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Background: Variant-adapted COVID-19 vaccines are recommended for patients with inflammatory bowel disease (IBD). However, many patients rely on pre-existing immunity by original vaccines or prior infections., Aim: To assess whether such immunity sufficiently combats the highly immune-evasive SARS-CoV-2 JN.1 variant., Methods: Utilising two longitudinal cohorts, we evaluated immunity against JN.1 induced by original vaccines (IBD: n = 98; healthy: n = 48), omicron breakthrough infection (IBD: n = 55; healthy: n = 57) or XBB.1.5-adapted vaccines (IBD: n = 18). Neutralisation and anti-receptor-binding domain (RBD) IgG levels against wild-type SARS-CoV-2 and JN.1 were assessed using multiplex immunoassays. Study outcomes were wild-type and JN.1 neutralisation following three doses of original mRNA vaccines, stratified by immunosuppressive therapy (primary outcome), and JN.1 neutralisation following third-dose breakthrough infection or a fourth dose of XBB.1.5-adapted mRNA vaccines (secondary outcomes)., Results: Following original vaccines, JN.1 neutralisation was lower than wild-type neutralisation in all study groups (healthy, anti-TNF and non-anti-TNF; each p < 0.001); most individuals lacked JN.1 neutralisation (healthy: 97.9%; anti-TNF: 98.3% and non-anti-TNF: 92.3%). Confounder-adjusted multivariable modelling strongly associated anti-TNF therapy with low levels of anti-JN.1-RBD IgG (fold-change 0.48 [95% CI 0.39-0.59]). JN.1 neutralisation was similar in patients with or without breakthrough infection (anti-TNF, non-anti-TNF; each p > 0.05); neutralisation failure was 100% despite breakthrough infection. XBB.1.5-adapted vaccines enhanced JN.1 neutralisation (p < 0.001) and reduced neutralisation failure rates in patients with IBD (94.4% pre-vaccination vs. 44.4% post-vaccination; p = 0.003)., Conclusions: Only variant-adapted vaccines protect against emerging SARS-CoV-2 variants. Patients with IBD and healthy individuals without recent vaccination may lack protection against the JN.1 subvariant KP.3 which causes current COVID-19 surges., (© 2024 John Wiley & Sons Ltd.)

Background: Despite findings from translational and genetic studies in the event-related potential (ERP) literature, the validity and reliability of P50 suppression as a schizophrenia spectrum endophenotype has been questioned. Here, we aimed to examine sensory registration and gating measures derived from P50 and N100 amplitude, as well as N100 area-a novel approach proposed herein-in early psychosis versus health., Methods: Individuals at clinical high risk for psychosis (CHR; n = 77), first-episode psychosis (FE; n = 52), and healthy controls (HC; n = 65) were assessed in a paired-click auditory ERP paradigm. Eight CHR converted to psychosis (CHRC) and 39 did not (CHR-NC) by 24 months, while 30 CHR were lost to follow-. Group differences, test-retest reliability, and associations with neurocognitive function were assessed in nine ERP measures., Results: Significant differences were observed in N100 S1 amplitude, S1 area, and area difference between HC and FE, as well as in N100 S1 area between HC and CHR, among the total population. Furthermore, significant differences were found in N100 S1 area between HC and CHR-NC (Cliff's delta, Δ = 0.32), as well as in N100 area difference between HC and CHR-C (Δ = 0.55). Both N100 S1 area and area difference demonstrated moderate to acceptable reliability (intraclass correlation coefficients: 0.61-0.78). Processing speed negatively correlated with both N100 S1 area and area difference, while executive function negatively correlated with N100 S1 area alone in CHR and FE., Conclusion: Among the ERP measures studied, N100 area measures may serve as a reliable biomarker of aberrant sensory processing and neurocognition in early psychosis., Competing Interests: Declaration of competing interest Drs. Cadenhead, Light, and Braff contributed to the design of the study. Drs. Machiraju, Wyss and Cadenhead performed the data analyses. Dr. Machiraju assisted with the writing of the manuscript, along with other authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Rapidly progressive osteoarthritis of the hip is an unusual subset of hip osteoarthritis in which a >2 mm/yr rate of joint space narrowing occurs. Rapidly progressive osteoarthritis of the hip has been associated with intra-articular steroid injection, with the incidence of rapidly progressive osteoarthritis of the hip after intra-articular steroid injection ranging from 2.8% to 21%. The occurrence of rapidly progressive osteoarthritis of the hip unrelated to intra-articular steroid injection is rare, and not frequently reported. This report presents a unique case of rapidly progressive osteoarthritis of the hip in the bilateral hips of one patient. The first hip developed rapidly progressive osteoarthritis of the hip within 6 mos after an intra-articular steroid injection. Three years later, the second hip developed rapidly progressive osteoarthritis of the hip within 4 mos without any injection or use of systemic steroid medication. The etiology of rapidly progressive osteoarthritis of the hip in the absence of intra-articular steroid injection is unclear, and this case presents the opportunity to observe the development of rapidly progressive osteoarthritis of the hip due to different causes within the same individual., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The interspinous region is an atypical source of low back pain, and it can often be difficult to identify. There are many structural components in the interspinous region that can contribute to interspinous pain, including the interspinous ligament, which plays a role in providing stabilization to the spine. Successful treatments of interspinous pain have not been well characterized in the literature. This case presents the first documentation of the use of extracorporeal shockwave therapy as a noninvasive treatment for refractory interspinous-related low back pain. Extracorporeal shockwave therapy has previously been shown to facilitate regeneration and tissue healing in tendons and ligaments but has not previously been used to treat interspinous pain. A 24-yr-old former collegiate softball player presented with 5 mos of low back pain; the interspinous ligament was clinically suspected as a pain generator, and this was confirmed via an ultrasound-guided injection. She underwent a course of physical therapy that improved function but did not improve pain, and nonsteroidal anti-inflammatory drugs only provided minimal and temporary relief. Three consecutive extracorporeal shockwave therapy treatment sessions provided 90% improvement in pain and function, and she was able to return to exercise and recreational sports. At more than 6 mos after extracorporeal shockwave therapy treatment, she reported no recurrences or functional limitations., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Liver steatosis is the most frequent liver disorder and its advanced stage, non-alcoholic steatohepatitis (NASH), will soon become the main reason for liver fibrosis and cirrhosis. The "multiple hits hypothesis" suggests that progression from simple steatosis to NASH is triggered by multiple factors including the gut microbiota composition. The Epstein Barr virus induced gene 2 (EBI2) is a receptor for the oxysterol 7a, 25-dihydroxycholesterol synthesized by the enzymes CH25H and CYP7B1. EBI2 and its ligand control activation of immune cells in secondary lymphoid organs and the gut. Here we show a concurrent study of the microbial dysregulation and perturbation of the EBI2 axis in a mice model of NASH.We used mice with wildtype, or littermates with CH25H -/- , EBI2 -/- , or CYP7B1 -/- genotypes fed with a high-fat diet (HFD) containing high amounts of fat, cholesterol, and fructose for 20 weeks to induce liver steatosis and NASH. Fecal and small intestinal microbiota samples were collected, and microbiota signatures were compared according to genotype and NASH disease state.We found pronounced differences in microbiota composition of mice with HFD developing NASH compared to mice did not developing NASH. In mice with NASH, we identified significantly increased 33 taxa mainly belonging to the Clostridiales order and/ or the family, and significantly decreased 17 taxa. Using an Elastic Net algorithm, we suggest a microbiota signature that predicts NASH in animals with a HFD from the microbiota composition with moderate accuracy (area under the receiver operator characteristics curve = 0.64). In contrast, no microbiota differences regarding the studied genotypes (wildtype vs knock-out CH25H -/- , EBI2 -/- , or CYP7B1 -/- ) were observed.In conclusion, our data confirm previous studies identifying the intestinal microbiota composition as a relevant marker for NASH pathogenesis. Further, no link of the EBI2 - oxysterol axis to the intestinal microbiota was detectable in the current study., (© 2024. The Author(s).)

Purpose: Pediatric patients with cancer often develop chemotherapy-induced fever in neutropenia (FN), requiring emergency broad-spectrum antibiotics. Continuous temperature monitoring can lead to earlier FN detection and therapy with improved outcomes. We aimed to compare the feasibility of continuous core temperature monitoring with timely data availability between two wearable devices (WDs) in pediatric oncology patients undergoing chemotherapy., Methods: In this prospective observational two-center study, 20 patients (median age: 8 years) undergoing chemotherapy simultaneously wore two WDs (CORE®, Everion®) for 14 days. The predefined goal was core temperature recorded in sufficient quality and available within ≤ 30 min during ≥ 18/24 h for ≥ 7/14 days in more than 15 patients., Results: More patients reached the goal with CORE® (n = 13) versus Everion® (n = 3) (difference, 50% p < 0.001). After correcting for the transmission bottleneck caused by two WDs transmitting via one gateway, these numbers increased (n = 15 versus n = 14; difference, 5%; p = 0.69). CORE® measurements corresponded better to ear temperatures (n = 528; mean bias, - 0.07 °C; mean absolute difference, 0.35 °C) than Everion® measurements (n = 532; - 1.06 °C; 1.10 °C). Acceptance rates for the WDs were 95% for CORE® and 89% for Everion®., Conclusion: The CORE® fulfilled the predefined feasibility criterion (15 of 20 patients) after correction for transmission bottleneck, and the Everion® nearly fulfilled it. Continuous core temperature recording of good quality and with timely data availability was feasible from preschool to adolescent patients undergoing chemotherapy for cancer. These results encourage the design of randomized controlled trials on continuously monitored core temperature in pediatric patients., Clinicaltrials: gov (NCT04914702) on June 7, 2021., (© 2024. The Author(s).)

Fluent and automatized handwriting frees cognitive resources for more complex elements of writing (i.e., spelling or text generation) or even math tasks (i.e., operating) and is therefore a central objective in primary school years. Most previous research has focused on the development of handwriting automaticity across the school years and characteristics of handwriting difficulties in advanced writers. However, the relative and absolute predictive power of the different kinematic aspects for typically developing beginning handwriting remains unclear. The purpose of the present study was to investigate whether and to what extent different kinematic aspects contribute to handwriting proficiency in typically developing beginning handwriters. Further, we investigated whether gender, socioeconomic background, or interindividual differences in executive functions and visuomotor integration contribute to children's acquisition of handwriting. Therefore, 853 first-grade children aged seven copied words on a digitized tablet and completed cognitive performance tasks. We used a confirmatory factor analysis to investigate how predefined kinematic aspects of handwriting, specifically the number of inversions in velocity (NIV), pen stops, pen lifts, and pressure on the paper, are linked to an underlying handwriting factor. NIV, pen stops, and pen lifts showed the highest factor loadings and therefore appear to best explain handwriting proficiency in beginning writers. Handwriting proficiency was superior in girls than boys but, surprisingly, did not differ between children from low versus high socioeconomic backgrounds. Handwriting proficiency was related to working memory but unrelated to inhibition, shifting, and visuomotor integration. Overall, these findings highlight the importance of considering different kinematic aspects in children who have not yet automatized pen movements. Results are also important from an applied perspective, as the early detection of handwriting difficulties has not yet received much research attention, although it is the base for tailoring early interventions for children at risk for handwriting difficulties., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Truxius et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The acquisition of handwriting skills is a crucial goal in early primary school. Yet our comprehension of handwriting development, encompassing graphomotor skills and spelling, remains fragmented. The identification of predictors for handwriting skills is essential for providing early support. This longitudinal study aimed to explore the predictive roles of gender, working memory, and motivation to handwrite for graphomotor skills six months later and spelling skills one year later. Paper-and-pencil tasks (graphomotor skills, spelling), a tablet task (working memory), and a questionnaire (teachers' ratings of children's handwriting motivation) were employed. This study included 363 first-grade children (49.8% girls) aged 6-9 years. Results from a structural equation model, controlling for age and socioeconomic background, revealed that girls exhibited superior performance in graphomotor skills, while boys tended to spell more accurately. Furthermore, working memory predicted graphomotor skills but not spelling. Additionally, motivation to handwrite predicted both first-grade graphomotor skills and second-grade spelling. This study extends contemporary evidence, demonstrating that graphomotor skills predict spelling while considering gender and motivation. The findings underscore the pivotal role of graphomotor skills in spelling acquisition and suggest their contribution to spelling difficulties.

Introduction: Combination antiretroviral therapy (cART) effectively controls HIV; however, chronic low-level viremia and gut microbiota dysbiosis remain significant drivers of gut and systemic inflammation. In this study, we explored the relationship between gut microbiota composition, intestinal inflammation, microbial translocation, and systemic inflammation in women on cART in Sub-Saharan Africa., Methods: We conducted a study in HIV-infected and HIV-uninfected lactating women followed up at 6 weeks and 6 months postpartum in Harare, Zimbabwe. We used 16S ribosomal Ribonucleic Acid (rRNA) sequencing and MesoScale Discovery V-Plex assays to examine the gut microbiome and to quantify plasma inflammatory biomarkers, respectively. In addition, we measured fecal calprotectin, plasma lipopolysaccharide-binding protein (LBP), and soluble cluster of differentiation 14 (sCD14) by enzyme-linked immunosorbent assay to assess gut inflammation, microbial translocation, and monocyte/macrophage activation., Results: A group of 77 lactating women were studied, of which 35% were HIV-infected. Fecal calprotectin levels were similar by HIV status at both follow-up time points. In the HIV-infected group at 6 weeks postpartum, fecal calprotectin was elevated: median (interquartile range) [158.1 µg/g (75.3-230.2)] in women who had CD4+ T-lymphocyte counts <350 cells/µL compared with those with ≥350 cells/µL [21.1 µg/g (0-58.4)], p = 0.032. Plasma sCD14 levels were significantly higher in the HIV-infected group at both 6 weeks and 6 months postpartum, p < 0.001. Plasma LBP levels were similar, but higher levels were observed in HIV-infected women with elevated fecal calprotectin. We found significant correlations between fecal calprotectin, LBP, and sCD14 with proinflammatory cytokines. Gut microbial alpha diversity was not affected by HIV status and was not affected by use of antibiotic prophylaxis. HIV significantly affected microbial beta diversity, and significant differences in microbial composition were noted. The genera Slackia and Collinsella were relatively more abundant in the HIV-infected group, whereas a lower relative abundance of Clostriduim sensu&#95;stricto&#95;1 was observed. Our study also found correlations between gut microbial taxa abundance and systemic inflammatory biomarkers., Discussion and Conclusion: HIV-infected lactating women had increased immune activation and increased microbial translocation associated with increased gut inflammation. We identified correlations between the gut inflammation and microbial composition, microbial translocation, and systemic inflammation. The interplay of these parameters might affect the health of this vulnerable population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Munjoma, Chandiwana, Wyss, Mazhandu, Jordi, Gutsire, Katsidzira, Yilmaz, Misselwitz and Duri.)

Background: Microbiota composition is fundamental to human health with the intestinal microbiota undergoing critical changes within the first two years of life. The developing intestinal microbiota is shaped by maternal seeding, breast milk and its complex constituents, other nutrients, and the environment. Understanding microbiota-dependent pathologies requires a profound understanding of the early development of the healthy infant microbiota., Methods: Two hundred and fifty healthy pregnant women (≥20 weeks of gestation) from the greater Bern area will be enrolled at Bern University hospital's maternity department. Participants will be followed as mother-baby pairs at delivery, week(s) 1, 2, 6, 10, 14, 24, 36, 48, 96, and at years 5 and 10 after birth. Clinical parameters describing infant growth and development, morbidity, and allergic conditions as well as socio-economic, nutritional, and epidemiological data will be documented. Neuro-developmental outcomes and behavior will be assessed by child behavior checklists at and beyond 2 years of age. Maternal stool, milk, skin and vaginal swabs, infant stool, and skin swabs will be collected at enrolment and at follow-up visits. For the primary outcome, the trajectory of the infant intestinal microbiota will be characterized by 16S and metagenomic sequencing regarding composition, metabolic potential, and stability during the first 2 years of life. Secondary outcomes will assess the cellular and chemical composition of maternal milk, the impact of nutrition and environment on microbiota development, the maternal microbiome transfer at vaginal or caesarean birth and thereafter on the infant, and correlate parameters of microbiota and maternal milk on infant growth, development, health, and mental well-being., Discussion: The Bern birth cohort study will provide a detailed description and normal ranges of the trajectory of microbiota maturation in a high-resource setting. These data will be compared to data from low-resource settings such as from the Zimbabwe-College of Health-Sciences-Birth-Cohort study. Prospective bio-sampling and data collection will allow studying the association of the microbiota with common childhood conditions concerning allergies, obesity, neuro-developmental outcomes , and behaviour. Trial registration The trial has been registered at www., Clinicaltrials: gov , Identifier: NCT04447742., (© 2023. The Author(s).)

Purpose: Cochlear implant (CI) recipients struggle to hear in competing background noise. ForwardFocus is a spatial noise reduction setting from Cochlear Ltd. (Sydney) that can simultaneously attenuate noise from multiple sources behind the listener. This study assessed hearing performance with ForwardFocus in an off-the-ear (OTE) sound processor., Method: Twenty-two experienced adult CI recipients participated. Speech reception data was collected in fixed noise acutely in the clinic. After three to five weeks take home experience, subjective impressions were recorded, and evaluations were conducted for speech reception in quiet and roving noise., Results: Group mean speech reception thresholds (SRT) were below 0 dB in two spatially-separated noise test conditions when using ForwardFocus in the OTE sound processor. SRT were -8.5 dB (SD 2.9) in 4-talker babble roving in a rear hemi-field (S0Nrearhemi) and -3.9 dB (SD 3.3) in 12-talker babble presented laterally and behind (S0N3). Results in S0N3 were significantly better with ForwardFocus On ( p  = 0.0018). Subjective ratings with the OTE were comparable to, or better than, with their walk-in BTE or OTE sound processor., Conclusions: ForwardFocus provides significant benefits for speech recognition in competing background noise in an OTE sound processor. These results support clinicians in counselling CI recipients on potential sound processor options to consider.

Background: Vaccine-elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti-TNF biologics., Aims: To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD., Methods: This prospective multicentre case-control study included 98 biologic-treated patients with IBD and 48 healthy controls. Anti-spike IgG concentrations and surrogate neutralisation against SARS-CoV-2 wild-type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2-16 weeks and 22-40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Primary outcome was surrogate neutralisation against tested SARS-CoV-2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti-spike IgG concentration., Results: Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti-TNF biologics compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti-TNF therapy (odds ratio 0.29 [95% CI 0.19-0.46]) and time since vaccination (0.85 [0.72-1.00]) were associated with low, and mRNA-1273 vaccination (1.86 [1.12-3.08]) with high wild-type surrogate neutralisation in a β-regression model. Accordingly, higher proportions of patients treated with anti-TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti-spike IgG concentrations correlated with surrogate neutralisation., Conclusions: Patients with IBD who are treated with anti-TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant-adapted vaccines., (© 2023 John Wiley & Sons Ltd.)

Background: While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce., Objectives: We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients., Design: In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally., Methods: Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants' positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1-6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model., Results: Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms ( p  < 0.05). A higher percentage of variability in positive emotions was explained by pain (36%) and depressive symptoms (13%) than by epidemiological characteristics (0.3%), or characteristics of IBD and its treatment (2.4%). Patients with higher levels of positive emotions (score > 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p  < 0.05)., Conclusions: The absence of pain and depressive symptoms were the strongest drivers for high positive affect. Higher scores of positive affect were associated with longer disease-free survival in IBD patients., Competing Interests: BML, ML, SBUJ, NB, NK, JW, RvK and PJ have no competing interests to declare. LB reports fees for consulting/advisory board from Abbvie, MSD, Vifor, Falk, Esocap, Calypso, Ferring, Pfizer, Shire, Takeda, Janssen, Ewopharma. PS received consulting fees from Pfizer, Abbvie, Takeda and Janssen-Cilag and travel support from Falk, UCB and Pfizer. SRV has received consulting fees, speakers honorary and unrestricted research grants from Abbott, Alfasigma, Amgen, Arenapharm, Falk Pharma GmbH, Ferring Pharmaceuticals, Gilead, iQuone, Janssen, MSD, Permamed, Pfizer Inc, Sanofi-Aventis, Takeda, Tillotts, UCB, and Vifor. JZ reports fees for consulting/advisory board from Abbvie, Janssen and traveling fees from Abbvie, Takeda and Vifor. GR declares consulting fees from Abbvie, Augurix, BMS, Boehringer, Calypso, Celgene, FALK, Ferring, Fisher, Genentech, Gilead, Janssen, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller; speaker’s honoraria from Astra Zeneca, Abbvie, FALK, Janssen, MSD, Pfizer, Phadia, Takeda, Tillots, UCB, Vifor and Zeller; and grants support from Abbvie, Ardeypharm, Augurix, Calypso, FALK, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB and Zeller. BM reports traveling fees from Takeda, Vifor, Gilead and MSD. BM received fees as a speaker from Takeda. BM has served at an advisory board for Gilead, Takeda and BMS. BM has received research grants from MSD and BMS unrelated to the submitted work., (© The Author(s), 2023.)

Background: Human immunodeficiency virus (HIV) severely damages the epithelial cells of the gut lining leading to an inflamed leaky gut, translocation of microbial products, and dysbiosis resulting in systemic immune activation. Also, microbiota composition and maternal gut function can be altered in pregnancy through changes in the immune system and intestinal physiology. The aim of this study was to investigate the gut microbiota in HIV-infected and HIV-uninfected pregnant women and to compare and identify the association between gut microbial composition and adverse birth outcomes., Results: A total of 94 pregnant women (35 HIV-infected and 59 HIV-uninfected controls) were recruited in Harare from 4 polyclinics serving populations with relatively poor socioeconomic status. Women were of a median age of 28 years (interquartile range, IQR: 22.3-32.0) and 55% of women were 35 weeks gestational age at enrolment (median 35.0 weeks, IQR: 32.5-37.2). Microbiota profiling in these participants showed that species richness was significantly lower in the HIV-infected pregnant women compared to their HIV-uninfected peers and significant differences in β-diversity using Bray-Curtis dissimilarity were observed. In contrast, there was no significant difference in α-diversity between immune-compromised (CD4 +  < 350 cells/µL) and immune-competent HIV-infected women (CD4 +  ≥ 350 cells/µL) even after stratification by viral load suppression. HIV infection was significantly associated with a reduced abundance of Clostridium, Turicibacter, Ruminococcus, Parabacteroides, Bacteroides, Bifidobacterium, Treponema, Oscillospira, and Faecalibacterium and a higher abundance of Actinomyces, and Succinivibrio. Low infant birth weight (< 2500 g) was significantly associated with high abundances of the phylum Spirochaetes, the families Spirochaeteceae, Veillonellaceae, and the genus Treponema., Conclusion: The results reported here show that the species richness and taxonomy composition of the gut microbiota is altered in HIV-infected pregnant women, possibly reflecting intestinal dysbiosis. Some of these taxa were also associated with low infant birth weight., (© 2023. The Author(s).)

Background: Immunosuppressed patients with inflammatory bowel disease (IBD) experience increased risk of vaccine-preventable diseases such as COVID-19., Aims: To assess humoral and cellular immune responses following SARS-CoV-2 booster vaccination in immunosuppressed IBD patients and healthy controls., Methods: In this prospective, multicentre, case-control study, 139 IBD patients treated with biologics and 110 healthy controls were recruited. Serum anti-SARS-CoV-2 spike IgG concentrations were measured 2-16 weeks after receiving a third mRNA vaccine dose. The primary outcome was to determine if humoral immune responses towards booster vaccines differ in IBD patients under anti-TNF versus non-anti-TNF therapy and healthy controls. Secondary outcomes were antibody decline, impact of previous infection and SARS-CoV-2-targeted T cell responses., Results: Anti-TNF-treated IBD patients showed reduced anti-spike IgG concentrations (geometric mean 2357.4 BAU/ml [geometric SD 3.3]) when compared to non-anti-TNF-treated patients (5935.7 BAU/ml [3.9]; p < 0.0001) and healthy controls (5481.7 BAU/ml [2.4]; p < 0.0001), respectively. In multivariable modelling, prior infection (geometric mean ratio 2.00 [95% CI 1.34-2.90]) and vaccination with mRNA-1273 (1.53 [1.01-2.27]) increased antibody concentrations, while anti-TNF treatment (0.39 [0.28-0.54]) and prolonged time between vaccination and antibody measurement (0.72 [0.58-0.90]) decreased anti-SARS-CoV-2 spike antibodies. Antibody decline was comparable in IBD patients independent of anti-TNF treatment and antibody concentrations could not predict breakthrough infections. Cellular and humoral immune responses were uncoupled, and more anti-TNF-treated patients than healthy controls developed inadequate T cell responses (15/73 [20.5%] vs 2/100 [2.0%]; p = 0.00031)., Conclusions: Anti-TNF-treated IBD patients have impaired humoral and cellular immunogenicity following SARS-CoV-2 booster vaccination. Fourth dose administration may be beneficial for these patients., (© 2022 John Wiley & Sons Ltd.)

Background: The bidirectional "gut-brain axis" has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). While the influence of stress and depressive symptoms on IBD is well-characterized, the role of personality remains insufficiently investigated., Methods: Personality was assessed in 1154 Swiss IBD cohort study (SIBDCS) patients via the NEO-Five-Factor Inventory (NEO-FFI) as well as in 2600 participants of the population-based CoLaus¦PsyCoLaus cohort study (NEO-FFI-revised). The NEO-FFI subcomponents activity, self-reproach and negative affect were associated with higher IBD disease activity and were combined to a NEO-FFI risk score. This risk score was validated and its effect on clinical IBD course and psychological endpoints was analysed in time-to-event and cumulative incidence analyses., Results: In time-to-event analyses, a high NEO-FFI risk score was predictive for the clinical endpoints of new extraintestinal manifestation [EIM, adjusted hazard ratio (aHR) = 1.64, corrected p value (q) = 0.036] and two established composite flare endpoints (aHR = 1.53-1.63, q = 0.003-0.006) as well as for the psychological endpoints depressive symptoms (aHR = 7.06, q < 0.001) and low quality of life (aHR = 3.06, q < 0.001). Furthermore, cumulative incidence analyses showed that patients at high NEO-FFI risk experienced significantly more episodes of active disease, new EIMs, one of the flare endpoints, depressive episodes and low disease-related quality of life. Personalities of IBD patients showed only minor differences from the general population sample (Pearson's r = 0.03-0.14)., Conclusions: Personality assessed by the NEO-FFI contained considerable predictive power for disease recurrence, depressive symptoms and low quality of life in IBD patients. Nevertheless, the personalities of IBD patients did not substantially differ from the general population., (© 2022. The Author(s).)

Background: Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM., Methods: We conducted a systematic literature search in PubMed and Embase, including reports published in English from 2010 to 2021. We included randomized trials, cohort studies and case series. Phase I trials were not analyzed. We followed PRISMA guidelines, assessed the quality of the eligible reports using the Newcastle-Ottawa scale (NOS) and the RoB-2 tool and registered the protocol on PROSPERO., Results: We included 6 out of 1122 screened reports. All six selected reports were prospective, multicenter phase II trials (five single-arm and one randomized controlled trial). None of the investigated novel treatment modalities showed any benefit regarding overall or progression free survival., Conclusions: To date, the role of pharmacological approaches regarding pediatric GBM remains unclear, since no novel treatment approach could provide a significant impact on overall or progression free survival. Further research should aim to combine different treatment strategies in large international multicenter trials with central comprehensive diagnostics regarding subgrouping. These novel treatment approaches should include targeted and immunotherapeutic treatments, potentially leading to a more successful outcome.

Introduction: Survivors of pediatric central nervous system (CNS) tumors are at high risk for late effects and long-term morbidity. The quality of survival became increasingly important, as advances in diagnostics, multimodal treatment strategies, and supportive care have led to significant increases in long-term survival. Aim: This review aims to provide a global overview of the potential late effects and long-term follow-up care of CNS tumor survivors, directed to trainees and practitioners with less targeted training in pediatric oncology. Late effects in CNS tumor survivors: A specific focus on CNS tumor survivors relies on cognitive and psychosocial late effects, as they may have an impact on education, professional career, independent living, and quality of life. Further important late effects in CNS tumor survivors include endocrine, metabolic, cardiovascular, and cerebrovascular diseases. Conclusions: Comprehensive long-term follow-up care is essential for pediatric CNS tumor survivors to improve their quality of survival and quality of life. An individualized approach, taking all potential late effects into account, and carried out by an interdisciplinary team, is recommended, and should continue into adulthood. Existing recommendations and guidelines on long-term follow-up care guide the multidisciplinary teams.

Purpose: Cochlear implantation can restore access to sound and speech understanding in subjects with substantial hearing loss. The Health Utilities Index Mark III (HUI3) measures the impact of an intervention on the patient's quality of life and is sensitive to changes in hearing. In the current study we used factor analysis to predict a clinically important gain in HUI3 scores in adult cochlear implant recipients., Methods: Data were collected in an observational study for 137 adult recipients from a single center who had at least 1-year HUI3 follow-up. Demographic and other baseline parameters were retrospectively analyzed for their association with a clinically important HUI3 scale gain, defined as at least 0.1 points. Data were also collected for the speech spatial qualities (SSQ) scale., Results: Baseline telephone use and HUI3 hearing, speech and emotion attribute levels were significantly associated with clinically important gains in HUI3 scores. However, SSQ scores increased significantly with or without clinically important HUI3 gains., Conclusion: Those subjects who were unhappy or experienced difficulties communicating with strangers or in a group were twice as likely to obtain a clinically important gain in health utility compared to those who were happy or had less difficulty communicating. Subjects who were unable to use the telephone prior to cochlear implantation were one and a half times more likely to obtain a clinically important gain. The SSQ scale was more sensitive to hearing improvements due to cochlear implantation. An inability to use the telephone is an easy to assess biomarker for candidacy for cochlear implantation., (© 2021. The Author(s).)

Background: Registries are powerful clinical investigational tools. Although in hospitals registries may be mandated, industry-sponsored, international registries are voluntary and therefore can require clearer objectives and more planning. The registry also needs sufficient resources and appropriate measurement tools to motivate long-term participation and ensure success., Methods: We summarize our learnings from 10 years of running a medical device registry that surveys patient-reported benefits of hearing implants., Results: We enlisted 77 participating clinics globally, who actively recruited a total of more than 1500 hearing implant users. We identified the stages in developing a registry specific to hearing loss. Furthermore, we report the challenges and successes in design and implementation and make recommendations for future registries., Conclusions: Data collection infrastructure needs to be kept up to date throughout the defined registry lifetime, and it is essential to oversee data quality and completeness. Compliance at registry sites is important for data quality and needs to be weighed against the cost of site monitoring. To motivate sites to enter data accurately and expeditiously, we facilitated easy access to their own data which helped to support their clinical routine., Trial Registration: ClinicalTrials.gov NCT02004353. 9 th December 2013., (© 2021. The Author(s).)

STEM internships for both high school and college students provide early opportunities for students to discover careers of interest and career paths they may not otherwise experience. For over 25 years, the University of Alabama at Birmingham's (UAB) Center for Community OutReach Development (CORD) has provided rising high school seniors with opportunities to conduct research in federally-funded laboratories under the mentorship of UAB faculty. This paper evaluates CORD's High School Summer Science Institute III Program (SSI III) and its impact on participants' STEM career trajectories. Outcomes were tracked for SSI III participants over an eight-year period, and former interns' perceptions of the program reported. Over 99% of surveyed interns (N=102) chose a STEM undergraduate major, and 97% of the former interns reported they were pursuing STEM careers. Nearly all interns indicated their SSI-III experience was very positive and influenced their career decision. Over half of the interns matriculated into an undergraduate STEM major at UAB, providing the university with return as more excellent students for their investment in the program. These results highlight the importance of high school student involvement in STEM internships as a pathway that leads towards STEM careers.

A year of COVID-19 quarantine required educators to switch from in-person to virtual learning platforms, causing a dramatic reimagining of their daily praxis. Their experiences are likely to influence new norms for K-12 education. While virtual learning can be effective, student engagement, student retention, and student attention can be challenging. This paper discusses how we adapted a materials-heavy, hands-on, annual summer teacher professional development (PD) program from an in-person to a virtual platform in the initial months of the pandemic. We successfully maintained effective and hands-on components, giving authentic learning experiences to the participants. The 2020 virtual version of the program effectively engaged in-service teachers with high daily participation and retention rates. Nearly all participants rated the workshops as very good or excellent, and an assessment of participants' learning outcomes was comparable to that of the highly-rated in-person 2018 version of the program. Following the PD session, teachers reported feeling more prepared to facilitate their students' learning, increased inquiry-based science teaching knowledge and skills, and their enthusiasm for utilizing workshop strategies. While there are challenges to implementing virtual learning, virtual teacher PD can be widely adaptable and replicable for many institutions, especially in situations in which distance or finances deter in-person participation.

Background: The use of telehealth saw a rapid surge during the early months of the COVID-19 pandemic. There remains little data on how effectively telehealth replicates traditional office visits in the treatment of spinal disorders and how telehealth is perceived by patients with spinal disorders., Questions/purposes: We sought to evaluate patient satisfaction with telehealth visits as a platform for delivering care for the treatment of spinal pathology., Methods: Patients undergoing a telehealth visit with providers specializing in the treatment of spinal disorders (one surgeon and two physiatrists) were provided with an anonymous, online survey. Data on patient satisfaction, effectiveness of the telehealth visit (in comparison with in-person visits), and clarity of communication were collected through 5-point Likert scales; visit characteristics and free-text responses were also collected., Results: Eighty-four patients responded to the survey. Their attitudes were largely positive, with an overall mean patient satisfaction score of 4.79. Patients gave high scores for clarity of communication during the visit, and for satisfaction with the formulation of treatment plans and their ability to ask questions, they gave the lowest scores to the effectiveness of telemedicine in replacing an in-person visit and ease of interface navigation., Conclusions: The high overall patient satisfaction reported by our patients seeking care for a spinal pathology supports the growing body of evidence promoting the use of telehealth for orthopedic care. Further research is needed in a standardized telehealth examination of patients with spinal disorders., Competing Interests: Conflict of InterestKarim Shafi, MD; Francis Lovecchio, MD; Katherine Fortson, BA; James Wyss, MD; Ellen Casey, MD; Joel Press, MD; Andrew Creighton, DO; Harvinder Sandhu, MD; and Sravisht Iyer, MD declare that they have no conflicts of interest., (© Hospital for Special Surgery 2020.)

Background: Given an increase in the aging population and its impact on healthcare systems, policy makers for provision of health and social services are aiming to keep older adults in good health for longer, in other words towards 'healthy aging'. Our study objective is to show that rehabilitation with cochlear implant treatment in the elderly with hearing impairment improves the overall health-related quality of life and general well-being that translate into healthy aging., Methods: The multicentre, prospective, repeated measures, single-subject, clinical observational study will accrue 100 elderly, first-time, unilateral CI recipients (≥ 60 years) and analyze changes on specific measurement tools over ca. 20 months from preimplant to postimplant. Evaluations will consist of details collected through case history and interview questionnaires by clinicians, data logging, self-report questionnaires completed by the recipients and a series of commonly used audiometric measures and geriatric assessment tools. The primary indicator of changes in overall quality of life will be the HUI-3., Discussion: The protocol is designed to make use of measurement tools that have already been applied to the hearing-impaired population in order to compare effects of CI rehabilitation in adults immediately before their implantation, (pre-implant) and after gaining 1-1.5 years of experience (post-implant). The broad approach will lead to a greater understanding of how useful hearing impacts the quality of life in elderly individuals, and thus improves potentials for healthy aging. Outcomes will be described and analyzed in detail., Trial Registration: This research has been registered in ClinicalTrials.gov (http://www.clinicaltrials.gov/), 7 March 2017 under the n° NCT03072862 .

Objective: To assess the relationship and agreement between mean total scores for the Speech Spatial Qualities of Hearing Scale (SSQ49) and the shorter SSQ12 to measure daily hearing function for a large group of auditory implant recipients., Methods: Prospective, longitudinal self-assessment by 1013 implant recipients using the SSQ49 at preimplant and at annual post-implant intervals (one, two and three-years) via an international registry. Mean total scores were calculated for the SSQ49 and the extracted SSQ12 responses. Pearson correlation and Bland-Altman agreement were examined between the SSQ49, SSQ12 and transformed SSQ12 versions. Longitudinal mixed-effects models were used to compare changes over time., Results: Very high correlation was shown between mean total scores for all versions while perfect agreement was not reached. Clinically acceptable agreement (<1.0 unit) between all versions was obtained with the transformed SSQ12 being least biased. All versions showed statistically significant improvement at one-year post-implant (>2.2 units; p  < 0.001)., Conclusions: All scale-versions showed comparable sensitivity to changes in self-reported hearing function over time. TheSSQ12 may be considered as a potential time-efficient self-assessment of hearing function for implant recipients in routine practice. Further research may involve independent repeated administration of each scale version.

Introduction: The programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays an important role in controlling immune suppression by down-regulating T effector cell activities, enabling tumor cells to escape from the host's antitumor immunsurveillance. While only a small part of colon cancer cells express PD-L1, we sought to evaluate the differential impact of stromal and epithelial PD-L1 expression of primary tumors and liver metastasis on overall survival (OS) in colon cancer patients., Patients and Methods: Using a next-generation tissue microarray approach, we assessed both epithelial and stromal PD-L1 expression levels in primary tumors (n = 279) and corresponding liver metastases (n = 14) of colon cancer patients. PD-L1 positivity was graded according to the percentage (0.1%-1%, > 1%, > 5%, > 50%) of tumor cells with membranous PD-L1 expression or as the percentage of positive stroma cells and associated inflammatory infiltrates. We also assessed the interplay between stromal PD-1/PD-L1 and both intratumoral and stromal CD8 count and their impact on outcome. The primary end point was OS., Results: Stromal PD-L1 and PD-1 expression were both associated with less aggressive tumor behavior in colon cancer patients, which translated into better OS and disease-free survival, respectively. Conversely, PD-L1 staining in the tumor cells was less frequent than stromal staining and was associated with features of aggressive tumor biology, although without impact on outcome. Interestingly, the PD-L1 staining pattern remained similar between primary tumors and corresponding liver metastases. Stromal PD-1 expression correlated significantly with stromal PD-L1 staining and both intratumoral and stromal CD8 expression., Conclusion: Stromal PD-1/PD-L1 expression might serve as a prognostic marker in colon cancer patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We previously demonstrated independent effects of early-life experience (ELE) and trait aggression (TA) on resting heart rate (HR) and mean arterial pressure (MAP) in rats. The present study examined the effects of TA and ELE on stress-evoked cardiovascular reactivity and recovery. Pups born to Wistar-Kyoto dams were exposed to daily 180-min periods of maternal separation (MS) during the first two weeks of life, and aggression was assessed in adult offspring using the resident-intruder test. Radiotelemetry was then used to record stress-evoked HR and MAP responses in response to: strobe light, novel environment, intruder rat, or restraint. Maximal HR and MAP responses were quantified as indices of reactivity, and exponential decay curves were fitted to determine decay constants as a measure of recovery. Strobe light was the weakest stressor, evoking the lowest increases in MAP and HR, which were significantly greater in MS-exposed rats irrespective of TA. In contrast, reactivity to and recovery from exposure to a novel environment or an intruder were significantly influenced by TA, but not ELE. TA animals exhibited greater reactivity in both of these paradigms, with either decreased (novel environment) or increased (intruder) recovery. Restraint stress induced the largest changes in HR and MAP with the slowest recovery, and these responses were shaped by a significant ELE x TA interaction. These data indicate that cardiovascular reactivity and recovery are influenced by ELE, TA, or ELE x TA interaction depending on stressor aversiveness as well as its physical and psychological dimensions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study describes a program that the University of Alabama at Birmingham (UAB) carried out in partnership with Birmingham City Schools (BCS) to test an educational intervention, i.e., Hands-On Physics (HOP), among 8th grade students in predominantly minority schools. It also evaluated teachers' demographics and educational backgrounds. The students conducted four physics experiments during a three day period. They performed better on post-tests. The actual and the percent gains in knowledge for each school were essentially equal for the schools that had passing versus failing grades in annual state assessment (20.4±5.6/49.0±5.6%, 20.4±2.7/48.4±8.3%, respectively). Most students (53%) stated that they were comfortable with science, 88% indicated that they were planning to enter higher education, and 86% agreed that higher education was very important for their future. The students' major perceived obstacles to higher education were education cost and low grades. The teachers were primarily between 40-59 years old (60%), female (80%) and African-American (93%), and 87% majored in biology (93%). Forty percent had a bachelor's degree and 60% had a master's degree. They reported that they needed more support teaching physics and reported that a lack of materials and time were the main obstacles to provide the highest quality science educational experiences.

Objectives: The purpose of this observational study was to determine the accuracy of musculoskeletal palpation of the medial joint line of the knee, medial patellar tendon, and posterior tibialis tendon verified by ultrasound imaging among physical medicine and rehabilitation residents., Methods: Eighteen physical medicine and rehabilitation resident physicians at a single specialized institution were asked to identify the medial joint line of the knee, medial patellar tendon, and posterior tibialis tendon on 2 separate standardized patient models during a single data collection. They were asked to place a paper clip flat on the surface of the skin parallel to the specified anatomic structure. A high-frequency linear array transducer was used to identify whether the paper clip was correctly placed over the structures and to measure the distance from the intended structure., Results: The accuracy rates for palpation of the medial joint line, medial patellar tendon, and posterior tibialis tendon in both models were 14%, 36%, and 28%, respectively, for all levels of residents. Accuracy rates for all of the structures by level of education were 19%, 29%, and 31% for postgraduate years 2, 3, and 4. Median confidence scores were 3.75, 3.5, and 2 for the medial joint line, medial patellar tendon, and posterior tibialis tendon., Conclusions: This study highlights the level of inaccuracy of musculoskeletal palpation skills and draws further attention to an area of much-needed improvement in our musculoskeletal residency training programs. Ultrasound imaging is an effective noninvasive method for providing swift feedback to medical students and residents and thereby reduce the instances of inaccurate musculoskeletal palpation., (© 2017 by the American Institute of Ultrasound in Medicine.)

Background: Definitive surgical interventions for Dominican children with congenital heart disease, like those of other low- and middle-income countries, have been historically limited., Methods: We undertook review of a case series focusing on the surgical correction of complex forms of tetralogy of Fallot at a single center, CEDIMAT Centro Cardiovascular, in the Dominican Republic, over a 30-month period., Results: According to our criteria, 43 cases were determined to be complex tetralogy of Fallot repairs from the two-year period. Besides tetralogy of Fallot, the cohort had an additional 55 anatomic anomalies that had to be addressed at the time of surgery. Median age at the time of surgery was notably 30 months, and an average of 42 months elapsed from the time of diagnosis to the time of surgery for this group. Only 33% of the cases reviewed had no hypercyanotic crises before repair. Median time to extubation for this group of patients was one day, with a three-day median length of stay in the intensive care setting., Conclusions: Our study importantly captures the present experience of a surgical congenital heart program that has recently transitioned from a traditional "mission model" to a now self-sustaining local practice. Both the number and the complexity of the lesions corrected in this caseload represent an advance from the level of care previously provided to children in the Dominican Republic.

Objectives: To assess subjectively perceived, real-world benefits longitudinally for unilateral cochlear implant (CI) recipients in a multinational population treated routinely. To identify possible predictors of self-reported benefits., Design: This was a prospective, multicenter, repeated-measures study. Self-assessment of performance at preimplantation and postimplantation at 1, 2, and 3 years using standardized, validated, local language versions of the Speech, Spatial, and Qualities of Hearing Scale (SSQ), and the Health Utilities Index Mark 3 (HUI3) was performed. Outcomes were analyzed using a longitudinal mixed-effects model incorporating country effect. Patient demographics were explored for associations with change over time., Subjects: Two hundred ninety-one routinely treated, unilateral CI recipients, aged 13-81 years, from 9 clinics across 4 countries., Results: Highly significant improvements were observed for all outcome measures (p < 0.0001). Postimplantation, mean outcome scores remained stable beyond 1 year, with notable individual variability. A significant association for one or more outcomes with preimplantation contralateral hearing aid use, telephone use, age at implantation, implantation side, preimplantation comorbidities, dizziness, and tinnitus was observed (p < 0.004)., Conclusions: Longitudinal benefits of CI treatment can be measured using clinically standardized self-assessment tools to provide a holistic view of patient-related benefits in routine clinical practice for aggregated data from multinational populations. Self-reported outcomes can provide medical-based evidence regarding CI treatment to support decision-making by health service providers., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

This study tests the hypothesis that taurine supplementation reduces sugar-induced increases in renal sympathetic nerve activity related to renin release in adult male rats. After weaning, male rats were fed normal rat chow and drank water containing 5% glucose (CG) or water alone (CW) throughout the experiment. At 6-7 weeks of age, each group was supplemented with or without 3% taurine in drinking water until the end of experiment. At 7-8 weeks of age, blood chemistry and renal nerve activity were measured in anesthetized rats. Body weights slightly and significantly increased in CG compared to CW groups but were not significantly affected by taurine supplementation. Plasma electrolytes except bicarbonate, plasma creatinine, and blood urea nitrogen were not significantly different among the four groups. Mean arterial pressure significantly increased in both taurine treated groups compared to CW, while heart rates were not significantly different among the four groups. Further, all groups displayed similar renal nerve firing frequencies at rest and renal nerve responses to sodium nitroprusside and phenylephrine infusion. However, compared to CW group, CG significantly increased the power density of renin release-related frequency component, decreased that of sodium excretion-related frequency component, and decreased that of renal blood flow-related frequency component. Taurine supplementation completely abolished the effect of high sugar intake on renal sympathetic activity patterns. These data indicate that in adult male rats, high sugar intake alters the pattern but not firing frequency of sympathetic nerve activity to control renal function, and this effect can be improved by taurine supplementation.

This study tests the hypothesis that perinatal taurine imbalance impairs renal function in adult female rats via alterations in estrogen activity. Female Sprague-Dawley rats were fed normal rat chow and water containing 3% beta-alanine (TD), 3% taurine (TS) or water alone (C) from conception until weaning. Then, female offspring received normal rat chow and water with (CG, TDG, TSG) or without (CW, TDW, TSW) 5% glucose. At 7-8 weeks of age, renal function at rest and after acute saline load was tested in conscious, restrained female rats treated with non-selective estrogen receptor blocker tamoxifen for a week. Compared to control, TD or TS did not affect mean arterial pressure (MAP). Tamoxifen significantly increased resting MAP only in TDG compared to TDW groups. Although renal blood flow did not significantly differ among the groups, renal vascular resistance increased in TSG compared to CW, CG, and TSW groups. Glomerular filtration rate and water and sodium excretion were not significantly different among the groups. Compared to CW, saline load significantly depressed fractional water excretion in CG, TDW, TDG, and TSW, and fractional sodium excretion in CG, TDW, TDG, TSW, and the TSG groups. Potassium excretion was not significantly different among the corresponding groups. Fractional potassium excretion significantly increased in TDW compared to CG and in TSG compared to CG and TSW groups. These differences were abolished by tamoxifen treatment. These data indicate that in adult female rats, perinatal taurine imbalance, particularly followed by high sugar intake, alters renal function via an estrogenic mechanism.

This study tests the hypothesis that perinatal taurine supplementation followed by a high sugar diet since weaning impairs renal function via renin-angiotensin system (RAS) overactivity in adult female rats. Female Sprague-Dawley rats were fed normal rat chow and given water alone or water containing 3% taurine from conception until weaning. After weaning, the female rats received normal rat chow and water with (CG, TSG) or without (CW, TSW) 5% glucose throughout the experiment. At 7-8 weeks of age, renal function at rest and after an acute saline load was tested in conscious female rats after a week of captopril treatment. Body, heart, and kidney weights were not significantly different among the eight groups. Mean arterial pressures and heart rates were also not different among the groups. While effective renal blood flow did not significantly differ among the eight groups, TSG displayed higher renal vascular resistance compared to CW, CG, and TSW groups. Glomerular filtration rate, filtration fraction, and water and sodium excretion did not significantly differ among the groups. Compared to CW, the saline load significantly depressed fractional water excretion in CG and TSW and fractional sodium excretion in CG, TSW, and TSG groups. Captopril treatment abolished these differences but significantly decreased potassium excretion in CG, TSW, and TSG compared to CW and abolished the increased fractional potassium excretion in TSG compared to CG and TSW groups. These data strongly suggest that in adult female rats, perinatal taurine supplementation, particularly followed by high sugar intake, alters renal function via altered RAS activity.

Background: Rural compared to urban Thai populations have a higher incidence of sudden unexplained nocturnal death syndrome (SUNDS). This study tests the hypothesis that compared to young urban Thai men, the young rural northeast Thai men display autonomic system dysfunction that may contribute to their relatively high risk to develop SUNDS., Methods: Forty-seven healthy second and third year students from Khon Kaen University (20-22years old) were divided into central, urban northeastern, and rural northeastern groups, based on the locality in which they had grown up and in which their parents had lived prior to their birth., Results: Body weight, body height, serum sodium, serum potassium, fasting blood sugar, glucose tolerance, resting mean arterial pressure, resting heart rate, ulnar nerve conduction velocity, and sympathetic and parasympathetic nervous system activity were not significantly different among the three groups. In contrast, compared to urban northeasterners and central Thais, rural northeasterners displayed low sympathetic and high parasympathetic responses to cold stress and oral saline load; however, baroreflex sensitivity and the autonomic nervous system responses to upright tilt were not significantly different among the three groups. In addition, respiratory rates at rest and in response to upright tilt, cold stress, and oral saline load were not significantly different among the three groups., Conclusions: These data indicate that compared to central or urban, individuals from rural origin display decreased sympathetic and increased parasympathetic responses to stresses. These altered responses could predispose the individuals to inappropriate autonomic control during the stresses, including those resulting in SUNDS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Perinatal taurine depletion followed by high sugar intake after weaning adversely affects myocardial and arterial pressure function following a myocardial ischemia and reperfusion (IR) insult in adult female rats. This study tests the hypothesis that taurine supplementation ameliorates this adverse effect. Female Sprague-Dawley rats were fed normal rat chow and drank water containing β-alanine from conception until weaning (taurine depletion, TD). After weaning, female offspring were fed normal rat chow and drank either water containing 5% glucose (TDG) or water alone (TDW). At 6-7 weeks of age, half the rats in each group were supplemented with taurine and 1 week later subjected to cardiac IR. Body weight, heart weight, plasma electrolytes, plasma creatinine, blood urea nitrogen, and hematocrit were not significantly different among the four groups. The mean arterial pressures significantly increased in all groups after IR, but values were not significantly different among the four groups. Heart rates were significantly increased after IR only in TDW group. Compared to TDW, TDG displayed increased plasma cardiac injury markers (creatinine kinase-MB, troponin T, and N-terminal prohormone brain natriuretic peptide), increased sympathetic activity, decreased parasympathetic activity, and decreased baroreflex sensitivity after IR. Taurine supplementation completely restored the baroreflex and autonomic dysfunction of TDG to TDW levels and partially decreased myocardial injury after cardiac IR. The present study indicates that in adult female rats, perinatal taurine depletion followed by high sugar intake after weaning exacerbates cardiac IR injury and arterial pressure dysregulation and these adverse effects can be partially prevented by taurine supplementation.

Introduction: DYT1 dystonia is an autosomal-dominant movement disorder characterized by abnormal, often repetitive, movements and postures. Its hallmark feature is sustained or intermittent contractions of muscles involving co-contractions of antagonist muscle pairs. The symptoms are relieved with the anticholinergic drug trihexyphenidyl. The primary mutation is a trinucleotide deletion (ΔGAG) in DYT1/TOR1A, which codes for torsinA. Previous studies showed that (1) heterozygous Dyt1 ΔGAG knock-in mice, which have an analogous mutation in the endogenous gene, exhibit motor deficits and altered corticostriatal synaptic plasticity in the brain and (2) these deficits can be rescued by trihexyphenidyl. However, brain imaging studies suggest that the Dyt1 knock-in mouse models nonmanifesting mutation carriers of DYT1 dystonia. The aim of this work was to examine the hallmark features of DYT1 dystonia in the Dyt1 knock-in mice by analyzing muscular activities., Methods: Wireless telemetry devices with biopotential channels were implanted to the bicep and the rectus femori muscles in Dyt1 knock-in mice, and muscular activities were recorded before and after trihexyphenidyl administration., Results: (1) Consistent with DYT1 dystonia patients, Dyt1 knock-in mice showed sustained contractions and co-contractions of the antagonistic bicep femoris and rectus femoris. (2) The abnormal muscle contractions were normalized by trihexyphenidyl., Conclusion: The results suggest that the motor deficits in Dyt1 knock-in mice are likely produced by abnormal muscle contractions, and Dyt1 knock-in mice can potentially be used as a manifesting disease model to study pathophysiology and develop novel therapeutics. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Early-life stress (ELS) can alter neurodevelopment in variable ways, ranging from producing deleterious outcomes to stress resilience. While most ELS studies focus on its harmful effects, recent work by our laboratory and others shows that ELS elicits positive effects in certain individuals. We exposed Wistar Kyoto (WKY) rats, known for a stress reactive, anxiety/depression-like phenotype, to maternal separation (MS), a model of ELS. MS exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult WKY offspring. This study interrogates an epigenetic mechanism (DNA methylation) that may confer the adaptive effects of MS in WKY offspring. We quantified global genome methylation levels in limbic brain regions of adult WKYs exposed to daily 180-min MS or neonatal handling from postnatal day 1-14. MS exposure triggered dramatic DNA hypermethylation specifically in the hippocampus. Next-generation sequencing methylome profiling revealed reduced methylation at intragenic sites within two key nodes of insulin signaling pathways: the insulin receptor and one of its major downstream targets, mitogen-activated protein kinase kinase kinase 5 (Map3k5). We then tested the hypothesis that enhancing DNA methylation in WKY rats would elicit adaptive changes akin to the effects of MS. Dietary methyl donor supplementation improved WKY rats' anxiety/depression-like behaviors and also improved cardiovascular measures, similar to previous observations following MS. Overall, these data suggest a potential molecular mechanism that mediates a predicted adaptive response, whereby ELS induces DNA methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Early-life experience (ELE) can significantly affect life-long health and disease, including cardiovascular function. Specific dimensions of emotionality also modify risk of disease, and aggressive traits along with social inhibition have been established as independent vulnerability factors for the progression of cardiovascular disease. Yet, the biological mechanisms mediating these associations remain poorly understood. The present study utilized the inherently stress-susceptible and socially inhibited Wistar-Kyoto rats to determine the potential influences of ELE and trait aggression (TA) on cardiovascular parameters throughout the lifespan. Pups were exposed to maternal separation (MS), consisting of daily 3-h separations of the entire litter from postnatal day (P)1 to P14. The rats were weaned at P21, and as adults were instrumented for chronic radiotelemetry recordings of blood pressure and heart rate (HR). Adult aggressive behavior was assessed using the resident-intruder test, which demonstrated that TA was independent of MS exposure. MS-exposed animals (irrespective of TA) had significantly lower resting HR accompanied by increases in HR variability. No effects of MS on resting blood pressure were detected. In contrast, TA correlated with increased resting mean, systolic, and diastolic arterial pressures but had no effect on HR. TA rats (relative to nonaggressive animals) also manifested increased wall-to-lumen ratio in the thoracic aorta, increased sensitivity to phenylephrine-induced vascular contractility, and increased norepinephrine content in the heart. Together these data suggest that ELE and TA are independent factors that impact baseline cardiovascular function., (Copyright © 2016 the American Physiological Society.)

"Sickle cell anemia: tracking down a mutation" is a full-day, inquiry-based, biology experience for high school students enrolled in genetics or advanced biology courses. In the experience, students use restriction endonuclease digestion, cellulose acetate gel electrophoresis, and microscopy to discover which of three putative patients have the sickle cell genotype/phenotype using DNA and blood samples from wild-type and transgenic mice that carry a sickle cell mutation. The inquiry-based, problem-solving approach facilitates the students' understanding of the basic concepts of genetics and cellular and molecular biology and provides experience with contemporary tools of biotechnology. It also leads to students' appreciation of the causes and consequences of this genetic disease, which is relatively common in individuals of African descent, and increases their understanding of the first principles of genetics. This protocol provides optimal learning when led by well-trained facilitators (including the classroom teacher) and carried out in small groups (6:1 student-to-teacher ratio). This high-quality experience can be offered to a large number of students at a relatively low cost, and it is especially effective in collaboration with a local science museum and/or university. Over the past 15 yr, >12,000 students have completed this inquiry-based learning experience and demonstrated a consistent, substantial increase in their understanding of the disease and genetics in general., (Copyright © 2016 The American Physiological Society.)

Despite advances in surgical and catheter-based treatment for congenital heart disease (CHD), there remain wide disparities across the globe. Ongoing international humanitarian and in-country programmes are working to address these issues with the ultimate goal to increase the quality and quantity of paediatric cardiac care, particularly in under-served regions of the world. This review aims to illustrate the reasons for these inequalities and suggests novel ways of improving access and sustainability of CHD programmes in low-income and middle-income countries., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

In recent years the use of hadrons for cancer radiation treatment has grown in importance, and many facilities are currently operational or under construction worldwide. To fully exploit the therapeutic advantages offered by hadron therapy, precise body imaging for accurate beam delivery is decisive. Proton computed tomography (pCT) scanners, currently in their R&D phase, provide the ultimate 3D imaging for hadrons treatment guidance. A key component of a pCT scanner is the detector used to track the protons, which has great impact on the scanner performances and ultimately limits its maximum speed. In this article, a novel proton-tracking detector was presented that would have higher scanning speed, better spatial resolution and lower material budget with respect to present state-of-the-art detectors, leading to enhanced performances. This advancement in performances is achieved by employing the very latest development in monolithic active pixel detectors (to build high granularity, low material budget, large area silicon detectors) and a completely new proprietary architecture (to effectively compress the data)., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The α2 adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α2A subtype elicits a hypotensive response whereas the α2B subtype mediates a hypertensive effect that counteracts the hypotensive response by the α2A subtype. We have previously shown that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin null mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the α2BAR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α2BAR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 α2BAR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining α2BAR signaling. Consistent with this notion, our in vivo study reveals that the α2BAR-elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α2AAR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

Objective: Little information exists on how perception of the food (or "energetic") environment affects body composition and reproductive investment. The hypothesis was tested that female mice, who are themselves consuming standard chow diets but who are exposed to conspecifics eating a rich "cafeteria diet," will exhibit altered weight gain and reproductive investment., Methods: Female C57BL/6 mice were raised on a cafeteria diet. At maturity, subjects were switched to a standard chow diet, and their cage-mates were assigned to consume either a cafeteria diet (treatment, n = 20) or standard chow (control, n = 20). Subjects were mated and pups raised to weaning. Subjects and pups were analyzed for body composition., Results: Treatment had no discernable effect on dam body weight or composition but caused pups to have lower body weight (P = 0.036) and less fat mass (P = 0.041). A nearly significant treatment effect on "time to successful reproduction" (avg. 55 versus 44 days), likely due to increased failed first pregnancies, (14/19 versus 8/19, P = 0.099) was found., Conclusions: These data indicate that perceived food environment (independent of the diet actually consumed) can produce small pups with less body fat and possibly induce difficulties in pregnancy for dams. Replication and mechanistic studies should follow., (© 2015 The Obesity Society.)