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The COVID-19 pandemic has disrupted the lives of US students both at home and at school. Little is known regarding how adolescents perceive COVID-19 has impacted (both positively and negatively) their academic and social lives and how protective factors, such as hope, may assist with resilience. Importantly, not all pandemic experiences are necessarily negative, and positive perceptions, as well as potential protective factors, are key to understanding the pandemic's role in students' lives.Utilizing quantitative and qualitative approaches, the present study descriptively examined 726 6th through 12th grade (51% female, 53% White) students' perceptions of how COVID-19 related to educational and life disruptions, and positive aspects of their lives, within the United States. Analyses additionally explored the role of pre-pandemic hope in improving feelings of school connectedness during the pandemic.Results showed that most students felt that switching to online learning had been difficult and their education had suffered at least moderately, with a sizeable proportion of students feeling less academic motivation compared with last year. When asked to share qualitative answers regarding perceived challenges and positive aspects of life, themes were consistent with quantitative perceptions. Students' pre-pandemic hope positively predicted students' feelings of school connectedness.Findings paint a complex picture of youth's COVID-19 experiences and have implications for proactive ways to support students as COVID-19 continues to affect daily life and educational structures and practices.

Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD.A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10 years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for10 to 15 and15 years.Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15 years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15 years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10 years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors.Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15 years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.

Introduction Feeling hopeful is an important condition for adolescents’ health, well-being, and educational success and attainment, yet limited research has examined hope at different ages throughout adolescence. Information regarding hope levels across grade could help educators know when to capitalize on goal-setting behaviors, and when to intervene should hope levels be low. Additionally, hope could help with the middle to high school transition because it presents opportunities and challenges, including school-related stress, as students adjust to new environments and expectations. Methods To investigate hope levels across adolescence, inter- and intra-personal analyses examined hope levels across grade-level in two cohorts of southwestern U.S. students (n = 1,018, 6th-10th grade students, 47% female, 55% White/45% non-White, (predominately Latinx)). The study used online self-report surveys to collect data. Next, longitudinal regression analyses across one year investigated relations of school stress and hope, and hope and achievement across the transition to high school. Results Students in both cohorts reported relatively stable hope levels from 6th to 10th grade, except for large decreases in hope during 8th grade, which recovered during 9th grade. For longitudinal analyses across the high school transition, student stress about school performance primarily influenced 8th graders who had relatively low hope. Eighth grade hope predicted 9th grade academic achievement. Conclusion Findings regarding hope across adolescence show that hope is similar across grade, except for a large decrease in hope that may occur before the transition to high school. Longitudinal analyses showed that school performance stress may contribute to this decrease but may also assist in hope recovery after the transition. Findings support educational practices and policies that target student hope before the high school transition to potentially buffer student stress and promote high school achievement.

Aims We aimed to investigate if differences in gut microbiota diversity and composition are associated with post-operative alcohol intake following bariatric surgery in a rat model. Methods Twenty-four female rats were randomized to three treatment groups: sham surgery, vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB). Stool was collected pre- and post-operatively and 16S rRNA gene amplification and sequencing was performed. Analysis focused on correlating microbial diversity, type of surgery and alcohol (EtOH) intake. Results Pre-operative stools samples on regular diet showed similar taxonomic composition and Shannon diversity among the three treatment groups. There was a significant decrease in Shannon diversity and a change in taxonomic composition of the gut microbiota after rats was fed high fat diet. Post-operatively, the RYGB group showed significantly lower taxonomic diversity than the VSG and sham groups, while the VSG and sham groups diversity were not significantly different. Taxonomic composition and function prediction based on PICRUSt analysis showed the RYGB group to be distinct from the VSG and sham groups. Shannon diversity was found to be negatively associated with EtOH intake. Conclusions Changes in the taxonomic profile of the gut microbiota following bariatric surgery, particularly RYGB, are associated with increased EtOH intake and may contribute to increased alcohol use disorder risk through the gut-brain-microbiome axis.

PURPOSE Women who develop gestational hypertension have evidence of elevated muscle sympathetic nerve activity (MSNA) in early pregnancy, which continues to rise after diagnosis. Exercise has been shown to play a preventative role in the development of gestational hypertension and has been shown to reduce resting and reflex MSNA in nonpregnant populations. We sought to investigate whether aerobic exercise affected the sympathetic regulation of blood pressure between the second and third trimesters of pregnancy. METHODS We conducted a randomized controlled trial of structured aerobic exercise (n = 31) compared with no intervention (control, n = 28) beginning at 16-20 wk and continuing until 34-36 wk of gestation (NCT02948439). Women in the exercise group were prescribed aerobic activity at 50%-70% of their heart rate reserve, on 3-4 d·wk-1 for 25-40 min with a 5-min warm-up and 5-min cool-down (i.e., up to 160 min total activity per week). At preintervention and postintervention assessments, data from ~10 min of quiet rest and a 3-min cold pressor test were analyzed to determine sympathetic nervous system activity and reactivity. RESULTS MSNA was obtained in 51% of assessments. Resting MSNA burst frequency and burst incidence increased across gestation (main effect of gestational age, P = 0.002). Neurovascular transduction was blunted in the control group (P = 0.024) but not in exercisers (P = 0.873) at the postintervention time point. Lastly, MSNA reactivity during the cold pressor test was not affected by gestational age or exercise (P = 0.790, interaction). CONCLUSIONS These data show that exercise attenuates both the rise in MSNA and the blunting of neurovascular transduction. This may partially explain the lower risk of developing gestational hypertension in women who are active during their pregnancies.

Background Access to antiretroviral therapy (ART) during pregnancy and breastfeeding for mothers with HIV has resulted in fewer children acquiring HIV peri- and postnatally, resulting in an increase in the number of children who are exposed to the virus but are not infected (HEU). HEU infants have an increased likelihood of childhood infections and adverse growth outcomes, as well as increased mortality compared to their HIV-unexposed (HUU) peers. We explored potential differences in the gut microbiota in a cohort of 272 Nigerian infants born to HIV-positive and negative mothers in this study during the first 18 months of life. Results The taxonomic composition of the maternal vaginal and gut microbiota showed no significant differences based on HIV status, and the composition of the infant gut microbiota at birth was similar between HUU and HEU. Longitudinal taxonomic composition of the infant gut microbiota and weight-for-age z-scores (WAZ) differed depending on access to breast milk. HEU infants displayed overall lower WAZ than HUU infants at all time points. We observed a significantly lower relative abundance of Bifidobacterium in HEU infants at 6 months postpartum. Breast milk composition also differed by time point and HIV infection status. The antiretroviral therapy drugs, lamivudine and nevirapine, as well as kynurenine, were significantly more abundant in the breast milk of mothers with HIV. Levels of tiglyl carnitine (C5) were significantly lower in the breast milk of mothers without HIV. ART drugs in the breast milk of mothers with HIV were associated with a lower relative abundance of Bifidobacterium longum. Conclusions Maternal HIV infection was associated with adverse growth outcomes of HEU infants in this study, and these differences persist from birth through at least 18 months, which is a critical window for the development of the immune and central nervous systems. We observed that the relative abundance of Bifidobacterium spp. was significantly lower in the gut microbiota of all HEU infants over the first 6 months postpartum, even if HEU infants were receiving breast milk. Breastfeeding was of benefit in our HEU infant cohort in the first weeks postpartum; however, ART drug metabolites in breast milk were associated with a lower abundance of Bifidobacterium.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Endothelium dysfunction produces peripheral vascular disease comorbidities in type 2 diabetes, including hypertension, and critical limb ischemia. In this study we aimed to test endothelial dysfunction, the vasodilator effects of a proteinase-activated receptor 2 (PAR2) agonist (2fLIGRLO), and thromboxane A

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.

This case-control study investigates the association between nasal microbial profiles and odds of infection after elective surgical procedures., Key Points Question Can characterization of microbiota present on preoperative nasal swab estimate risk for postoperative infection in patients undergoing elective surgical procedures? Findings In this case-control study, 167 patients were classified to nasal microbial profile cluster 1 and 30 patients to cluster 2 based on 16S ribosomal RNA gene sequencing. Classification to cluster 2 was associated with statistically significantly higher odds of infection (ie, deep surgical site infection, bacteremia, or pneumonia) after surgical procedure, independent of covariates, including nasal carriage of Staphylococcus aureus on preoperative culture and intrasample microbial diversity (ie, α diversity). Meaning These findings suggest that the nasal microbiome is an independent risk factor associated with infectious outcomes after elective surgical procedures., Importance The association of the nasal microbiome with outcomes in surgical patients is poorly understood. Objective To characterize the composition of nasal microbiota in patients undergoing clean elective surgical procedures and to examine the association between characteristics of preoperative nasal microbiota and occurrence of postoperative infection. Design, Setting, and Participants Using a nested matched case-control design, 53 individuals who developed postoperative infection were matched (approximately 3:1 by age, sex, and surgical procedure) with 144 individuals who were not infected (ie, the control group). The 2 groups were selected from a prospective cohort of patients undergoing surgical procedures at 2 tertiary care university hospitals in Baltimore, Maryland, who were at high risk for postoperative infectious complications. Included individuals were aged 40 years or older; had no history of autoimmune disease, immunocompromised state, immune-modulating medication, or active infection; and were scheduled to undergo elective cardiac, vascular, spinal, or intracranial surgical procedure. Data were analyzed from October 2015 through September 2020. Exposures Nasal microbiome cluster class served as the main exposure. An unsupervised clustering method (ie, grades of membership modeling) was used to classify nasal microbial samples into 2 groups based on features derived from 16S ribosomal RNA gene sequencing. The microbiome cluster groups were derived independently and agnostic of baseline clinical characteristics and infection status. Main Outcomes and Measures Composite of surgical site infection, bacteremia, and pneumonia occurring within 6 months after surgical procedure. Results Among 197 participants (mean [SD] age, 64.1 [10.6] years; 63 [37.7%] women), 553 bacterial taxa were identified from preoperative nasal swab samples. A 2-cluster model (with 167 patients in cluster 1 and 30 patients in cluster 2) accounted for the largest proportion of variance in microbial profiles using grades of membership modeling and was most parsimonious. After adjusting for potential confounders, the probability of assignment to cluster 2 was associated with 6-fold higher odds of infection after surgical procedure (odds ratio [OR], 6.18; 95% CI, 3.33-11.7; P

ObjectiveTo test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.MethodsExome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.ResultsWe identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114–4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.ConclusionsThese results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

High-altitude (>2,500 m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neurocardiovascular transduction and 2) whether differences exist in neurocardiovascular transduction between low- and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in 1) lowlanders (n = 14) at low (344 m) and high altitude (5,050 m), 2) Sherpa highlanders (n = 8; 5,050 m), and 3) Andean (with and without excessive erythrocytosis) highlanders (n = 15; 4,300 m). Cardiovascular responses to MSNA burst sequences (i.e., singlet, couplet, triplet, and quadruplet) were quantified using custom software (coded in MATLAB, v.2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neurocardiovascular transduction in lowlanders (MAP slope: high altitude, 0.0075 ± 0.0060 vs. low altitude, 0.0134 ± 0.080; P = 0.03). Transduction was elevated in Sherpa (MAP slope, 0.012 ± 0.007) compared with Andeans (0.003 ± 0.002, P = 0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, P = 0.08) or Andeans (MAP slope, P = 0.07). When resting MSNA is accounted for (ANCOVA), transduction was inversely related to basal MSNA (bursts/minute) independent of population (RRI, r = 0.578 P < 0.001; MAP, r = -0.627, P < 0.0001). Our results demonstrate that transduction is blunted in individuals with higher basal MSNA, suggesting that blunted neurocardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.NEW & NOTEWORTHY This study has identified that sympathetically mediated blood pressure regulation is reduced following ascent to high-altitude. Additionally, we show that high altitude Andean natives have reduced blood pressure responsiveness to sympathetic nervous activity (SNA) compared with Nepalese Sherpa. However, basal sympathetic activity is inversely related to the magnitude of SNA-mediated fluctuations in blood pressure regardless of population or condition. These data set a foundation to explore more precise mechanisms of blood pressure control under conditions of persistent sympathetic activation and hypoxia.

We demonstrate that during acute sympathoinhibition, women demonstrate more sustained increases in blood pressure following sympathetic bursts of activity than men. Likewise, during prolonged sympathetic quiescence, blood pressure is less labile in women than men. This suggests that lower overall blood pressure in young women may not be mediated by smaller beat-by-beat changes in blood pressure in response to sympathetic outflow but may instead be mediated by a lower frequency of sympathetic bursts.

Management of laryngopharyngeal reflux (LPR) typically comprises alginates and proton pump inhibitors (PPIs) alone or in combination, yet evidence to support any particular treatment regimen is lacking. We sought to evaluate the efficacy of Gaviscon® Advance alone versus co-prescription with a PPI in treating LPR. One hundred consecutive LPR patients with a reflux symptom index (RSI) score > 10 attending our joint voice clinic (JVC) were studied prospectively. All were treated with Gaviscon® Advance four times daily. If patients had been started on a PPI prior to their JVC attendance, this was optimised to a twice-daily dosing regimen and continued. RSI scores were recorded at first attendance and 3 months post-treatment via postal questionnaire. Scores were analysed using t tests and Levene’s test for equality of variances. Follow-up RSI scores were returned by 72 patients, 39 of whom were treated with Gaviscon® Advance only (group A) and 33 with Gaviscon® Advance + PPI (group B). Mean pre-treatment RSI scores were similar between groups [group A: 19.2, 95% confidence interval (CI) ± 2.4; group B: 21.3, 95% CI ± 3.2 (p = 0.65)]. No significant differences were observed with respect to 3-month post-treatment RSI scores [group A: 9.9, 95% CI ± 2.8; group B: 12.6, 95% CI ± 4.2 (p = 0.82)] and change in RSI scores [group A: 9.3, 95% CI ± 3.0; group B: 8.7, 95% CI ± 2.9 [p = 0.75]). Gaviscon® Advance alone is effective in treating symptoms of LPR, while co-prescription with a high-dose PPI offers no additional benefit.

Background A growth mindset is a significant factor in the motivation and achievement of learners. Previous research has shown one-off interventions do encourage growth mindset thinking but only improvements are only short-lived. A sustainable and embedded approach may therefore be the only way to engender long-term changes to an individual's mindset. Aims This research explores the application and implementation of growth mindset approaches to teaching and learning within a primary school, aiming to identify the strengths of the application and implementation of the growth mindset principles as well as areas for improvement. Sample Participants were the head teacher, five teachers, and 28 pupils at a primary school in Scotland. Method Semi-structured interviews were undertaken with members of staff, focus groups were undertaken with the pupils, and six observations were undertaken across three different classes. The data were thematically analysed using an inductive approach. Results The analysis of the data produced four overarching themes important to the implementation and application of growth mindset teaching and learning: embarking on the process; classroom culture and teaching; outside the classroom; and pupil approach to learning. Conclusions Among the strengths of the implementation was the collaborative approach that had been taken in the school and the understanding that staff had of the evidence base of growth mindset teaching and learning. Areas for development included the planning of the implementation such as the lack of a readiness assessment being undertaken.

Empathy has been a key focus of social, developmental, and affective neuroscience for some time. However, research using neural measures to study empathy in response to social victimization is sparse, particularly for young children. In the present study, 58 children's (White, non-Hispanic; five to nine years old) mu suppression was measured using electroencephalogram methods (EEG) as they viewed video scenarios depicting social injustices toward White and Black children. We found evidence of increased mu suppression in response to social victimization; however, contrary to well-documented findings of ingroup racial bias in empathic responses among adults, we found no evidence of racial bias in mu suppression in young children. Implications of these findings for neuroscience research on empathy and the development of ingroup bias are discussed.

Background Malignant neoplasms of the auricle make up 6% of all skin cancers. Management of cutaneous neoplasms of the conchal bowl presents a unique challenge in visualizing and defining margins that may extend into the external auditory canal (EAC). Objectives The objective of this study was to create a multidisciplinary pathway for cutaneous carcinoma of the conchal bowl extending into the EAC. Methods We present a series of patients that were referred to dermatology or otolaryngology, with cutaneous neoplasms arising in the conchal bowl. A consensus approach from otolaryngology and dermatology, for evaluation and treatment, was created based on evaluation of these cases, and review of the otolaryngology and dermatology literature, in collaboration between the two specialties. Results Initial evaluation should be done by both dermatology and otolaryngology, with otomicroscopic evaluation of the canal. Imaging is recommended for lesions that approach the EAC, for bony and soft tissue spread. Excision of the tumor with Mohs micrographic surgery to achieve clearance in the conchal bowl should be performed initially. If extension into the external auditory meatus is present, otolaryngology would proceed with en bloc resection. Repair is dictated by the defect, with both specialties involved in follow-up. Conclusions In collaboration between dermatology and otolaryngology, and following review of the literature, a pathway was created to manage skin cancer of the conchal bowl. This resulted in a stepwise approach for evaluation and management, ensuring that patients have a streamlined pathway for the treatment of these lesions.

Preeclampsia is a complication of pregnancy characterised by gestational hypertension, proteinuria and/or end organ disease. The reduced uteroplacental perfusion (RUPP) model, via partial occlusion of the lower abdominal aorta, mimics insufficient placental perfusion as a primary causal characteristic of preeclampsia. However, a major limitation of the RUPP model is that perfusion is reduced to the entire hindquarters of the rat resulting in hindlimb ischemia. We hypothesised that clipping the uterine and ovarian arteries in the selective (s)RUPP model would provoke signs of preeclampsia while avoiding systemic ischemia. Sham, RUPP or sRUPP procedures were performed in pregnant Sprague Dawley rats on gestational day (GD)14. On GD21 uterine blood flow was significantly reduced in both the RUPP and sRUPP models while aortic flow was reduced only in RUPP. Both models resulted in increased MAP, increased vascular oxidative stress (superoxide generation), increased pro-inflammatory (RANTES) and reduced pro-angiogenic (endoglin) mediators. Vascular compliance and constriction were unaltered in either RUPP or sRUPP groups. In summary, refinements to the RUPP model simultaneously maintain the characteristic phenotype of preeclampsia and avoid peripheral ischemia; providing a useful tool which may be used to increase our knowledge and bring us closer to a solution for women affected by preeclampsia.

Background Gut bacteria are strongly suspected to play a key role in the pathogenesis of Crohn's disease (CD). Studies have demonstrated alterations in the gut microbiota in this patient population. The purpose of this study was to characterize the gut microbiota of fistulizing perianal CD. Materials and Methods Stool and fistula samples were obtained from patients undergoing surgery for CD-related anorectal fistulae. Microbial compositions of matched stool and fistula samples were characterized using 16S rRNA gene profiling. The effect of sample type, patient gender, disease classification (Montreal A/B), disease activity (Harvey Bradshaw Index), antibiotic use, and presence of active proctitis on microbial composition was assessed. Results Samples were obtained from 18 patients. Bacteroides was the most abundant genera across all samples collected, followed by Streptococcus and Bifidobacterium. Bifidobacterium was present at significantly higher levels in fecal samples than fistula samples, whereas Achromobacter and Corynebacterium were present at significantly higher levels in fistula samples. Antibiotic, but not thiopurine or antitumor necrosis factor medication, exposure affected the gut microbial composition. Patient gender, disease classification, disease activity, and presence of active proctitis did not alter stool or fistula microbiota. Conclusions Our data show that the gut microbiota within CD-related anorectal fistulae is distinct from that in stool samples obtained from the same patients. We also observe a dysbiosis in patients treated with antibiotics compared with those not treated with antibiotics.

Background The gut microbiome plays a fundamental role in the human host’s overall health by contributing key biological functions such as expanded metabolism and pathogen defense/immune control. In a healthy individual, the gut microbiome co-exists within the human host in a symbiotic, non-inflammatory relationship that enables mutual benefits, such as microbial degradation of indigestible food products into small molecules that the host can utilize, and enhanced pathogen defense. In abnormal conditions, such as Crohn’s disease, this favorable metabolic relationship breaks down and a variety of undesirable activities result, including chronic inflammation and other health-related issues. It has been difficult, however, to elucidate the overall functional characteristics of this relationship because the microbiota can vary substantially in composition for healthy humans and possibly even more in individuals with gut disease conditions such as Crohn’s disease. Overall, this suggests that microbial membership composition may not be the best way to characterize a phenotype. Alternatively, it seems to be more informative to examine and characterize the functional composition of a gut microbiome. Towards that end, this study examines 25 metaproteomes measured in several Crohn’s disease patients’ post-resection surgery across the course of 1 year, in order to examine persistence of microbial taxa, genes, proteins, and metabolic functional distributions across time in individuals whose microbiome might be more variable due to the gut disease condition. Results The measured metaproteomes were highly personalized, with all the temporally-related metaproteomes clustering most closely by individual. In general, the metaproteomes were remarkably distinct between individuals and to a lesser extent within individuals. This prompted a need to characterize the metaproteome at a higher functional level, which was achieved by annotating identified protein groups with KEGG orthologous groups to infer metabolic modules. At this level, similar and redundant metabolic functions across multiple phyla were observed across time and between individuals. Tracking through these various metabolic modules revealed a clear path from carbohydrate, lipid, and amino acid degradation to central metabolism and finally the production of fermentation products. Conclusions The human gut metaproteome can vary quite substantially across time and individuals. However, despite substantial intra-individual variation in the metaproteomes, there is a clear persistence of conserved metabolic functions across time and individuals. Additionally, the persistence of these core functions is redundant across multiple phyla but is not always observable in the same sample. Finally, the gut microbiome’s metabolism is not driven by a set of discrete linear pathways but a web of interconnected reactions facilitated by a network of enzymes that connect multiple molecules across multiple pathways. Electronic supplementary material The online version of this article (10.1186/s40168-019-0631-8) contains supplementary material, which is available to authorized users.

KEY POINTS Normotensive pregnancy is associated with elevated sympathetic nervous system activity yet normal or reduced blood pressure. It represents a unique period of apparent healthy sympathetic hyperactivity. The present study models the blood pressure and heart rate (ECG R-R interval) responses to fluctuations in sympathetic nervous system activity aiming to understand neurocardiovascular transduction. The reported data clearly demonstrate that transduction of sympathetic nervous system signalling to systemic cardiovascular outcomes is reduced in normotensive pregnancy. These data are important for understanding how blood pressure regulation adapts during normotensive pregnancy and set the foundation for exploring similar mechanisms in hypertensive pregnancies. ABSTRACT Previously, we described sympathetic nervous system hyperactivity yet decreased blood pressure responses to stress in normotensive pregnancy. To address the hypothesis that pregnant women have blunted neurocardiovascular transduction we assessed the relationship between spontaneous bursts of sympathetic nerve activity (SNA) and fluctuations in mean arterial blood pressure and R-R interval. Resting SNA, blood pressure and ECG were obtained in pregnant (third trimester, n = 18) and non-pregnant (n = 18) women matched for age and pre-/non-pregnant body mass index. Custom software modelled beat-by-beat pressure (photoplethysmography) and R-R interval in relation to sequences of SNA bursts and non-bursts (peroneal microneurography). Sequences were grouped by the number of bursts and non-bursts [singlets, doublets, triplets and quadruplet (four or more)] and mean blood pressure and R-R interval were tracked for 15 subsequent cardiac cycles. Similar sequences were overlaid and averaged. Peak mean pressure in relation to sequences of SNA was reduced in pregnant vs. non-pregnant women (doublets: 1.6 ± 1.1 mmHg vs. 3.6 ± 3.1 mmHg, P

This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract., The stability of the Escherichia coli populations in the human gastrointestinal tract is not fully appreciated, and represents a significant knowledge gap regarding gastrointestinal community structure, as well as resistance to incoming pathogenic bacterial species and antibiotic treatment. The current study examines the genomic content of 240 Escherichia coli isolates from 30 children, aged 2 to 35 months old, in Tanzania. The E. coli strains were isolated from three time points spanning a six-month time period, with and without antibiotic treatment. The resulting isolates were sequenced, and the genomes compared. The findings in this study highlight the transient nature of E. coli strains in the gastrointestinal tract of these children, as during a six-month interval, no one individual contained phylogenomically related isolates at all three time points. While the majority of the isolates at any one time point were phylogenomically similar, most individuals did not contain phylogenomically similar isolates at more than two time points. Examination of global genome content, canonical E. coli virulence factors, multilocus sequence type, serotype, and antimicrobial resistance genes identified diversity even among phylogenomically similar strains. There was no apparent increase in the antimicrobial resistance gene content after antibiotic treatment. The examination of the E. coli from longitudinal samples from multiple children in Tanzania provides insight into the genomic diversity and population variability of resident E. coli within the rapidly changing environment of the gastrointestinal tract of these children. IMPORTANCE This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract.

The Publisher's final version can be found by following the DOI link. Open access article. Background Severe mental illness is a major driver of worldwide disease burden. Shared decision-making is critical for high quality care, and can enhance patient satisfaction and outcomes. However, it has not been translated into routine practice. This reflects a lack of evidence on the best way to implement shared decision-making, and the challenges of implementation in routine settings with limited resources. Our aim was to test whether we could deliver a practical and feasible intervention in routine community mental health services to embed shared decision-making for patients with severe mental illness, by improving patient and carer involvement in care planning. Methods We cluster randomised community mental health teams to the training intervention or usual care, to avoid contamination. Training was co-delivered to a total of 350 staff in 18 teams by clinical academics, working alongside patients and carers. The primary outcome was the Health Care Climate Questionnaire, a self-report measure of `autonomy support'. Primary and secondary outcomes were collected by self-report, six months after allocation. Findings In total, 604 patients and 90 carers were recruited to main trial cohort. Retention at six months was 82% (n = 497). In the main analysis, results showed no statistically significant difference in the primary outcome between the intervention and usual care at 6 months (adjusted mean difference -0.064, 95% CI -0.343 to 0.215, p = 0.654). We found significant effects on only 1 secondary outcome. Conclusions An intervention to embed shared decision-making in routine practice by improving involvement in care planning was well attended and acceptable to staff, but had no significant effects on patient outcomes. Enhancing shared decision-making may require considerably greater investment of resources and effects may only be apparent over the longer term.

Insights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum. Immunization with one of two live oral attenuated vaccines against S. Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S. Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S. Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S. Typhi., IMPORTANCE S. Typhi is a significant cause of systemic febrile morbidity in settings with poor sanitation and limited access to clean water. It has been demonstrated that the human gut microbiota can influence mucosal immune responses, but there is little information available on the impact of the human gut microbiota on clinical outcomes following exposure to enteric pathogens. Here, we describe differences in the composition and function of the gut microbiota in healthy adult volunteers enrolled in a typhoid vaccine trial and report that these differences are associated with host susceptibility to or protection from typhoid after challenge with wild-type S. Typhi. Our observations have important implications in interpreting the efficacy of oral attenuated vaccines against enteric pathogens in diverse populations.

The purpose of this study was to examine the functional and structural capillary density in the reduced uterine perfusion pressure (RUPP) model, which when performed during pregnancy is an established animal model of preeclampsia. We hypothesized that the RUPP model would be associated with capillary rarefaction and impaired capillary perfusion, which would be more pronounced in the pregnant state. Female Sprague-Dawley rats ( n = 32) were randomized to nonpregnancy (Nonpregnant) or breeding (Pregnant) at 12 wk of age and again to RUPP or SHAM surgeries on gestational day (GD) 14 (or equivalent age in nonpregnant rats). On GD 20 (or equivalent), capillary structure and perfusion of the extensor digitorum longus were imaged using digital intravital video microscopy. Functional videos were analyzed by a blinded observer to measure capillary density, expressed as capillaries per millimeter intersecting three staggered reference lines (200 μm). Flow was scored as the percentage of capillaries having 1) continuous, 2) intermittent, or 3) stopped flow. Total capillary density was not different between groups. There was a main effect of RUPP surgery resulting in decreased continuous flow vessels ( P < 0.01) and increased stopped flow ( P < 0.01), which was driven by differences between pregnant animals (Continuous flow: pregnant SHAM 80.1 ± 7.8% vs. pregnant RUPP 67.8 ± 11.2%, P < 0.05) (Stopped flow: pregnant SHAM 8.7 ± 3.2% vs. pregnant RUPP 17.9 ± 5.7%, P < 0.01). Our results demonstrate that the RUPP surgery is associated with a decrease in functional capillary density in skeletal muscle that is more pronounced in the pregnant state, which may contribute to the vascular pathophysiology observed in preeclampsia.

The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not.To examine genetic variants in patients with PNTM, their unaffected family members, and a control group.Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person.A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10(-6) and P = 2.7 × 10(-8), respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10(-17)), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category.Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.

The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn’s disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects’ fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects’ baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella. The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker., IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.

Genetic factors underlying the human limb abnormality congenital talipes equinovarus (‘clubfoot’) remain incompletely understood. The spontaneous autosomal recessive mouse ‘peroneal muscular atrophy’ mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4–Limk1–Cfl1/cofilin–actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial.

Research suggests that spatial ability may predict success in complex disciplines including anatomy, where mastery requires a firm understanding of the intricate relationships occurring along the course of veins, arteries, and nerves, as they traverse through and around bones, muscles, and organs. Debate exists on the malleability of spatial ability, and some suggest that spatial ability can be enhanced through training. It is hypothesized that spatial ability can be trained in low-performing individuals through visual guidance. To address this, training was completed through a visual guidance protocol. This protocol was based on eye-movement patterns of high-performing individuals, collected via eye-tracking as they completed an Electronic Mental Rotations Test (EMRT). The effects of guidance were evaluated using 33 individuals with low mental rotation ability, in a counterbalanced crossover design. Individuals were placed in one of two treatment groups (late or early guidance) and completed both a guided, and an unguided EMRT. A third group (no guidance/control) completed two unguided EMRTs. All groups demonstrated an increase in EMRT scores on their second test (P 0.001); however, an interaction was observed between treatment and test iteration (P = 0.024). The effect of guidance on scores was contingent on when the guidance was applied. When guidance was applied early, scores were significantly greater than expected (P = 0.028). These findings suggest that by guiding individuals with low mental rotation ability "where" to look early in training, better search approaches may be adopted, yielding improvements in spatial reasoning scores. It is proposed that visual guidance may be applied in spatial fields, such as STEMM (science, technology, engineering, mathematics and medicine), surgery, and anatomy to improve student's interpretation of visual content. Anat Sci Educ. © 2018 American Association of Anatomists.

Aims To explore the experiences of breastfeeding women. Background There is a plethora of data demonstrating that human breast milk provides complete nutrition for human infants. While the rate of initiation of breastfeeding in the United Kingdom has shown a steady increase in the last 25 years, rates of exclusive breastfeeding in the early weeks and months over the same time period have shown only marginal increases. This study was designed to extend current knowledge around breastfeeding experiences, decisions and behaviours. Design Qualitative, interpretive phenomenological approach. Methods Data were collected between July 2009–January 2010 through in‐depth interviews with 22 women from a city in the East Midlands where the prevalence of breastfeeding has showed a decreasing trend. Data were collected between 3–6 months after the birth of their youngest baby. Findings Analysis of data uncovered a key theme: illusions of compliance. The findings revealed that women's breastfeeding behaviours were socially mediated. They adopted a good mother image by conforming to the moral obligation to breastfeed immediately after their babies were born. Those women who struggled to establish breastfeeding tried to hide their difficulties rather than admit that they were not coping. Conclusion This study provides insights into women's infant feeding decisions and behaviours, building on understandings of ‘good mothering’ in the wider literature. Importantly we highlight some of the previously unknown strategies that women employed to portray themselves as calm, coping and in control when in reality they were struggling and not enjoying breastfeeding.

The current study examined bidirectional relations between adolescents' moral personality (prosocial values, self-regulation, and sympathy) and low- and high-cost prosocial behavior toward strangers. Participants included 682 adolescents (M age of child = 14.31, SD = 1.07, 50% female) who participated at two time points, approximately one year apart. Cross-lag analyses suggested that adolescents' values were associated with both low- and high-cost prosocial behavior one year later, self-regulation was associated with high-cost prosocial behavior, and sympathy was associated with low-cost prosocial behavior. Findings also suggested that low-cost prosocial behavior was associated with sympathy one year later, and high-cost prosocial behavior was associated with values. Discussion focuses on reciprocal relations between moral personality and prosocial behavior, and the need to consider a more multidimensional approach to prosocial development during adolescence.

Background:The specific circumstances and contexts that may affect overweight and obese children’s participation in physical activity have thus far been given little attention. The qualitative study discussed in this paper explores the experiences of overweight and obese children and young people who have successfully increased their activity levels.Methods:The study sample was recruited from a community health and fitness scheme for children aged 5 to 16, with a Body Mass Index (BMI) at or above the 91st centile. Semistructured interviews were conducted with 58 children and young people. Data were analyzed using template analysis.Results:The children increased their feelings of capability to undertake physical activity, both while on the scheme and in other physical activity settings. They valued the range of ‘noncompetitive’ activities available and the nonthreatening atmosphere created. The ‘emotional’ support offered by the instructors was perceived as being integral to their enjoyment and continued participation.Conclusions:Physical activity providers need to be able to generate opportunities which allow children of any weight status to participate without fear of stigmatization or bullying. The findings of the current study suggest that to be effective what we should be focusing on is improving the physical activity experience from the child’s perspective.

Plasma chemistry is widely used in diagnostic and research settings in sea turtles. However, plasma discolorations such as hemolysis are often not considered in data interpretation. The objectives of this study were to (1) evaluate the effects of moderate hemolysis on plasma electrolytes, minerals, and proteins using dry chemistry analysis (DCA) and protein electrophoresis from nesting leatherback sea turtles (Dermochelys coriacea) from Florida and to (2) establish blood analyte reference intervals. Twenty-six plasma samples with absence of hemolysis were selected and sub-divided into one non-hemolytic aliquot and an aliquot that was experimentally manipulated to mimic moderate hemolysis. Plasma samples were analyzed for hemoglobin using a handheld photometer; sodium, potassium, chloride, magnesium, calcium, phosphorus, and total protein using DCA; and protein electrophoresis. Packed cell volume and hemoglobin were measured in corresponding whole blood samples. Reference intervals were established. All analytes except calcium and pre-albumin were significantly higher and the calcium:phosphorus and albumin:globulin ratios were significantly lower in hemolytic plasma compared to non-hemolytic plasma. Alpha2-globulins and potassium were the analytes most impacted by hemolysis, averaging 3.3- and 2.0-fold higher in hemolyzed samples, respectively, indicating that (1) hemoglobin migrates into the alpha2-globulin region in this species and (2) notable intracellular potassium is released into plasma with hemolysis. Attempted conversion factors for compensation of hemolysis were considered inaccurate for 4 of 16 analytes due to non-significant regression lines. We also report that PCV provides an estimate of hemoglobin (g/L) using the formula: (2.59 × PCV) + 24.59. Given the spurious effects of hemolysis, the degree of this artifact should be reported with biochemistry data, and samples with moderate to severe hemolysis should be excluded from datasets when interpreting electrolyte, mineral, and protein results. This will ensure accurate data interpretation for individual turtles in rehabilitation or research settings and population-level data relevant to conservation-focused projects.

Summary Midwifery education in the UK has been delivered through the University sector since the mid-1990s, with the requirement to create safe, effective clinicians who are equipped to engage with research and evidence based practice. This paper presents an in-depth analysis of focus group data from 120 senior midwifery students at six British universities to explore the experience of learning to be a midwife. Thematic analysis of the data suggests the following themes pertain to the experience of a number of students: ‘teach yourself midwifery’, knowing it all, right way of doing things, the importance of physical skills. These themes suggest a dissonance for some students between the andragogical methods of learning espoused by universities, and the expectations of students, who express the belief that there is a fixed and finite body of knowledge, without which they feel disempowered, anxious and ill-prepared for clinical practice. This paper argues that there are unresolved tensions between the perceived demands of practice environments and regulatory bodies and the philosophical stance of universities. For some students the concept of a broad discursive education is a distraction from training in discrete clinical skills.

To investigate the impact of chronic periodontitis on oral health-related quality of life (OHRQoL) using the full version of the Oral Health Impact Profile (OHIP-49) and the Oral Health Quality of Life-UK (OHQoL-UK) questionnaires.89 patients with chronic periodontitis and 89 age- and gender-matched patients without chronic periodontitis were recruited. OHIP-49 and OHQoL-UK were self-completed by participants and mean scores were calculated for each item, domain and the overall summary score (additive method) for each instrument in each group.The mean age of participants was 47 ± 9 years, and the periodontitis patients had, on average, 33 ± 23 sites demonstrating probing depths ≥ 5 mm. OHRQoL was significantly poorer in the periodontitis patients compared to the periodontally healthy patients, when assessed by either instrument. When considering OHIP-49, fourteen of the forty-nine items indicated significantly poorer OHRQoL in the periodontitis group, and the overall OHIP-49 summary score was 48.6 ± 32.0 for periodontitis patients compared to 36.8 ± 29.8 in periodontally healthy patients (p0.01). When considering OHQoL-UK, fifteen of the sixteen items indicated significantly poorer OHRQoL in the periodontitis group, and the overall OHQoL-UK summary score was 47.1 ± 9.7 for periodontitis patients compared to 53.1 ± 11.3 in periodontally healthy patients (p0.01). Overall, those items with the greatest differences between periodontitis patients and the healthy group related to psychological concerns, halitosis, pain and aesthetics.Subjects with periodontitis report substantial functional, physical, psychological, and social OHRQoL impacts.This study has identified that patients with chronic periodontitis report significantly poorer oral health-related quality of life (OHRQoL) than age- and gender-matched periodontally healthy patients, with significant functional, social and psychological impacts. Clinicians should be aware of the impacts that periodontitis may have on OHRQoL, including psychological concerns, halitosis, pain and aesthetics.

Background: India is a patchwork of tribal and non-tribal populations that speak many different languages from various language families. Indo-European, spoken across northern and central India, and also in Pakistan and Bangladesh, has been frequently connected to the so-called "Indo-Aryan invasions" from Central Asia similar to 3.5 ka and the establishment of the caste system, but the extent of immigration at this time remains extremely controversial. South India, on the other hand, is dominated by Dravidian languages. India displays a high level of endogamy due to its strict social boundaries, and high genetic drift as a result of long-term isolation which, together with a very complex history, makes the genetic study of Indian populations challenging. Results: We have combined a detailed, high-resolution mitogenome analysis with summaries of autosomal data and Y-chromosome lineages to establish a settlement chronology for the Indian Subcontinent. Maternal lineages document the earliest settlement similar to 55-65 ka (thousand years ago), and major population shifts in the later Pleistocene that explain previous dating discrepancies and neutrality violation. Whilst current genome-wide analyses conflate all dispersals from Southwest and Central Asia, we were able to tease out from the mitogenome data distinct dispersal episodes dating from between the Last Glacial Maximum to the Bronze Age. Moreover, we found an extremely marked sex bias by comparing the different genetic systems. Conclusions: Maternal lineages primarily reflect earlier, pre-Holocene processes, and paternal lineages predominantly episodes within the last 10 ka. In particular, genetic influx from Central Asia in the Bronze Age was strongly male-driven, consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. This was part of a much wider process of Indo-European expansion, with an ultimate source in the Pontic-Caspian region, which carried closely related Y-chromosome lineages, a smaller fraction of autosomal genome-wide variation and an even smaller fraction of mitogenomes across a vast swathe of Eurasia between 5 and 3.5 ka., This work was supported by FEDER funds through COMPETE (FCOMP-01-0124FEDER-029291) and COMPETE 2020 (Project number 016899) and by national funds through the Portuguese Foundation for Science and Technology (FCT) through the research projects PTDC/IVC-ANT/4917/2012 and PTDC/EPH-ARQ/4164/2014. MS is supported by a Leverhulme Doctoral Scholarship awarded to MBR.AB, MO and TR are supported by FCT grants (SFRH/BD/78990/2011, SFRH/BD/95626/2013 and SFRH/BPD/108126/2015). PS is supported by FCT, ESF, POPH and the FCT Investigator Programme (IF/01641/2013) and acknowledges FCT I. P. and ERDF (through COMPETE2020-POCI) for CBMA's strategic programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569). I3S is financed by FEDER funds through the COMPETE 2020-POCI, Portugal 2020, and by Portuguese funds through FCT/Ministerio da Ciencia, Tecnologia e Inovacao in the framework of the project "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274)., info:eu-repo/semantics/publishedVersion

Background Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. Methods We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1β, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. Results One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. Conclusions Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. Trial Registration Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426; Date Registered 09/03/2007). Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0790-z) contains supplementary material, which is available to authorized users.

Background Patient and public involvement in research (PPIR) may improve trial recruitment rates, but it is unclear how. Where trials use PPIR to improve design and conduct, many do not communicate this clearly to potential participants. Better communication of PPIR might encourage patient enrolment, as trials may be perceived as more socially valid, relevant and trustworthy. We aimed to evaluate the impact on recruitment of directly advertising PPIR to potential trial participants. Methods This is a cluster trial, embedded within a host trial (‘EQUIP’) recruiting service users diagnosed with severe mental illness. The intervention was informed by a systematic review, a qualitative study, social comparison theory and a stakeholder workshop including service users and carers. Adopting Participatory Design approaches, we co-designed the recruitment intervention with PPIR partners using a leaflet to advertise the PPIR in EQUIP and sent potential participants invitations with the leaflet (intervention group) or not (control group). Primary outcome was the proportion of patients enrolled in EQUIP. Secondary outcomes included the proportions of patients who positively responded to the trial invitation. Results Thirty-four community mental health teams were randomised and 8182 service users invited. For the primary outcome, 4% of patients in the PPIR group were enrolled versus 5.3% of the control group. The intervention was not effective for improving recruitment rates (adjusted OR = 0.75, 95% CI = 0.53 to 1.07, p = 0.113). For the secondary outcome of positive response, the intervention was not effective, with 7.3% of potential participants in the intervention group responding positively versus 7.9% of the control group (adjusted OR = 0.74, 95% CI = 0.53 to 1.04, p = 0.082). We did not find a positive impact of directly advertising PPIR on any other outcomes. Conclusion To our knowledge, this is the largest ever embedded trial to evaluate a recruitment or PPIR intervention. Advertising PPIR did not improve enrolment rates or any other outcome. It is possible that rather than advertising PPIR being the means to improve recruitment, PPIR may have an alternative impact on trials by making them more attractive, acceptable and patient-centred. We discuss potential reasons for our findings and implications for recruitment practice and research. Trial registration numbers ISRCTN, ISRCTN16488358. Registered on 14 May 2014. Study Within A Trial, SWAT-26. Registered on 21 January 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1718-1) contains supplementary material, which is available to authorized users.

Individuals with an aptitude for interpreting spatial information (high mental rotation ability: HMRA) typically master anatomy with more ease, and more quickly, than those with low mental rotation ability (LMRA). This article explores how visual attention differs with time limits on spatial reasoning tests. Participants were assorted to two groups based on their mental rotation ability scores and their eye movements were collected during these tests. Analysis of salience during testing revealed similarities between MRA groups in untimed conditions but significant differences between the groups in the timed one. Question-by-question analyses demonstrate that HMRA individuals were more consistent across the two timing conditions (κ = 0.25), than the LMRA (κ = 0.013). It is clear that the groups respond to time limits differently and their apprehension of images during spatial problem solving differs significantly. Without time restrictions, salience analysis suggests LMRA individuals attended to similar aspects of the images as HMRA and their test scores rose concomitantly. Under timed conditions however, LMRA diverge from HMRA attention patterns, adopting inflexible approaches to visual search and attaining lower test scores. With this in mind, anatomical educators may wish to revisit some evaluations and teaching approaches in their own practice. Although examinations need to evaluate understanding of anatomical relationships, the addition of time limits may induce an unforeseen interaction of spatial reasoning and anatomical knowledge. Anat Sci Educ 10: 528-537. © 2017 American Association of Anatomists.

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable.

We present a draft sequence of the genome of Aedes aegypti , the primary vector for yellow fever and dengue fever, which at ∼1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae . Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of ∼4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster . Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of ∼2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.

Learning in anatomy can be both spatially and visually complex. Pedagogical investigations have begun exploration as to how spatial ability may mitigate learning. Emerging hypotheses suggests individuals with higher spatial reasoning may attend to images differently than those who are lacking. To elucidate attentional patterns associated with different spatial ability, eye movements were measured in individuals completing a timed electronic mental rotation test (EMRT). The EMRT was based on the line drawings of Shepherd and Metzler. Individuals deduced whether image pairs were rotations (same) or mirror images (different). It was hypothesized that individuals with high spatial ability (HSA) would demonstrate shorter average fixation durations during problem solving and attend to different features of the EMRT than low spatial ability (LSA) counterparts. Moreover, question response accuracy would be associated with fewer fixations and shorter average response times, regardless of spatial reasoning ability. Average fixation duration in the HSA group was shorter than LSA (F(1,8) = 7.99; P = 0.022). Importantly, HSA and LSA individuals looked to different regions of the EMRT images (Fisher Exact Test: 12.47; P = 0.018); attending to the same locations only 34% of the time. Correctly answered questions were characterized by fewer fixations per question (F(1, 8) = 18.12; P = 0.003) and shorter average response times (F(1, 8) = 23.89; P = 0.001). The results indicate that spatial ability may influence visual attention to salient areas of images and this may be key to problem solving processes for low spatial individuals. Anat Sci Educ 10: 224-234. © 2016 American Association of Anatomists.

The current study examined how parents' use of restrictive and active monitoring and deference changed over three years, and examined both adolescent and parent characteristics as predictors of initial levels of media monitoring, as well as change in media monitoring. Participants included 276 mother-child dyads (M age of child = 12.08, SD = .63, 50% female) taken from Time 2 of the Flourishing Families Project, 96% of whom had complete data for Time 4 (N = 266). Active monitoring was the most common approach at the first and second time points, while active monitoring and deference were equally common by the final time point. Latent growth curve analysis revealed that restrictive and active monitoring decreased over time, while deference increased. In addition, both adolescent and parent characteristics were predictive of initial levels of all three types of monitoring, and of change in restrictive monitoring. Discussion focuses on developmental implications of these findings.

Angiogenesis and vascular regression are critical for the female ovulatory cycle. They enable progression and regression of follicular development, and corpora lutea formation and regression. Angiogenesis in the ovary occurs under the control of the vascular endothelial growth factor-A (VEGFA) family of proteins, which are generated as both pro-(VEGF165) and anti(VEGF165b)-angiogenic isoforms by alternative splicing. To determine the role of the VEGF165b isoforms in the ovulatory cycle, we measured VEGF165b expression in marmoset ovaries by immunohistochemistry and ELISA, and used transgenic mice over-expressing VEGF165b in the ovary. VEGF165b was expressed in the marmoset ovaries in granulosa cells and theca, and the balance of VEGF165b:VEGF165 was regulated during luteogenesis. Mice over-expressing VEGF165b in the ovary were less fertile than wild-type littermates, had reduced secondary and tertiary follicles after mating, increased atretic follicles, fewer corpora lutea and generated fewer embryos in the oviduct after mating, and these were more likely not to retain the corona radiata. These results indicate that the balance of VEGFA isoforms controls follicle progression and luteogenesis, and that control of isoform expression may regulate fertility in mammals, including in primates.

Using specific inhibitors established that angiogenesis in the ovarian follicle and corpus luteum is driven by vascular endothelial growth factor. Recently, it has been demonstrated that the Notch ligand, delta-like ligand 4 (Dll4) negatively regulates vascular endothelial growth factor-mediated vessel sprouting and branching. To investigate the role of Dll4 in regulation of the ovarian vasculature, we administered a neutralizing antibody to Dll4 to marmosets at the periovulatory period. The vasculature was examined on luteal d 3 or d 10: angiogenesis was determined by incorporation of bromodeoxyuridine, staining for CD31 and cell death by staining for activated caspase-3. Ovulatory progesterone rises were monitored to determine effects of treatment on luteal function and time to recover normal cycles in a separate group of animals. Additionally, animals were treated in the follicular or midluteal phase to determine effects of Dll4 inhibition on follicular development and luteal function. Controls were treated with human IgG (Fc). Corpora lutea from marmosets treated during the periovulatory period exhibited increased angiogenesis and increased vascular density on luteal d 3, but plasma progesterone was significantly suppressed. By luteal d 10, corpora lutea in treated ovaries were significantly reduced in size, with involution of luteal cells, increased cell death, and suppressed plasma progesterone concentrations. In contrast, initiation of anti-Dll4 treatment during the midluteal phase produced only a slight suppression of progesterone for the remainder of the cycle. Moreover, Dll4 inhibition had no appreciable effect on follicular development. These results show that Dll4 has a specific and critical role in the development of the normal luteal vasculature.

OBJECTIVE: We hypothesized that exposure to profanity in media would be directly related to beliefs and behavior regarding profanity and indirectly to aggressive behavior. METHODS: We examined these associations among 223 adolescents attending a large Midwestern middle school. Participants completed a number of questionnaires examining their exposure to media, attitudes and behavior regarding profanity, and aggressive behavior. RESULTS: Results revealed a positive association between exposure to profanity in multiple forms of media and beliefs about profanity, profanity use, and engagement in physical and relational aggression. Specifically, attitudes toward profanity use mediated the relationship between exposure to profanity in media and subsequent behavior involving profanity use and aggression. CONCLUSIONS: The main hypothesis was confirmed, and implications for the rating industry and research field are discussed.

The European corn borer, Ostrinia nubilalis (Lepidoptera: Crambidae), is an introduced crop pest in North America that causes major damage to corn and reduces yield of food, feed, and biofuel materials. The Cry1F toxin from Bacillus thuringiensis (Bt) expressed in transgenic hybrid corn is highly toxic to O. nubilalis larvae and effective in minimizing feeding damage. A laboratory colony of O. nubilalis was selected for high levels of Cry1F resistance (>12,000-fold compared to susceptible larvae) and is capable of survival on transgenic hybrid corn. Genetic linkage maps with segregating AFLP markers show that the Cry1F resistance trait is controlled by a single quantitative trait locus (QTL) on linkage group 12. The map position of single nucleotide polymorphism (SNP) markers indicated that midgut Bt toxin-receptor genes, alkaline phosphatase, aminopeptidase N, and cadherin, are not linked with the Cry1F QTL. Evidence suggests that genes within this genome interval may give rise to a novel Bt toxin resistance trait for Lepidoptera that appears independent of known receptor-based mechanisms of resistance.

Macrophages are the most abundant immune cell within the ovary. Their dynamic distribution throughout the ovarian cycle and heterogenic array of functions suggest the involvement in various ovarian processes, but their functional role has yet to be fully established. The aim was to induce conditional macrophage ablation to elucidate the putative role of macrophages in maintaining the integrity of ovarian vasculature. Using the CD11b-diphtheria toxin receptor (DTR) mouse, in which expression of human DTR is under the control of the macrophage-specific promoter sequence CD11b, ovarian macrophages were specifically ablated in adult females by injections of diphtheria toxin (DT). CD11b-DTR mice were given DT treatment or vehicle and ovaries collected at 2, 8, 16, 24 and 48 h. Histochemical stains were employed to characterise morphological changes, immunohistochemistry for F4/80 to identify macrophages and the endothelial cell marker CD31 used to quantify vascular changes. In normal ovaries, macrophages were detected in corpora lutea and in the theca layer of healthy and atretic follicles. As macrophage ablation progressed, increasing amounts of ovarian haemorrhage were observed affecting both luteal and thecal tissue associated with significant endothelial cell depletion, increased erythrocyte accumulation and increased follicular atresia by 16 h. These events were followed by necrosis and profound structural damage. Changes were limited to the ovary, as DT treatment does not disrupt the vasculature of other tissues likely reflecting the unique cyclical nature of the ovarian vasculature and heterogeneity between macrophages within different tissues. These results show that macrophages play a critical role in maintaining ovarian vascular integrity.

SUMMARY Lake Malawi boasts the highest diversity of freshwater fishes in the world. Nearshore sites are categorized according to their bottom substrate, rock or sand, and these habitats host divergent assemblages of cichlid fishes. Sexual selection driven by mate choice in cichlids led to spectacular diversification in male nuptial coloration. This suggests that the spectral radiance contrast of fish, the main determinant of visibility under water, plays a crucial role in cichlid visual communication. This study provides the first detailed description of underwater irradiance, radiance and beam attenuation at selected sites representing two major habitats in Lake Malawi. These quantities are essential for estimating radiance contrast and, thus, the constraints imposed on fish body coloration. Irradiance spectra in the sand habitat were shifted to longer wavelengths compared with those in the rock habitat. Beam attenuation in the sand habitat was higher than in the rock habitat. The effects of water depth, bottom depth and proximity to the lake bottom on radiometric quantities are discussed. The radiance contrast of targets exhibiting diffused and spectrally uniform reflectance depended on habitat type in deep water but not in shallow water. In deep water, radiance contrast of such targets was maximal at long wavelengths in the sand habitat and at short wavelengths in the rock habitat. Thus, to achieve conspicuousness, color patterns of rock- and sand-dwelling cichlids would be restricted to short and long wavelengths, respectively. This study provides a useful platform for the examination of cichlid visual communication.