporter that depend on MAOA genotype. MAOA genotype may be important to consider when treating children with fluoxetine.

Vascular endothelial growth factor-A (VEGF) plays a critical role in stimulating angiogenesis in normal and disease states. Anti-VEGF antibodies have been developed to manage pathological angiogenesis. Bevacizumab, sold under the brand name Avastin, is a humanized mAb that binds VEGF and blocks its binding to its signaling receptor, VEGF receptor 2, and is used to treat patients with a variety of cancers or retinal disorders. The ability of Avastin to modulate other nonreceptor interactions of VEGF has not been fully defined. In this study, we investigated Avastin's capacity to modulate VEGF165 binding to porcine aortic endothelial cells and to heparin and fibronectin (FN) across a range of pH values (pH 5–8). We observed that Avastin slightly enhanced VEGF binding to heparin and that heparin increased VEGF binding to Avastin. In contrast, Avastin inhibited VEGF binding to cells and FN, yet Avastin could still bind to VEGF that was bound to FN, indicating that these binding events are not mutually exclusive. Avastin binding to VEGF was dramatically reduced at acidic pH values (pH 5.0–6.5), whereas VEGF binding to FN and nonreceptor sites on cells was enhanced. Interestingly, the reduced Avastin–VEGF binding at acidic pH was rescued by heparin, as was Avastin's ability to inhibit VEGF binding to cells. These results suggest that heparin might be used to expand the clinical utility of Avastin. Our findings highlight the importance of defining the range of VEGF interactions to fully predict antibody activity within a complex biological setting.

BACKGROUND: This study examined condom use and sexually transmitted infection (STI) testing among unmarried, non-cohabiting women and men who had multiple past-year partnerships or perceived their partner’s involvement in another sexual relationship. METHODS: We identified 5868 and 5330 unmarried, non-cohabiting sexually active women and men aged 15 to 44 years using National Survey of Family Growth data for 2011 to 2017. To measure multiple partnerships, we created 4 dichotomous variables that included both past-year number of opposite-sex sex partners (1, 2 or more) and perceived partner nonmonogamy (PPNM) (yes, no). Results were stratified by relationship type at last sex (“steady” vs “casual”). RESULTS: Overall, 39.4% of women and 48.3% of men reported multiple partnerships and 23.4% and 24.0% reported PPNM. Lower condom use was seen for women and men who had 2 or more partners in the past year and PPNM than those with only 1 partner and no PPNM (women, 28.5%; 95% confidence interval [CI], 24.1–32.9 vs 39.3%; 95% CI, 36.6–41.9) (men, 37.7%; 33.5–41.8 vs 54.9%; 51.9–57.9). STI testing was higher for groups with PPNM. Men with a steady sex partner had higher prevalence of past-year STI testing if they reported PPNM than not (adjusted prevalence ratio, 2.00; 95% CI, 1.63–2.45). CONCLUSIONS: Screening practices that include a standardized sexual risk assessment could identify those with multiple sex partners or PPNM and improve linkage to STI services. Availability of point-of-care tests and expedited partner therapy could provide targeted strategies that prioritize rapid diagnosis and effective partner treatment which may prevent further STI spread.

Distress tolerance (DT) is central to major etiological theories of, and popular treatments for, borderline personality disorder (PD), but empirical evidence for the connection between DT and borderline PD is inconclusive. Such inconsistency is partly due to limited concordance across DT indices from different measurement domains (e.g., behavioral, physiological). In a student sample (N = 267), we assessed subjective perceptions of DT capabilities, task performance on a distressing laboratory challenge, and borderline pathology. Subjective and behavioral indices of DT were largely unrelated. Further, borderline PD features were moderately associated with self-perceived DT (r = –.53); in contrast, they were weakly related to performance on the DT task (r = –.09). We conclude that there is mixed evidence for an association between borderline pathology and DT. Further, we propose a systematic approach to examining the construct validity of DT in multimethod, multimeasure research that might resolve the equivocal results from prior work.

Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), the protein that shuttles LPL to the capillary lumen, is essential for plasma triglyceride metabolism. When GPIHBP1 is absent, LPL remains stranded within the interstitial spaces and plasma triglyceride hydrolysis is impaired, resulting in severe hypertriglyceridemia. While the functions of GPIHBP1 in intravascular lipolysis are reasonably well understood, no one has yet identified DNA sequences regulating GPIHBP1 expression. In the current studies, we identified an enhancer element located ∼3.6 kb upstream from exon 1 of mouse Gpihbp1. To examine the importance of the enhancer, we used CRISPR/Cas9 genome editing to create mice lacking the enhancer (Gpihbp1(Enh/Enh)). Removing the enhancer reduced Gpihbp1 expression by >90% in the liver and by ∼50% in heart and brown adipose tissue. The reduced expression of GPIHBP1 was insufficient to prevent LPL from reaching the capillary lumen, and it did not lead to hypertriglyceridemia—even when mice were fed a high-fat diet. Compound heterozygotes (Gpihbp1(Enh/−) mice) displayed further reductions in Gpihbp1 expression and exhibited partial mislocalization of LPL (increased amounts of LPL within the interstitial spaces of the heart), but the plasma triglyceride levels were not perturbed. The enhancer element that we identified represents the first insight into DNA sequences controlling Gpihbp1 expression.

BACKGROUND Although adhesive small-bowel obstruction (ASBO) is frequently managed nonoperatively, little is known regarding outcomes on readmission following this approach. Using a large population-based dataset, we evaluated risk factors for operative intervention and mortality at readmission in patients with ASBO who were initially managed nonoperatively. METHODS The ASBO patients were identified in the California Office of Statewide Health Planning and Development 2007 to 2014 patient discharge database. Patients who were managed operatively at index admission or had an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for nonadhesive obstructive small bowel disease were excluded. Associations between risk factors and both operative intervention and death following readmission were evaluated using survival analysis. RESULTS Among 15,963 ASBO patients, 3,103 (19.4%) had at least one readmission. The 1,069 (34.5%) who received an operation during their first readmission presented sooner (175 days vs. 316 days, p < 0.001) and were more likely to die during that readmission (5.2% vs. 0.7%, p < 0.001). Operative management at first readmission was associated with younger age, fewer comorbidities, and shorter times to readmission. Patients operatively managed at first readmission had longer times to second readmission compared with nonoperative patients. Stratified analyses using nonoperative patients as the reference over the study period revealed that patients who underwent lysis of adhesions and bowel resection were 5.04 times (95% confidence interval [CI], 2.82-9.00) as likely to die while those who underwent lysis only were 2.09 times (95% CI, 1.14-3.85) as likely to die. Patients with bowel resection only were at an increased risk for subsequent interventions beyond the first readmission (hazard ratio, 1.79; 95% CI, 1.11-2.87). CONCLUSION In a large cohort readmitted for ASBO and initially managed nonoperatively, subsequent operative intervention conferred a greater risk of death and a longer time to readmission among survivors. Prospective research is needed to further delineate outcomes associated with initial nonoperative management of ASBO. LEVEL OF EVIDENCE Prognostic and epidemiological, level III.

Background Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood. Methods Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types. Results AS03-adjuvanted vaccine induced the strongest differential signals on day 1 postvaccination, activating multiple innate immune pathways including interferon and JAK-STAT signaling, Fcγ receptor (FcγR)-mediated phagocytosis, and antigen processing and presentation. Changes in signal transduction and immunoglobulin genes predicted peak hemagglutinin inhibition (HAI) titers. Compared with individual immune cell types, activated PBMC genes and pathways were most similar to innate immune cells. However, several pathways were unique to PBMCs, and several pathways identified in individual cell types were absent in PBMCs. Conclusions Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early activation of innate immune signaling, including a 5- to 8-fold upregulation of FcγR1A/1B/1C genes. Several early gene responses were correlated with HAI titer, indicating links with the adaptive immune response. Although PBMCs and cell-specific results shared key innate immune signals, unique signals were identified by both approaches.

Background: Vascular smooth muscle cells (VSMC) exhibit phenotypic plasticity in atherosclerotic plaques, and among other approaches, has been modeled in vitro by cholesterol loading. Methods: Meta-analysis of scRNA-seq data from VSMC lineage traced cells across five experiments of murine atherosclerosis was performed. In vivo expression profiles were compared to three in vitro datasets of VSMCs loaded with cholesterol and three datasets of polarized macrophages. Results: We identified 24 cell clusters in the meta-analysis of single cells from mouse atherosclerotic lesions with notable heterogeneity across studies, especially for macrophage populations. Trajectory analysis of VSMC lineage positive cells revealed several possible paths of state transitions with one traversing from contractile VSMC to macrophages by way of a proliferative cell cluster. Transcriptome comparisons between in vivo and in vitro states underscored that data from three in vitro cholesterol-treated VSMC experiments did not mirror cell state transitions observed in vivo. However, all in vitro macrophage profiles analyzed (M1, M2, and oxLDL) were more similar to in vivo profiles of macrophages than in vitro VSMCs were to in vivo profiles of VSMCs. oxLDL loaded macrophages showed the most similarity to in vivo states. In contrast to the in vitro data, comparison between mouse and human in vivo data showed many similarities. Conclusions: Identification of the sources of variation across single cell datasets in atherosclerosis will be an important step towards understanding VSMC fate transitions in vivo. Also, we conclude that cholesterol-loading in vitro is insufficient to model the VSMC cell state transitions observed in vivo, which underscores the need to develop better cell models. Mouse models, however, appear to reproduce a number of the features of VSMCs in human plaques

Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.

BackgroundDamage control laparotomy (DCL) is a life-saving procedure in patients with abdominal hemorrhage. After DCL, patients are sometimes left with an open abdomen (OA) so they may undergo multiple exploratory laparotomies (EXLAP), or re-explorations. Patients with OA are at increased risk of infectious complications (ICs). The association between number of re-explorations after DCL and the number of ICs is not clear. We hypothesized that each additional re-exploration increases the risk of developing IC.MethodsThis 6-year retrospective cohort study included patients aged ≥16 years from the NTDB who had DCL defined as EXLAP within 2 hours of arrival (ICD-9: 54.11, 54.12, 54.19) with at least one re-exploration. The primary outcome was IC (ie, superficial surgical site infection (SSI), organ space SSI, deep SSI, sepsis, pneumonia, or catheter-related bloodstream infection), examined dichotomously (present/absent) and ordinally as the number of ICs. Multivariate Poisson regression was used to assess the association between number of re-explorations and number of ICs. Significance was assigned at pResultsThere were 7431 patients who underwent DCL; 2509 (34%) patients developed at least one IC. The rate of IC was lowest in patients who were closed during the first re-exploration (27%) and significantly increased with each re-exploration to 59% in patients who had five or more re-explorations (Cochran-Armitage trend pDiscussionFor patients requiring DCL, each re-exploration of the abdomen is associated with increased rate of ICs.Level of evidenceIII, retrospective epidemiological study.

Purpose: Mechanical loading of bone defects through rehabilitation is a promising approach to stimulate repair and reduce nonunion risk; however, little is known about how therapeutic mechanical stimuli modulate early-stage repair before mineralized bone formation. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression and angiogenesis during the first 3 weeks of BMP-2 mediated segmental bone defect repair. Materials and Methods: A rat model of BMP-2 mediated bone defect repair was subjected to an osteogenic mechanical loading protocol using ambulatory rehabilitation and a compliant, load-sharing fixator with an integrated implantable strain sensor. The effect of fixator load-sharing on local tissue strain, angiogenesis, and cytokine expression was evaluated. Results: Using sensor readings for local measurements of boundary conditions, finite element simulations showed strain became amplified in remaining soft tissue regions between 1 and 3 weeks (Week 3: load-sharing: ���1.89 �� 0.35% and load-shielded: ���1.38 �� 0.35% vs. Week 1: load-sharing: ���1.54 �� 0.17%; load-shielded: ���0.76 �� 0.06%). Multivariate analysis of cytokine arrays revealed that load-sharing significantly altered expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF (p = 0.052) and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects at 3 weeks. Conclusions: Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification.

The purpose of this study was to compare the independent and combined effects of high‐intensity interval training (HIIT) and essential amino acids (EAA) on lean mass, muscle characteristics of the quadriceps, and 24‐hr whole‐body protein turnover (WBPT) in overweight and obese adults. An exploratory aim was to evaluate potential modulatory effects of sex. Sixty‐six adults (50% female; Age: 36.7 ± 6.0 yrs; %BF: 36.0 ± 7.8%) were assigned to 8 wks of: (a) HIIT, 2 days/wk; (b) EAA supplementation, 3.6 g twice daily; (c) HIIT + EAA; or (d) control. At baseline, 4 wks, and 8 wks, total body, thigh LM and muscle characteristics were measured via dual‐energy x‐ray absorptiometry and B‐mode ultrasound, respectively. In a subsample, changes in WBPT was measured using [N15]alanine. Differences between groups were assessed using linear mixed models adjusted for baseline values, followed by 95% confidence intervals on adjusted mean change scores (Δ). HIIT and HIIT + EAA improved thigh LM (Δ: +0.17 ± 0.05 kg [0.08, 0.27]; +0.22 ± 0.05 kg [0.12,0.31]) and vastus lateralis cross‐sectional area (Δ: +2.73 ± 0.52 cm2 [1.69,3.77]; +2.64 ± 0.53 cm2 [1.58,3.70]), volume (Δ: +54.50 ± 11.69 cm3 [31.07, 77.92]; +62.39 ± 12.05 cm3 [38.26, 86.52]), and quality (Δ: −5.46 ± 2.68a.u. [−10.84, −0.09]; −7.97 ± 2.76a.u.[−13.49, −2.45]). Protein synthesis, breakdown, and flux were greater with HIIT + EAA and EAA compared to HIIT (p, In overweight and obese adults, eight weeks of high‐intensity interval training, with or without essential amino acid supplementation (EAA), improved thigh lean mass size and quality; EAA may enhance muscular adaptation via increases in protein turnover, supporting greater improvements in muscular size and quality.

SUMMARY Klebsiella pneumoniae ST258 is a human pathogen associated with poor outcomes worldwide. We identify a member of the acyltransferase superfamily 3 (atf3), enriched within the ST258 clade, that provides a major competitive advantage for the proliferation of these organisms in vivo. Comparison of a wild-type ST258 strain (KP35) and a Δatf3 isogenic mutant generated by CRISPR-Cas9 targeting reveals greater NADH:ubiquinone oxidoreductase transcription and ATP generation, fueled by increased glycolysis. The acquisition of atf3 induces changes in the bacterial acetylome, promoting lysine acetylation of multiple proteins involved in central metabolism, specifically Zwf (glucose-6 phosphate dehydrogenase). The atf3-mediated metabolic boost leads to greater consumption of glucose in the host airway and increased bacterial burden in the lung, independent of cytokine levels and immune cell recruitment. Acquisition of this acyltransferase enhances fitness of a K. pneumoniae ST258 isolate and may contribute to the success of this clonal complex as a healthcare-associated pathogen., Graphical Abstract, In brief Klebsiella pneumoniae ST258 is a successful human pathogen. Here, Ahn et al. identify an acyltransferase of the superfamily 3 (atf3) concentrated within one of the ST258 clades. Acquisition of this gene leads to enhanced bioenergetic properties, giving the pathogen a competitive advantage in vivo.

Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.

The nonhuman primate provides a sophisticated animal model system both to explore neurobiological mechanisms underlying complex behaviors and to facilitate preclinical research for neurodevelopmental and neuropsychiatric disease. A better understanding of evolutionarily conserved behaviors and brain processes between humans and nonhuman primates will be needed to successfully apply recently released NIMH guidelines (NOT-MH-19-053) for conducting rigorous nonhuman primate neurobehavioral research. Here, we explore the relationship between two measures of social behavior that can be used in both humans and nonhuman primates-traditional observations of social interactions with conspecifics and eye gaze detection in response to social stimuli. Infant male rhesus macaques (Macaca mulatta) serving as controls (N=14) for an ongoing study were observed in their social rearing groups and participated in a noninvasive, longitudinal eye-tracking study. We found significant positive relationships between time spent viewing eyes of faces in an eye tracker and number of initiations made for social interactions with peers that is consistent with similar observations in human populations. Although future studies are needed to determine if this relationship represents species-typical social developmental processes, these preliminary results provide a novel framework to explore the relationship between social interactions and social attention in nonhuman primate models for neurobehavioral development.

Like other persistent intracellular pathogens, Toxoplasma gondii, a protozoan parasite, has evolved to evade the immune system and establish a chronic infection in specific cells and organs, including neurons in the CNS. Understanding T. gondii’s persistence in neurons holds the potential to identify novel, curative drug targets. The work presented here offers new insights into the neuron-T. gondii interaction in vivo. By transcriptionally profiling neurons manipulated by T. gondii, we unexpectedly revealed that immune cells, and specifically CD8+ T cells, appear to cluster around these neurons, suggesting that CD8+ T cells specifically recognize parasite-manipulated neurons. Such a possibility supports evidence from other labs that questions the long-standing dogma that neurons are often persistently infected because they are not directly recognized by immune cells such as CD8+ T cells. Collectively, these data suggest we reconsider the broader role of neurons in the context of infection and neuroinflammation., Toxoplasma gondii’s tropism for and persistence in the central nervous system (CNS) underlies the symptomatic disease that T. gondii causes in humans. Our recent work has shown that neurons are the primary CNS cell with which Toxoplasma interacts and which it infects in vivo. This predilection for neurons suggests that T. gondii’s persistence in the CNS depends specifically upon parasite manipulation of the host neurons. Yet, most work on T. gondii-host cell interactions has been done in vitro and in nonneuronal cells. We address this gap by utilizing our T. gondii-Cre system that allows permanent marking and tracking of neurons injected with parasite effector proteins in vivo. Using laser capture microdissection (LCM) and RNA sequencing using RNA-seq, we isolated and transcriptionally profiled T. gondii-injected neurons (TINs), Bystander neurons (nearby non-T. gondii-injected neurons), and neurons from uninfected mice (controls). These profiles show that TIN transcriptomes significantly differ from the transcriptomes of Bystander and control neurons and that much of this difference is driven by increased levels of transcripts from immune cells, especially CD8+ T cells and monocytes. These data suggest that when we used LCM to isolate neurons from infected mice, we also picked up fragments of CD8+ T cells and monocytes clustering in extreme proximity around TINs and, to a lesser extent, Bystander neurons. In addition, we found that T. gondii transcripts were primarily found in the TIN transcriptome, not in the Bystander transcriptome. Collectively, these data suggest that, contrary to common perception, neurons that directly interact with or harbor parasites can be recognized by CD8+ T cells. IMPORTANCE Like other persistent intracellular pathogens, Toxoplasma gondii, a protozoan parasite, has evolved to evade the immune system and establish a chronic infection in specific cells and organs, including neurons in the CNS. Understanding T. gondii’s persistence in neurons holds the potential to identify novel, curative drug targets. The work presented here offers new insights into the neuron-T. gondii interaction in vivo. By transcriptionally profiling neurons manipulated by T. gondii, we unexpectedly revealed that immune cells, and specifically CD8+ T cells, appear to cluster around these neurons, suggesting that CD8+ T cells specifically recognize parasite-manipulated neurons. Such a possibility supports evidence from other labs that questions the long-standing dogma that neurons are often persistently infected because they are not directly recognized by immune cells such as CD8+ T cells. Collectively, these data suggest we reconsider the broader role of neurons in the context of infection and neuroinflammation.

Background The uptake of point-of-care testing (POCT) within community pharmacies at state and national levels is largely unknown despite the endorsement and advocacy efforts of pharmacy organizations, recent legislative advances, and numerous models for successful POCT implementation within individual pharmacy sites. Objectives The study aimed to describe the current landscape of POCT in Wisconsin community pharmacies and identify opportunities for the advancement of testing and the key factors influencing the realization of these opportunities. Methods A survey was administered over the telephone to pharmacy managers of community pharmacies in Wisconsin. The sites were randomly selected from predefined geographic regions to mirror pharmacy distribution across Wisconsin. The survey items evaluated provision of POCT, future direction of POCT, barriers and motivators to offering POCT, and pharmacy demographics. Descriptive statistics and thematic analysis were used to analyze data. Results Pharmacy managers from 147 of the 938 registered community pharmacies (15.7%) participated in the survey. Only 17.1% of the pharmacies were offering POCT; however, 48.3% of managers reported that their pharmacy would likely implement or expand POCT within the next 5 years. The most commonly reported barriers to initiating or expanding POCT were the limitations on pharmacist availability to oversee testing and workflow restrictions. Continuing to advance the pharmacy profession was a top reason for offering or expanding testing services. Discussion While few pharmacies are offering POCT in Wisconsin, there is motivation for expansion in coming years. Understanding, anticipating and addressing common barriers can faciliate this process. Conclusion This needs analysis offers a blueprint for researchers, educators, and clinicians to shape POCT efforts by examining the landscape of pharmacy-based testing in their own states and communities.

Staphylococcus aureus is a Gram-positive pathogen capable of infecting nearly every vertebrate organ. Among these tissues, invasive infection of bone (osteomyelitis) is particularly common and induces high morbidity. Treatment of osteomyelitis is notoriously difficult and often requires debridement of diseased bone in conjunction with prolonged antibiotic treatment to resolve infection. During osteomyelitis, S. aureus forms characteristic multicellular microcolonies in distinct niches within bone. Virulence and metabolic responses within these multicellular microcolonies are coordinated, in part, by quorum sensing via the accessory gene regulator (agr) locus, which allows staphylococcal populations to produce toxins and adapt in response to bacterial density. During osteomyelitis, the Agr system significantly contributes to dysregulation of skeletal homeostasis and disease severity but may also paradoxically inhibit persistence in the host. Moreover, the Agr system is subject to complex crosstalk with other S. aureus regulatory systems, including SaeRS and SrrAB, which can significantly impact the progression of osteomyelitis. The objective of this review is to highlight Agr regulation, its implications on toxin production, factors that affect Agr activation, and the potential paradoxical influences of Agr regulation on disease progression during osteomyelitis.

Francisella tularensis (F. tularensis) is an intracellular pathogen that causes a potentially debilitating febrile illness known as tularemia. F. tularensis can be spread by aerosol transmission and cause fatal pneumonic tularemia. If untreated, mortality rates can be as high as 30%. To study the host responses to a live-attenuated tularemia vaccine, peripheral blood mononuclear cell (PBMC) samples were assayed from 10 subjects collected pre- and post-vaccination, using both the 2D-DIGE/MALDI-MS/MS and LC-MS/MS approaches. Protein expression related to antigen processing and presentation, inflammation (PPAR&gamma, nuclear receptor), phagocytosis, and gram-negative bacterial infection was enriched at Day 7 and/or Day 14. Protein candidates that could be used to predict human immune responses were identified by evaluating the correlation between proteome changes and humoral and cellular immune responses. Consistent with the proteomics data, parallel transcriptomics data showed that MHC class I and class II-related signals important for protein processing and antigen presentation were up-regulated, further confirming the proteomic results. These findings provide new biological insights that can be built upon in future clinical studies, using live attenuated strains as immunogens, including their potential use as surrogates of protection.

Skilled nursing facilities (SNFs) are focal points of the coronavirus disease 2019 (COVID-19) pandemic, and asymptomatic infections with SARS-CoV-2, the virus that causes COVID-19, among SNF residents and health care personnel have been described (1-3). Repeated point prevalence surveys (serial testing of all residents and health care personnel at a health care facility irrespective of symptoms) have been used to identify asymptomatic infections and have reduced SARS-CoV-2 transmission during SNF outbreaks (1,3). During March 2020, the Detroit Health Department and area hospitals detected a sharp increase in COVID-19 diagnoses, hospitalizations, and associated deaths among SNF residents. The Detroit Health Department collaborated with local government, academic, and health care system partners and a CDC field team to rapidly expand SARS-CoV-2 testing and implement infection prevention and control (IPC) activities in all Detroit-area SNFs. During March 7-May 8, among 2,773 residents of 26 Detroit SNFs, 1,207 laboratory-confirmed cases of COVID-19 were identified during three periods: before (March 7-April 7) and after two point prevalence surveys (April 8-25 and April 30-May 8): the overall attack rate was 44%. Within 21 days of receiving their first positive test results, 446 (37%) of 1,207 COVID-19 patients were hospitalized, and 287 (24%) died. Among facilities participating in both surveys (n = 12), the percentage of positive test results declined from 35% to 18%. Repeated point prevalence surveys in SNFs identified asymptomatic COVID-19 cases, informed cohorting and IPC practices aimed at reducing transmission, and guided prioritization of health department resources for facilities experiencing high levels of SARS-CoV-2 transmission. With the increased availability of SARS-CoV-2 testing, repeated point prevalence surveys and enhanced and expanded IPC support should be standard tools for interrupting and preventing COVID-19 outbreaks in SNFs.

Prognosis communication in heart failure is often narrowly defined as a discussion of life expectancy, but as clinical guidelines and research suggest, these discussions should provide a broader understanding of the disease, including information about disease trajectory, the experiences of living with heart failure, potential burden on patients and families, and mortality. Furthermore, despite clinical guidelines recommending early discussions, evidence suggests that these discussions occur infrequently or late in the disease trajectory. We review the literature concerning patient, caregiver, and clinician perspectives on discussions of this type, including the frequency, timing, desire for, effects of, and barriers to their occurrence. We propose an alternate view of prognosis communication, in which the patient and family/caregiver are educated about the nature of the disease at the time of diagnosis, and a process of engagement is undertaken so that the patient's full participation in their care is marshalled, and the care team engages the patient in the informed decision making that will guide care throughout the disease trajectory. We also identify and discuss evidence gaps concerning (i) patient preferences and readiness for prognosis information along the trajectory; (ii) best practices for communicating prognosis information; and (iii) effects of prognosis communication on patient's quality of life, mental health, engagement in critical self‐care, and clinical outcomes. Research is needed to determine best practices for engaging patients in prognosis communication and for evaluating the effects of this communication on patient engagement and clinical outcomes.

The immune response to live-attenuated Francisella tularensis vaccine and its host evasion mechanisms are incompletely understood. Using RNA-Seq and LC&ndash, MS on samples collected pre-vaccination and at days 1, 2, 7, and 14 post-vaccination, we identified differentially expressed genes in PBMCs, metabolites in serum, enriched pathways, and metabolites that correlated with T cell and B cell responses, or gene expression modules. While an early activation of interferon &alpha, /&beta, signaling was observed, several innate immune signaling pathways including TLR, TNF, NF-&kappa, B, and NOD-like receptor signaling and key inflammatory cytokines such as Il-1&alpha, Il-1&beta, and TNF typically activated following infection were suppressed. The NF-&kappa, B pathway was the most impacted and the likely route of attack. Plasma cells, immunoglobulin, and B cell signatures were evident by day 7. MHC I antigen presentation was more actively up-regulated first followed by MHC II which coincided with the emergence of humoral immune signatures. Metabolomics analysis showed that glycolysis and TCA cycle-related metabolites were perturbed including a decline in pyruvate. Correlation networks that provide hypotheses on the interplay between changes in innate immune, T cell, and B cell gene expression signatures and metabolites are provided. Results demonstrate the utility of transcriptomics and metabolomics for better understanding molecular mechanisms of vaccine response and potential host&ndash, pathogen interactions.

ObjectiveCondom use behaviours are proximal to recent STI increases in the USA, yet it remains unclear whether the use of condoms has changed over time among unmarried, non-cohabiting young men who have sex with women (MSW) and how this variability is influenced by STI risk factors.MethodsTo examine condom use over time among MSW aged 15–29, we used three cross-sectional surveys from the 2002, 2006–2010 and 2011–2017 National Survey of Family Growth. We estimated weighted percentages, adjusted prevalence ratios (APRs) and 95% confidence intervals (CI) to assess changes in condom use, stratified by whether MSW reported any STI risk factors in the past 12 months (ie, perceived partner non-monogamy, male-to-male sex, sex in exchange for money or drugs, sex partner who injects illicit drugs, or an HIV-positive sex partner).ResultsWe observed a divergence in trends in condom use at last sex between men aged 15 –29 with STI risk factors in the past 12 months and those without such history. We saw significant declines in condom use from 2002 to 2011–2017 among men with STI risk factors (APR=0.80, 95% CI 0.68 to 0.95), specifically among those aged 15–19 (APR=0.73, 95% CI 0.57 to 0.94) or non-Hispanic white (APR=0.71, 95% CI 0.54 to 0.93). In contrast, trends in condom use among men with no STI factors remained stable or increased. Across all time periods, the most prevalent STI risk factor reported was perception of a non-monogamous female partner (23.0%–26.9%). Post-hoc analyses examined whether condom use trends changed once this variable was removed from analyses, but no different patterns were observed.ConclusionsWhile STIs have been increasing, men aged 15–29 with STI risk factors reported a decline in condom use. Rising STI rates may be sensitive to behavioural shifts in condom use among young MSW with STI risk factors.

Purpose Lacritin is a tear glycoprotein with pro-tearing and pro-ocular surface homeostasis activities that is selectively deficient in most dry eye tears. Proteoforms include an active monomer, inactive polymers, and a splice variant termed lacritin-c. Quantitation of the different proteoforms of tear lacritin may provide a diagnostic tool for ocular diseases. Here, we report the development of an immunoassay for the quantification of multiple lacritin proteoforms in human tear samples. Methods Basal tears collected on Schirmer test strips with anesthesia were eluted by diffusion and centrifugation under optimized conditions. Tear protein concentrations were determined, and 2.56 µg of each sample was separated by SDS-PAGE followed by western blot analysis. Blots were challenged with anti-Pep Lac N-term antibodies. Detection was with fluorescent secondary antibodies visualized by the LI-COR Odyssey CLx imaging system and quantified with standard curves of recombinant lacritin. Results The percent total lacritin (ng lacritin/100 ng total protein) ranged from 1.8% to 14.8%. Monomer, lacritin-c, and polymer proteoform percent total protein ranged from 1.1% to 6.3%, 0.3% to 5.4%, and 0.7% to 5.7%, respectively. Monomer lacritin was detected at concentrations of 6 to 176 µM, with lacritin-c and polymer proteoforms at 2 to 46 µM and 1 to 23 µM, respectively. Conclusions This assay greatly exceeds the power and sensitivity of our prior lacritin enzyme-linked immunosorbent assay that was not capable of distinguishing monomer from polymers and lacritin-c proteoforms. Translational relevance A new method has been developed to quantitate multiple proteoforms of tear lacritin in preparation for analyses of samples from clinical trials.

Microfluidic devices are widely used for applications such as cell isolation. Currently, the most common method to improve throughput for microfluidic devices involves fabrication of multiple, identical channels in parallel. However, this 'numbering up' only occurs in one dimension, thereby limiting gains in volumetric throughput. In contrast, macro-fluidic devices permit high volumetric flow-rates but lack the finer control of microfluidics. Here, we demonstrate how a micro-pore array design enables flow homogenization across a magnetic cell capture device, thus creating a massively parallel series of micro-scale flow channels with consistent fluidic and magnetic properties, regardless of spatial location. This design enables scaling in 2-dimensions, allowing flow-rates exceeding 100 mL/hr while maintaining >90% capture efficiencies of spiked lung cancer cells from blood in a simulated circulating tumor cell system. Additionally, this design facilitates modularity in operation, which we demonstrate by combining two different devices in tandem for multiplexed cell separation in a single pass with no additional cell losses from processing.

The changing profession of pharmacy demands student preparation in dynamic courses that address the evolving healthcare landscape. Identifying an evidence-based approach to develop such coursework and content, however, can be a considerable challenge for curriculum innovators. This manuscript explores how curriculum design models can be applied as a guide to promote purposeful development of new curriculum, with the goal of promoting students as APPE, practice, and career-ready practitioners. Authors specifically describe a case study example for the process of creating a novel rural health course using the Taba curriculum design model as a guide for selecting course content, objectives, teaching strategies, learning experiences, and evaluative measures. Through the incorporation of the Taba model, this manuscript presents an evidence-based approach to curriculum development which can be replicated across schools and colleges of pharmacy. The described approach to curriculum design, which integrates models to guide the creative process, is a systematic approach to developing curriculum with purpose. Additional opportunities exist for curriculum innovators across the academy to explore incorporation of curriculum design models to guide course development, as well as to drive curricular assessment strategies and further curriculum refinement. Article Type: Idea Paper

Objective. To use an expert consensus-building process to develop a rubric used by multiple evaluator types to assess Doctor of Pharmacy students’ patient communication skills. Methods. Faculty and staff members from six schools and colleges of pharmacy collaborated on a multi-step expert consensus-building process to create the final version of a communication rubric. First, faculty and patient content experts evaluated each item in the rubric for its relevance, criticality, and global comprehensiveness using a five-point Likert scale (0=not at all, 4=to a high extent). Descriptive statistics were used to analyze the resulting data. Faculty members evaluated the results and came to a consensus on the second version of the rubric. A corresponding codebook was developed and refined through a two-phase process. Results. The initial communication rubric was evaluated by 13 expert reviewers. Mean global comprehensiveness on the rubric was 3.83 for faculty experts and 3.5 for patient experts. After evaluating results from the expert consensus-building process, 14 items on the rubric did not change, five items were revised, three items were removed, and two items were added. The second version of the instrument included 20 items in six topic areas. A codebook was finalized to increase scoring consistency for the 20 communication items. Conclusion. Overall, content experts concluded that the rubric had high global comprehensiveness. Collaboration involving faculty members from multiple schools of pharmacy resulted in a 20-item communication rubric and codebook that can be used to increase consistency in scoring student pharmacists’ patient communication skills.

Mycobacterium chelonae is a rapidly growing nontuberculous mycobacterium that is a common cause of nosocomial infections. Here we describe investigation of a possible nosocomial transmission of M. chelonae at the Hospital of the University of Pennsylvania (HUP). M. chelonae strains with similar high-level antibiotic resistance patterns were isolated from two patients who developed post-operative infections at HUP in 2017, suggesting a possible point source infection. The isolates, along with other clinical isolates from other patients, were sequenced using the Illumina and Oxford Nanopore technologies. The resulting short and long reads were hybrid assembled into draft genomes. The genomes were compared by quantifying single nucleotide variants in the core genome and assessed using a control dataset to quantify error rates in comparisons of identical genomes. We show that all M. chelonae isolates tested were highly dissimilar, as indicated by high pairwise SNV values, consistent with environmental acquisition and not a nosocomial point source. Our control dataset determined a threshold for evaluating identity between strains while controlling for sequencing error. Finally, antibiotic resistance genes were predicted for our isolates, and several single nucleotide variants were identified that have the potential to modulated drug resistance.

We profiled the liver transcriptome, proteome, and metabolome in 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wild-type and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into dietary and aging effects. Candidates were cross-examined in an independent diversity outbred mouse liver dataset segregating for similar diets, with 80%-90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections. ISSN:2405-4720

Previous work has demonstrated that dopamine and adenosine receptors are involved in drug-seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D2-like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation. Adult male Sprague–Dawley rats were trained to lever press for MA in daily 2-h self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days. After 1 day of abstinence, lever pressing was extinguished in six daily extinction sessions. Treatments were administered systemically prior to a 2-h reinstatement test session. An increase in MA seeking was observed following the administration of the dopamine D2-like agonist, quinpirole, or the D3 receptor agonist, 7-OH-DPAT. Stimulation of D2 or D4 receptors was ineffective at inducing MA seeking. Quinpirole-induced MA seeking was inhibited by D3 receptor antagonism (SB-77011A or PG01037), an adenosine A1 agonist, CPA, and an adenosine A2A agonist, CGS 21680. MA seeking induced by a MA priming injection or D3 receptor stimulation was inhibited by a pretreatment with the adenosine A1 agonist, CPA, but not the adenosine A2A agonist, CGS 21680. These results demonstrate the sufficiency of dopamine D3 receptors to reinstate MA seeking that is inhibited when combined with adenosine A1 receptor stimulation.

Adenosine signaling through adenosine A2A receptors (A2ARs) is known to influence cocaine-induced behaviors. These studies sought to elucidate how two A2AR antagonists distinguished by their antagonist effects at presynaptic and postsynaptic A2AR influence cocaine-induced locomotion and cocaine seeking. Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A2AR, respectively. We evaluated the effects of these antagonists on both basal and cocaine-induced locomotion in cocaine-naive rats and rats that received seven daily cocaine treatments. The effects of SCH 442416 or istradefylline on cocaine seeking were measured in animals extinguished from cocaine self-administration. We assessed the effects of the A2AR antagonists to induce cocaine seeking when administered alone and their effects on cocaine seeking induced by a cocaine-priming injection. Lastly, we evaluated the effects of the antagonists on sucrose seeking in animals extinguished from sucrose self-administration. Neither istradefylline nor SCH 442416 significantly altered basal locomotion. Istradefylline enhanced acute cocaine-induced locomotion but had no effect on the expression of locomotor sensitization. SCH 44216 had no effect on acute cocaine-induced locomotion but inhibited the expression of locomotor sensitization. Istradefylline was sufficient to induce cocaine seeking and augmented both cocaine-induced seeking and sucrose seeking. SCH 442416 inhibited cocaine-induced seeking, but had no effect on sucrose seeking and did not induce cocaine seeking when administered alone. These findings demonstrate differential effects of two A2AR antagonists distinguished by their effects at pre- and postsynaptic A2AR on cocaine-induced behaviors.

Objective The objective is to provide guidance for pregnant women, and obstetric care and exercise professionals, on prenatal physical activity. Outcomes The outcomes evaluated were maternal, fetal, or neonatal morbidity or fetal mortality during and following pregnancy. Evidence Literature was retrieved through searches of Medline, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science Core Collection, CINAHL Plus with Full-text, Child Development & Adolescent Studies, ERIC, Sport Discus, ClinicalTrials.gov, and the Trip Database from database inception up to January 6, 2017. Primary studies of any design were eligible, except case studies. Results were limited to English, Spanish, or French language materials. Articles related to maternal physical activity during pregnancy reporting on maternal, fetal, or neonatal morbidity or fetal mortality were eligible for inclusion. The quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Values The Guidelines Consensus Panel solicited feedback from end-users (obstetric care providers, exercise professionals, researchers, policy organizations, and pregnant and postpartum women). The development of this guideline followed the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument. Benefits, harms, and costs The benefits of prenatal physical activity are moderate, and no harms were identified; therefore, the difference between desirable and undesirable consequences (net benefit) is expected to be moderate. The majority of stakeholders and end-users indicated that following these recommendations would be feasible, acceptable, and equitable. Following these recommendations is likely to require minimal resources from both individual and health systems perspectives. Preamble This guideline provide evidence-based recommendations regarding physical activity throughout pregnancy in the promotion of maternal, fetal, and neonatal health. In the absence of contraindications (see later for a detailed list), following this guideline is associated with: (1) fewer newborn complications (i.e., large for gestational age); and (2) maternal health benefits (i.e., decreased risk of preeclampsia, gestational hypertension, gestational diabetes, Caesarean section, instrumental delivery, urinary incontinence, excessive gestational weight gain, and depression; improved blood glucose; decreased total gestational weight gain; and decreased severity of depressive symptoms and lumbopelvic pain). Physical activity is not associated with miscarriage, stillbirth, neonatal death, preterm birth, preterm/prelabour rupture of membranes, neonatal hypoglycemia, low birth weight, birth defects, induction of labour, or birth complications. In general, more physical activity (frequency, duration, and/or volume) is associated with greater benefits. However, evidence was not identified regarding the safety or additional benefit of exercising at levels significantly above the recommendations. Prenatal physical activity should be considered a front-line therapy for reducing the risk of pregnancy complications and enhancing maternal physical and mental health. For pregnant women not currently meeting this guideline, a progressive adjustment toward them is recommended. Previously active women may continue physical activity throughout pregnancy. Women may need to modify physical activity as pregnancy progresses. There may be periods when following the guideline is not possible due to fatigue and/or discomforts of pregnancy; women are encouraged to do what they can and to return to following the recommendations when they are able. This guideline were informed by an extensive systematic review of the literature, expert opinion, end-user consultation and considerations of feasibility, acceptability, costs, and equity. Recommendations The specific recommendations in this 2019 Canadian Guideline for Physical Activity Throughout Pregnancy are provided below with corresponding statements indicating the quality of the evidence informing the recommendations and the strength of the recommendations (explanations follow). Contraindications All pregnant women can participate in physical activity throughout pregnancy with the exception of those who have contraindications (listed below). Women with absolute contraindications may continue their usual activities of daily living but should not participate in more strenuous activities. Women with relative contraindications should discuss the advantages and disadvantages of moderate-to-vigorous intensity physical activity with their obstetric care provider prior to participation. Absolute contraindications to exercise are the following: Relative contraindications to exercise are the following: STRENGTH OF THE RECOMMENDATIONS: The GRADE system was utilized to grade the strength of the recommendations. Recommendations are rated as strong or weak based on the: (1) balance between benefits and harms; (2) overall quality of the evidence; (3) importance of outcomes (i.e., values and preferences of pregnant women); (4) use of resources (i.e., cost); (5) impact on health equity; (6) feasibility, and (7) acceptability. Strong recommendation: Most or all pregnant women will be best served by the recommended course of action. Weak recommendation: Not all pregnant women will be best served by the recommended course of action; there is a need to consider other factors such as the individual's circumstances, preferences, values, resources available, or setting. Consultation with an obstetric care provider may assist in decision-making. Quality of the evidence The quality of the evidence refers to the level of confidence in the evidence and ranges from very low to high. High quality: The Guideline Consensus Panel is very confident that the estimated effect of physical activity on the health outcome is close to the true effect. Moderate quality: The Guideline Consensus Panel is moderately confident in the estimated effect of physical activity on the health outcome; the estimate of the effect is likely to be close to the true effect, but there is a possibility that it is substantially different. Low quality: The Guideline Consensus Panel's confidence in the estimated effect of physical activity on the health outcome is limited; the estimate of the effect may be substantially different from the true effect. Very low quality: The Guideline Consensus Panel has very little confidence in the estimated effect of physical activity on the health outcome; the estimate of the effect is likely to be substantially different from the true effect. aThis was a weak recommendation because the quality of evidence was low, and the net benefit between women who were physically active and those who were not was small. bThis was a strong recommendation because, despite low quality evidence supporting physical activity during pregnancy for women categorized as overweight or obese, there was evidence from randomized controlled trials demonstrating an improvement in gestational weight gain and blood glucose. cModerate-intensity physical activity is intense enough to noticeably increase heart rate; a person can talk but not sing during activities of this intensity. Examples of moderate-intensity physical activity include brisk walking, water aerobics, stationary cycling (moderate effort), resistance training, carrying moderate loads, and household chores (e.g., gardening, washing windows). dThis was a weak recommendation because urinary incontinence was was not rated as a "critical" outcome and the evidence was low quality. eThis was a weak recommendation because: (1) the quality of evidence was very low; and (2) although harms were investigated there was limited available information to inform the balance of benefits and harms. This recommendation was primarily based on expert opinion.

Screening for blunt cerebrovascular injuries (BCVIs) in asymptomatic high-risk patients has become routine. To date, the length of this asymptomatic period has not been defined. Determining the time to stroke could impact therapy including earlier initiation of antithrombotics in multiply injured patients. The purpose of this study was to determine the time to stroke in patients with a BCVI-related stroke. We hypothesized that the majority of patients suffer stroke between 24 hours and 72 hours after injury.Patients with a BCVI-related stroke from January 2007 to January 2017 from 37 trauma centers were reviewed.During the 10-year study, 492 patients had a BCVI-related stroke; the majority were men (61%), with a median age of 39 years and ISS of 29. Stroke was present at admission in 182 patients (37%) and occurred during an Interventional Radiology procedure in six patients. In the remaining 304 patients, stroke was identified a median of 48 hours after admission: 53 hours in the 144 patients identified by neurologic symptoms and 42 hours in the 160 patients without a neurologic examination and an incidental stroke identified on imaging. Of those patients with neurologic symptoms, 88 (61%) had a stroke within 72 hours, whereas 56 had a stroke after 72 hours; there was a sequential decline in stroke occurrence over the first week. Of the 304 patients who had a stroke after admission, 64 patients (22%) were being treated with antithrombotics when the stroke occurred.The majority of patients suffer BCVI-related stroke in the first 72 hours after injury. Time to stroke can help inform clinicians about initiation of treatment in the multiply injured patient.Prognostic/Epidemiologic, level III.

Objectif L'objectif est de guider les femmes enceintes et les professionnels de l'obstetrique et de l'exercice en ce qui concerne l'activite physique prenatale. ReSULTATS: Les issues evaluees etaient la morbidite maternelle, fœtale ou neonatale et la mortalite fœtale pendant et apres la grossesse. DONNeES: Nous avons interroge MEDLINE, Embase, PsycINFO, la Cochrane Database of Systematic Reviews, le Cochrane Central Register of Controlled Trials, Scopus et la Web of Science Core Collection, CINAHL Plus with Full Text, Child Development & Adolescent Studies, ERIC, SPORTDiscus, ClinicalTrials.gov de leur creation jusqu'au 6 janvier 2017. Les etudes primaires de tous types etaient admissibles, a l'exception des etudes de cas. Seules les publications en anglais, en espagnol et en francais ont ete retenues. Les articles lies a l'activite physique durant la grossesse qui abordaient la morbidite maternelle, fœtale ou neonatale ou la mortalite fœtale etaient admissibles. La qualite des donnees probantes a ete evaluee au moyen de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation). Valeurs Le groupe d'experts responsable des lignes directrices a recueilli les commentaires d'utilisateurs finaux (fournisseurs de soins obstetricaux, professionnels de l'exercice, chercheurs, organismes responsables de politiques, et femmes enceintes et en periode postpartum). La directive clinique a ete elaboree au moyen de l'outil Appraisal of Guidelines for Research Evaluation (AGREE) II. AVANTAGES, INCONVeNIENTS, ET COuTS: Les avantages de l'activite physique prenatale sont moderes, et aucun inconvenient n'a ete releve; la difference entre les consequences desirables et indesirables (avantage net) devrait donc etre moderee. La majorite des intervenants et des utilisateurs finaux ont indique qu'il serait faisable, acceptable et equitable de suivre ces recommandations, qui necessitent generalement des ressources minimes de la part des personnes et des systemes de sante. PREAMBULE: Les presentes lignes directrices contiennent des recommandations fondees sur des donnees probantes au sujet de l'activite physique durant la grossesse visant a favoriser la sante maternelle, fœtale et neonatale. En l'absence de contre-indications (voir la liste detaillee plus loin), le fait de suivre ces lignes directrices est associe a : 1) moins de complications pour le nouveau-ne (p. ex., gros par rapport a l'âge gestationnel); et 2) des bienfaits pour la sante maternelle (p. ex., diminution du risque de preeclampsie, d'hypertension gravidique, de diabete gestationnel, de cesarienne, d'accouchement operatoire, d'incontinence urinaire, de gain de poids excessif durant la grossesse et de depression; amelioration de la glycemie; diminution du gain de poids total durant la grossesse; et diminution de la gravite des symptomes depressifs et de la douleur lombo-pelvienne). L'activite physique n'est pas associee a la fausse couche, a la mortinaissance, au deces neonatal, a l'accouchement premature, a la rupture prematuree preterme des membranes, a l'hypoglycemie neonatale, au poids insuffisant a la naissance, aux anomalies congenitales, au declenchement du travail, ou aux complications a la naissance. En general, une augmentation de l'activite physique (frequence, duree ou volume) est liee a une augmentation des bienfaits. Cependant, nous n'avons pas trouve de donnees probantes concernant l'innocuite ou l'avantage accru de l'exercice a des niveaux considerablement superieurs aux recommandations. L'activite physique prenatale devrait etre vue comme un traitement de premiere ligne pour reduire le risque de complications de la grossesse et ameliorer la sante physique et mentale de la mere. Pour les femmes enceintes qui n'atteignent actuellement pas le niveau recommande, nous recommandons une augmentation progressive pour l'atteindre. Les femmes deja actives peuvent continuer de l'etre tout au long de la grossesse. Elles pourraient devoir modifier le type d'activite a mesure que leur grossesse avance. Il peut devenir impossible de suivre les lignes directrices pendant certaines periodes en raison de la fatigue ou des inconforts de la grossesse; nous encourageons les femmes a faire ce qu'elles peuvent et a revenir aux recommandations lorsqu'elles en sont capables. Les recommandations qui suivent reposent sur une revue systematique approfondie de la litterature, l'opinion d'experts, la consultation d'utilisateurs finaux et des considerations de faisabilite, d'acceptabilite, de cout et d'equite. Recommandations Les recommandations des Lignes directrices canadiennes sur l'activite physique durant la grossesse 2019 sont fournies ci-dessous avec des enonces indiquant la qualite des donnees probantes utilisees et la force des recommandations (des explications suivent). Contre-indications Toutes les femmes enceintes peuvent faire de l'activite physique durant la grossesse, sauf celles qui presentent des contre-indications (voir ci-dessous). Celles presentant des contre-indications absolues peuvent poursuivre leurs activites quotidiennes habituelles, mais ne devraient pas faire d'activites plus vigoureuses. Celles presentant des contre-indications relatives devraient discuter des avantages et des inconvenients de l'activite physique d'intensite moderee a vigoureuse avec leur fournisseur de soins obstetricaux avant d'y prendre part. Contre-indications absolues Contre-indications relatives FORCE DES RECOMMANDATIONS: Nous avons utilise le systeme GRADE pour evaluer la force des recommandations. Les recommandations sont jugees fortes ou faibles en fonction de : 1) l'equilibre entre les avantages et les inconvenients; 2) la qualite globale des donnees probantes; 3) l'importance des issues (valeurs et preferences des femmes enceintes); 4) l'utilisation de ressources (cout); 5) l'incidence sur l'equite en matiere de sante; 6) la faisabilite et 7) l'acceptabilite. Recommandation forte : La majorite ou la totalite des femmes enceintes auraient avantage a suivre la recommandation. Recommandation faible : Les femmes enceintes n'auraient pas toutes avantage a suivre la recommandation; il faut tenir compte d'autres facteurs comme la situation, les preferences, les valeurs, les ressources et le milieu de chaque personne. La consultation d'un fournisseur de soins obstetricaux peut faciliter la prise de decisions. QUALITe DES DONNeES PROBANTES: La qualite des donnees probantes fait reference au degre de confiance dans les donnees et va de tres faible a elevee. Qualite elevee : Le groupe d'experts responsable des lignes directrices est tres convaincu que l'effet estime de l'activite physique sur l'issue de sante est pres de l'effet reel. Qualite moyenne : Le groupe d'experts responsable des lignes directrices a moyennement confiance en l'effet estime de l'activite physique sur l'issue de sante; l'effet estime est probablement pres de l'effet reel, mais il est possible qu'il soit tres different. Qualite faible : Le groupe d'experts responsable des lignes directrices a peu confiance en l'effet estime de l'activite physique sur l'issue de sante; l'effet estime pourrait etre tres different de l'effet reel. Qualite tres faible : Le groupe d'experts responsable des lignes directrices a tres peu confiance en l'effet estime de l'activite physique sur l'issue de sante; l'effet estime est probablement tres different de l'effet reel. a Il s'agit d'une recommandation faible parce que la qualite des donnees probantes etait faible et que l'avantage net entre les femmes qui etaient physiquement actives et celles qui ne l'etaient pas etait petit. b Il s'agit d'une recommandation forte parce que, malgre le fait que les donnees probantes appuyant l'activite physique durant la grossesse pour les femmes en surpoids ou obeses etaient de qualite faible, des donnees tirees d'essais cliniques randomises demontraient une diminution du gain de poids durant la grossesse et une amelioration de la glycemie. c On parle d'intensite moderee lorsque l'activite est assez intense pour augmenter la frequence cardiaque de facon perceptible; une personne peut parler, mais pas chanter durant les activites de cette intensite. Pensons par exemple a la marche rapide, a la gymnastique aquatique, au velo stationnaire (effort modere), a l'entrainement musculaire, au port de charges moderees et aux travaux menagers (p. ex., jardinage, lavage de fenetres). d Il s'agit d'une recommandation faible parce que l'incontinence urinaire n'etait pas jugee comme etant une issue « critique » et que les donnees etaient de qualite faible. e Il s'agit d'une recommandation faible parce que : 1) la qualite des donnees probantes etait tres faible; et 2) bien que nous ayons etudie les inconvenients, il y avait peu de renseignements disponibles sur l'equilibre entre les avantages et les inconvenients. Cette recommandation etait principalement fondee sur l'opinion d'experts.

In the last decade, an abundance of new research from Canada and internationally has provided substantial evidence for the efficacy of exercise in preventing pregnancy complications and improving long-term maternal and fetal outcomes. Indeed, guidelines for exercise during pregnancy are available from several countries. This includes the expert consensus-based 2003 Joint SOGC and Canadian Society for Exercise Physiology Clinical Practice Guidelines: Exercise in Pregnancy and the Postpartum Period. With the plethora of new scientific evidence, it was vital to re-examine the literature by using the rigorous process followed by previous Canadian health behaviour guidelines.The purpose of this document is to outline the process and outcomes for the re-development of the 2019 Canadian Guideline for Physical Activity Throughout Pregnancy, herein referred to as the Guidelines. The target users for these Guidelines are obstetric care providers, policymakers, and exercise professionals who provide guidance for pregnant women regarding prenatal physical activity.

ObjectiveTo examine the relationships between prenatal physical activity and prenatal and postnatal urinary incontinence (UI).DesignSystematic review with random effects meta-analysis and meta-regression.Data sourcesOnline databases were searched up to 6 January 2017.Study eligibility criteriaStudies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the Population (pregnant women without contraindication to exercise), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone [“exercise-only”] or in combination with other intervention components [e.g., dietary; “exercise + co-intervention”]), Comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and Outcome (prenatal or postnatal UI).Results24 studies (n=15 982 women) were included. ‘Low’ to ‘moderate’ quality evidence revealed prenatal pelvic floor muscle training (PFMT) with or without aerobic exercise decreased the odds of UI in pregnancy (15 randomised controlled trials (RCTs), n=2764 women; OR 0.50, 95% CI 0.37 to 0.68, I2=60%) and in the postpartum period (10 RCTs, n=1682 women; OR 0.63, 95% CI 0.51, 0.79, I2=0%). When we analysed the data by whether women were continent or incontinent prior to the intervention, exercise was beneficial at preventing the development of UI in women with continence, but not effective in treating UI in women with incontinence. There was ‘low’ quality evidence that prenatal exercise had a moderate effect in the reduction of UI symptom severity during (five RCTs, standard mean difference (SMD) −0.54, 95% CI −0.88 to –0.20, I2=64%) and following pregnancy (three RCTs, ‘moderate’ quality evidence; SMD −0.54, 95% CI −0.87 to –0.22, I2=24%).ConclusionPrenatal exercise including PFMT reduced the odds and symptom severity of prenatal and postnatal UI. This was the case for women who were continent before the intervention. Among women who were incontinent during pregnancy, exercise training was not therapeutic.

ObjectiveThe purpose of this review was to investigate the relationship between prenatal exercise, and low back (LBP), pelvic girdle (PGP) and lumbopelvic (LBPP) pain.DesignSystematic review with random effects meta-analysis and meta-regression.Data sourcesOnline databases were searched up to 6 January 2017.Study eligibility criteriaStudies of all designs were eligible (except case studies and reviews) if they were published in English, Spanish or French, and contained information on the population (pregnant women without contraindication to exercise), intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone [“exercise-only”] or in combination with other intervention components [eg, dietary; “exercise + co-intervention”]), comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and outcome (prevalence and symptom severity of LBP, PGP and LBPP).ResultsThe analyses included data from 32 studies (n=52 297 pregnant women). ‘Very low’ to ‘moderate’ quality evidence from 13 randomised controlled trials (RCTs) showed prenatal exercise did not reduce the odds of suffering from LBP, PGP and LBPP either in pregnancy or the postpartum period. However, ‘very low’ to ‘moderate’ quality evidence from 15 RCTs identified lower pain severity during pregnancy and the early postpartum period in women who exercised during pregnancy (standardised mean difference −1.03, 95% CI −1.58, –0.48) compared with those who did not exercise. These findings were supported by ‘very low’ quality evidence from other study designs.ConclusionCompared with not exercising, prenatal exercise decreased the severity of LBP, PGP or LBPP during and following pregnancy but did not decrease the odds of any of these conditions at any time point.

ObjectiveGestational weight gain (GWG) has been identified as a critical modifier of maternal and fetal health. This systematic review and meta-analysis aimed to examine the relationship between prenatal exercise, GWG and postpartum weight retention (PPWR).DesignSystematic review with random effects meta-analysis and meta-regression. Online databases were searched up to 6 January 2017.Study eligibility criteriaStudies of all designs in English, Spanish or French were eligible (except case studies and reviews) if they contained information on the population (pregnant women without contraindication to exercise), intervention (frequency, intensity, duration, volume or type of exercise, alone [“exercise-only”] or in combination with other intervention components [eg, dietary; “exercise + co-intervention”]), comparator (no exercise or different frequency, intensity, duration, volume or type of exercise) and outcomes (GWG, excessive GWG (EGWG), inadequate GWG (IGWG) or PPWR).ResultsEighty-four unique studies (n=21 530) were included. ‘Low’ to ‘moderate’ quality evidence from randomised controlled trials (RCTs) showed that exercise-only interventions decreased total GWG (n=5819; −0.9 kg, 95% CI −1.23 to –0.57 kg, I2=52%) and PPWR (n=420; −0.92 kg, 95% CI −1.84 to 0.00 kg, I2=0%) and reduced the odds of EGWG (n=3519; OR 0.68, 95% CI 0.57 to 0.80, I2=12%) compared with no exercise. ‘High’ quality evidence indicated higher odds of IGWG with prenatal exercise-only (n=1628; OR 1.32, 95% CI 1.04 to 1.67, I2=0%) compared with no exercise.ConclusionsPrenatal exercise reduced the odds of EGWG and PPWR but increased the risk of IGWG. However, the latter result should be interpreted with caution because it was based on a limited number of studies (five RCTs).

ObjectiveTo investigate the relationships between exercise and incidence of congenital anomalies and hyperthermia.DesignSystematic review with random-effects meta-analysis .Data sourcesOnline databases were searched from inception up to 6 January 2017.Study eligibility criteriaStudies of all designs were eligible (except case studies and reviews) if they were published in English, Spanish or French, and contained information on population (pregnant women without contraindication to exercise), intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone [“exercise-only”] or in combination with other intervention components [e.g., dietary; “exercise + co-intervention”]), comparator (no exercise or different frequency, intensity, duration, volume or type of exercise) and outcome (maternal temperature and fetal anomalies).ResultsThis systematic review and meta-analysis included ‘very low’ quality evidence from 14 studies (n=78 735) reporting on prenatal exercise and the odds of congenital anomalies, and ‘very low’ to ‘low’ quality evidence from 15 studies (n=447) reporting on maternal temperature response to prenatal exercise. Prenatal exercise did not increase the odds of congenital anomalies (OR 1.23, 95% CI 0.77 to 1.95, I2=0%). A small but significant increase in maternal temperature was observed from pre-exercise to both during and immediately after exercise (during: 0.26°C, 95% CI 0.12 to 0.40, I2=70%; following: 0.24°C, 95% CI 0.17 to 0.31, I2=47%).Summary/ConclusionsThese data suggest that moderate-to-vigorous prenatal exercise does not induce hyperthermia or increase the odds of congenital anomalies. However, exercise responses were investigated in most studies after 12 weeks’ gestation when the risk of de novo congenital anomalies is negligible.