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Introduction: Detailed Emergency Department attendance data for migraine are needed for service redesign. Methods: A service evaluation was undertaken, classifying adult emergency department headache attendances using the International Classification of Headache Disorders migraine C-E criteria, evaluating attendance characteristics. Results: Migraine/Probable migraine diagnosis was documented in 58% but coded in 24% attendances by ED clinicians. 29% of patients used no analgesia before attending, 43% attended ≥4 days after onset and 19% arrived by ambulance. Conclusion: This evaluation highlights sub-optimal acute management and discrepancy between migraine coding and diagnosis contributing to underreporting. We recommend further evaluation of identified cohorts and headache proforma use.

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

IntroductionPelvic fractures can have long-term consequences for health-related quality of life (HRQoL). The main purpose of this study is to provide insight into short-term HRQoL in the first year after pelvic injury and to identify short-term prognostic factors of decreased outcome.MethodsThis is a prospective, observational, multicenter, follow-up cohort study in which HRQoL and functional outcomes were assessed during 12-month follow-up of injured adult patients admitted to 1 of 10 hospitals in the county of Noord-Brabant, the Netherlands. The data were collected by self-reported questionnaires at 1 week (including preinjury assessment) and 1, 3, 6 and 12 months after injury. The EuroQoL-5D (EQ-5D), visual analog scale (VAS), Merle d'Aubigné Hip Score (MAHS) and Majeed Pelvic Score (MPS) were used. Multivariable mixed models were used to examine the course of the HRQoL and the prognostic factors for decreased HRQoL and functional outcomes over time.ResultsA total of 184 patients with pelvic fractures were identified between September 2015-September 2016; the fractures included 71 Tile A, 44 Tile B and 10 Tile C fractures and 59 acetabular fractures. At the pre-injury, 1 week, and 1, 3, 6 and 12 months after injury time points, the mean EQ-5D Index values were 0.90, 0.26, 0.45, 0.66, 0.77 and 0.80, respectively, and the mean EQ-VAS values were 83, 45, 57, 69, 75 and 75, respectively. At 6 and 12 months after injury, 22 and 25% of the MPS < 65 year group, 38 and 47% of the MPS ≥ 65 year group and 34 and 51% of the MAHS group, respectively, reached the maximum score. Pre-injury score, female gender and high Injury Severity Score (ISS) were important prognostic factors for a decreased HRQoL, and the EQ-5D VAS β = 0.43 (95% CI: 0.31 - 0.57), -6.66 (95% CI: -10.90 - -0.43) and -7.09 (95% CI: -6.11 - -5.67), respectively.DiscussionPatients with pelvic fractures experience a reduction in their HRQoL. Most patients do not achieve the HRQoL of their pre-injury state within 1 year after trauma. Prognostic factors for decreased HRQoL are a low pre-injury score, high ISS and female gender. We do not recommend using the MAHS and MPS in mid- or long-term follow-up of pelvic fractures because of ceiling effects. Trial registration number NCT02508675.

Objective: One strategy to address the health issues among college students is through bystander intervention. However, much is still unknown about bystander behavior. The purpose of the current study was to assess the feasibility of daily diary methodology as applied to bystander opportunity. Method: Using a convenience sample, we examined (1) the frequency at which students encounter alcohol use risk and SDV risk bystander opportunities, and (2) the association between participants' daily alcohol use and daily bystander opportunity. Participants were a small group of 32 college students (75% women; 100% heterosexual; 93.7% White; 6.3% multiracial; 3.1% Hispanic) who took up to nine daily diary surveys for a total of 207 days. Results: Over 80% of participants completed the required days. Participants experienced at least one bystander opportunity on 24% of days. Participants were significantly more likely to report an alcohol risk bystander opportunity on days when they drank alcohol, compared to non-drinking days.

Objective: The present study prospectively examined the association between fear of COVID-19 and anxiety and whether social support moderated this association among college students. Participants: 1,539 students from 11 universities in the United States completed two online surveys, one prior to the COVID-19 pandemic and one during the pandemic. Methods: Hierarchical linear regressions assessed the impact of COVID-19 fears and social support on anxiety, after accounting for pre-pandemic anxiety and demographics. Results: Results supported that adding fear of COVID-19 to the regression model resulted in a significant increase in variance explained over demographics and pre-pandemic anxiety. Social support did not moderate the association between fear of COVID-19 and anxiety. Conclusion: These data underscore the mental health impact of COVID-19 on students and the urgency with which campus-wide initiatives are needed to support students during this unprecedented time.

Abstract Background Low health literacy is costly and observed among justice-impacted adults (JIA), a group that often faces numerous barriers in accessing healthcare and a disproportionate burden of illness. Health literacy interventions for JIA are critically needed to improve healthcare access and related outcomes. Methods This manuscript describes the protocol for a longitudinal mixed-methods randomized clinical trial that assesses the effectiveness of a coach-guided health literacy intervention on JIA’s healthcare access. The intervention was previously piloted with justice impacted adults. We will recruit 300 JIA ages 18 + in San Diego, California. Participants will be randomized 1:1 to the Treatment Group (i.e., coach-guided intervention providing 12 sessions of individualized health coaching and service navigation over 6 months) or the Control Group (i.e., self-study of the health coaching program, and brief service navigation support). We will quantitatively assess JIA’s healthcare access defined as: use of healthcare, health insurance status, and regular source of care at 6-months as the primary outcomes. Participants will also be surveyed at 12-months. Statistical analyses will incorporate the intent-to-treat (ITT) principle and we will estimate mixed-effects logistic regression for the primary outcomes. We will also conduct qualitative interviews at 6 and 12-months with 40 purposively sampled participants, stratified by study arm, who reported healthcare access barriers at baseline. Interviews will explore participants’ satisfaction with the intervention, healthcare attitudes, self-efficacy for and barriers to healthcare access over time, perceived contribution of the intervention to health and well-being, and diffusion of intervention-related information within participants’ social networks. We will conduct deductive thematic analyses of qualitative data. Discussion Low health literacy among JIA is a foundational challenge requiring tailored intervention strategies. Findings from this trial may inform policies and the structure of service delivery models to build health literacy among JIA in institutional and community settings throughout the United States and elsewhere. Trial registration This study is registered with the United States’ ClinicalTrials.gov registry under protocol # 161,903.

Abstract Adult Neural Stem Cells (aNSCs) in the ventricular-subventricular zone (V-SVZ) are largely quiescent. Here, we characterize the mechanism underlying the functional role of a cell-signalling inhibitory protein, LRIG1, in the control of aNSCs proliferation. Using Lrig1 knockout models, we show that Lrig1 ablation results in increased aNSCs proliferation with no change in neuronal progeny and that this hyperproliferation likely does not result solely from activation of the epidermal growth factor receptor (EGFR). Loss of LRIG1, however, also leads to impaired activation of transforming growth factor beta (TGFβ) and bone morphogenic protein (BMP) signalling. Biochemically, we show that LRIG1 binds TGFβ/BMP receptors and the TGFβ1 ligand. Finally, we show that the consequences of these interactions are to facilitate SMAD phosphorylation. Collectively, these data suggest that unlike in embryonic NSCs where EGFR may be the primary mechanism of action, in aNSCs, LRIG1 and TGFβ pathways function together to fulfill their inhibitory roles.

Abstract Human cases of avian influenza virus (AIV) infections are associated with an age-specific disease burden. As the influenza virus N2 neuraminidase (NA) gene was introduced from avian sources during the 1957 pandemic, we investigate the reactivity of N2 antibodies against A(H9N2) AIVs. Serosurvey of healthy individuals reveal the highest rates of AIV N2 antibodies in individuals aged ≥65 years. Exposure to the 1968 pandemic N2, but not recent N2, protected against A(H9N2) AIV challenge in female mice. In some older adults, infection with contemporary A(H3N2) virus could recall cross-reactive AIV NA antibodies, showing discernable human- or avian-NA type reactivity. Individuals born before 1957 have higher anti-AIV N2 titers compared to those born between 1957 and 1968. The anti-AIV N2 antibodies titers correlate with antibody titers to the 1957 N2, suggesting that exposure to the A(H2N2) virus contribute to this reactivity. These findings underscore the critical role of neuraminidase immunity in zoonotic and pandemic influenza risk assessment.

Abstract The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.

Abstract Most rod-shaped bacteria elongate by inserting new cell wall material into the inner surface of the cell sidewall. This is performed by class A penicillin binding proteins (PBPs) and a highly conserved protein complex, the elongasome, which moves processively around the cell circumference and inserts long glycan strands that act as barrel-hoop-like reinforcing structures, thereby giving rise to a rod-shaped cell. However, it remains unclear how elongasome synthesis dynamics and termination events are regulated to determine the length of these critical cell-reinforcing structures. To address this, we developed a method to track individual elongasome complexes around the entire circumference of Bacillus subtilis cells for minutes-long periods using single-molecule fluorescence microscopy. We found that the B. subtilis elongasome is highly processive and that processive synthesis events are frequently terminated by rapid reversal or extended pauses. We found that cellular levels of RodA regulate elongasome processivity, reversal and pausing. Our single-molecule data, together with stochastic simulations, show that elongasome dynamics and processivity are regulated by molecular motor tug-of-war competition between several, likely two, oppositely oriented peptidoglycan synthesis complexes associated with the MreB filament. Altogether these results demonstrate that molecular motor tug-of-war is a key regulator of elongasome dynamics in B. subtilis, which likely also regulates the cell shape via modulation of elongasome processivity.

In times of growing concern about the impacts of air pollution across the globe, lower-cost sensor technology is giving the first steps in helping to enhance our understanding and ability to manage air quality issues, particularly in regions without established monitoring networks. While the benefits of greater spatial coverage and real-time measurements that these systems offer are evident, challenges still need to be addressed regarding sensor reliability and data quality. Given the limitations imposed by intellectual property, commercial implementations are often “black boxes”, which represents an extra challenge as it limits end users' understanding of the data production process. In this paper we present an overview of the QUANT (Quantification of Utility of Atmospheric Network Technologies) study, a comprehensive 3-year assessment across a range of urban environments in the United Kingdom, evaluating 43 sensor devices, including 119 gas sensors and 118 particulate matter (PM) sensors, from multiple companies. QUANT stands out as one of the most comprehensive studies of commercial air quality sensor systems carried out to date, encompassing a wide variety of companies in a single evaluation and including two generations of sensor technologies. Integrated into an extensive dataset open to the public, it was designed to provide a long-term evaluation of the precision, accuracy and stability of commercially available sensor systems. To attain a nuanced understanding of sensor performance, we have complemented commonly used single-value metrics (e.g. coefficient of determination, R2; root mean square error, RMSE; mean absolute error, MAE) with visual tools. These include regression plots, relative expanded uncertainty (REU) plots and target plots, enhancing our analysis beyond traditional metrics. This overview discusses the assessment methodology and key findings showcasing the significance of the study. While more comprehensive analyses are reserved for future detailed publications, the results shown here highlight the significant variation between systems, the incidence of corrections made by manufacturers, the effects of relocation to different environments and the long-term behaviour of the systems. Additionally, the importance of accounting for uncertainties associated with reference instruments in sensor evaluations is emphasised. Practical considerations in the application of these sensors in real-world scenarios are also discussed, and potential solutions to end-user data challenges are presented. Offering key information about the sensor systems' capabilities, the QUANT study will serve as a valuable resource for those seeking to implement commercial solutions as complementary tools to tackle air pollution.

Introduction: Musculoskeletal injuries (MSKi) are the most common injury type experienced by first-responders and health care providers (HCPs), making them a significant threat to physical and mental well-being. Female reproductive health and injury history has been related to physical fitness in female members of the Canadian Armed Forces. This relationship has not been explored in Canadian protective services personnel (first-responders) or HCPs. Methods: Fifty-seven females employed as firefighters, paramedics, law enforcements, or HCPs completed a physical fitness protocol to assess the following: (1) muscular power (standing long jump and medicine ball throw), (2) muscular strength (4 repetition maximum (4RM) back squats and bench press), (3) muscular endurance (Biering-Sorenson test, single-leg wall sit, and push-ups), (4) flexibility (sit-and-reach), and (5) aerobic capacity (graded treadmill VO2max test). Spearman rho correlation analyses were applied to descriptive analysis, independent-samples t-test, one-way ANCOVA (adjusted by age), and chi-square test. Spearman rho correlation analyses were used to compare physical fitness results for female reproductive health history (e.g., parity status), previous MSKi, and physical activity behaviors (e.g., sports participation). A p value of

Huntingtin encodes a 3144 amino acid protein, with a polyglutamine repeat tract at the N-terminus. Expansion of this repeat tract above a pathogenic threshold of 36 repeats is the causative mutation of Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. Here we have characterized twenty Huntingtin commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Summary: Genomic imprinting involves differential DNA methylation and gene expression between homologous paternal and maternal loci. It remains unclear, however, whether DNA replication also shows parent-of-origin-specific patterns at imprinted or other genomic regions. Here, we investigate genome-wide asynchronous DNA replication utilizing uniparental human embryonic stem cells containing either maternal-only (parthenogenetic) or paternal-only (androgenetic) DNA. Four clusters of imprinted genes exhibited differential replication timing based on parent of origin, while the remainder of the genome, 99.82%, showed no significant replication asynchrony between parental origins. Active alleles in imprinted gene clusters replicated earlier than their inactive counterparts. At the Prader-Willi syndrome locus, replication asynchrony spanned virtually the entirety of S phase. Replication asynchrony was carried through differentiation to neuronal precursor cells in a manner consistent with gene expression. This study establishes asynchronous DNA replication as a hallmark of large imprinted gene clusters.

Huntingtin encodes a 3144 amino acid protein, with a polyglutamine repeat tract at the N-terminus. Expansion of this repeat tract above a pathogenic threshold of 36 repeats is the causative mutation of Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. Here we have characterized twenty Huntingtin commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

ABSTRACT The bacterial pathogen Staphylococcus aureus responds to the host environment by increasing the thickness of its cell wall. However, the impact of cell wall thickening on susceptibility to host defenses is unclear. Using bacteria incubated in human serum, we show that host-induced increases in cell wall thickness led to a reduction in the exposure of bound antibody and complement and a corresponding reduction in phagocytosis and killing by neutrophils. The exposure of opsonins bound to protein antigens or lipoteichoic acid (LTA) was most significantly reduced, while opsonization by IgG against wall teichoic acid or peptidoglycan was largely unaffected. Partial digestion of accumulated cell wall using the enzyme lysostaphin restored opsonin exposure and promoted phagocytosis and killing. Concordantly, the antibiotic fosfomycin inhibited cell wall remodeling and maintained the full susceptibility of S. aureus to opsonophagocytic killing by neutrophils. These findings reveal that host-induced changes to the S. aureus cell wall reduce the ability of the immune system to detect and kill this pathogen through reduced exposure of protein- and LTA-bound opsonins.IMPORTANCEUnderstanding how bacteria adapt to the host environment is critical in determining fundamental mechanisms of immune evasion, pathogenesis, and the identification of targets for new therapeutic approaches. Previous work demonstrated that Staphylococcus aureus remodels its cell envelope in response to host factors and we hypothesized that this may affect recognition by antibodies and thus killing by immune cells. As expected, incubation of S. aureus in human serum resulted in rapid binding of antibodies. However, as bacteria adapted to the serum, the increase in cell wall thickness resulted in a significant reduction in exposure of bound antibodies. This reduced antibody exposure, in turn, led to reduced killing by human neutrophils. Importantly, while antibodies bound to some cell surface structures became obscured, this was not the case for those bound to wall teichoic acid, which may have important implications for vaccine design.

Midkine is a secreted protein that acts as a growth factor or cytokine involved in cell survival and inflammatory processes. It accumulates in amyloid plaques, which are hallmarks of Alzheimer’s Disease (AD). The reproducibility of Midkine research would be enhanced if the community had access to well-characterized anti-Midkine antibodies. In this study, we characterized 8 commercial Midkine antibodies for Western blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in a knockout cell line and isogenic parental control. These studies are part of a larger, collaborative initiative seeking to address the antibody reproducibility issue by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Midkine is a secreted protein that acts as a growth factor or cytokine involved in cell survival and inflammatory processes. It accumulates in amyloid plaques, which are hallmarks of Alzheimer’s Disease (AD). The reproducibility of Midkine research would be enhanced if the community had access to well-characterized anti-Midkine antibodies. In this study, we characterized 8 commercial Midkine antibodies for Western blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in a knockout cell line and isogenic parental control. These studies are part of a larger, collaborative initiative seeking to address the antibody reproducibility issue by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P

Abstract We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Abstract Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Abstract Background The purpose of this paper is to evaluate the impact of modifying the published scoring system to address identified potential weaknesses in the published scoring system for the Evaluation of Activity Surveys in Youth (EASY). A secondary purpose was to evaluate the EASY on children in Grades 1–5. The EASY is a self-report physical activity instrument for youth. Methods Original EASY survey results were collected at one time point from an online panel from participants across the United States as part of a larger cross-sectional University of Minnesota project looking at children’s specific activity and sports participation between June and August 2019. Data was evaluated using three common scoring methods: simple summation, mean, and transformed summation. Data was compared by Grades 1–5 and 6–8. Results The summary statistics of the scores show that there is no statistically significant difference across the scoring methods by population. A paired t-test evaluation of the different scoring methods shows that while the scores are very similar within methodology (simple summation, mean, transformed sum) they are all statistically significantly different from one another, which demonstrates that for any given individual the specific scoring methodology used can result in meaningful differences. The transformed sum provided the strongest methodologic result. Analysis also concluded that administering the scale by proxy to children from grades 1–5 resulted in similar responses to those in Grades 6–8 broadening the appropriate populations able to use this scale. Conclusion The transformed sum is the preferred scoring method. Trial registration Not applicable.

Abstract Background Gunshot wounds (GSW) to the heart are lethal, and most patients die before they arrive to the hospital. Survival decreases with number of cardiac chambers involved. We report a case of a 17-year-old male who survived a GSW injury involving two cardiac chambers with acute severe tricuspid regurgitation (TR) who subsequently developed cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO) support. Case Presentation A 17-year-old male sustained a single gunshot wound to the left chest, resulting in pericardial tamponade and right hemothorax. Emergency sternotomy revealed injury to the right ventricle and inferior cavoatrial junction with the adjacent pericardium contributing to a right hemothorax. The cardiac injuries were repaired primarily. Tricuspid regurgitation was confirmed immediately postoperatively. Five days after presentation, the patient developed cardiogenic shock secondary to TR requiring emergent stabilization with ECMO. He subsequently underwent successful tricuspid valve replacement. Conclusions This is the first report to our knowledge of successful ECMO support of severe TR due to gunshot injury to the heart.

Abstract The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.

Mesoporous silica nanoparticles (MSNs) are introduced as chemically and thermally stable nanomaterials with well-defined and controllable morphology and porosity. It is shown that these particles possess external and internal surfaces that can be selectively functionalized with multiple organic and inorganic groups. Silica nano-particles were synthesized by chemical methods from tetraethylorthosilicate (TEOS), methanol (CH3OH) and deionised water in the presence of sodium hydroxide as catalyst at 80°C temperature. The nature and morphology of particles was investigated by scanning electron microscopy (SEM), N2 adsorption/desorption method using BET instrument and X-ray diffraction (XRD). Silica nanoparticles are applicable to a wide range of therapeutic entities from small molecule to peptides and proteins including hydrophobic and hydrophilic entities. Drug loading does not require chemical modification of the molecule; there are no changes in the drug structure or activity after loading and subsequent release of the drug. Thus, well suited to solve formulation problems associated with hydrophobic drugs such as peptide and protein drugs like cyclosporine A. Silica nanoparticles improved the solubility of poorly water soluble drugs and enhanced the absorption and bioavailability of these compounds.

Research shows that engaged and continuously developing teachers are more effective in the classroom. However, with a significant proportion of adult English as a second language (ESL) instructional staff consisting of adjunct faculty, it is crucial to address issues such as high turnover rates, feelings of isolation and marginalization, limited availability for PD due to transient schedules and multiple jobs, and insufficient funding for robust offerings. This article explores several best practices for overcoming those challenges--mini-conferences, professional development (PD) swaps, study groups, individualized faculty development plans, and leveraging technology for flexible and asynchronous options--and encourages other programs to adopt such PD initiatives to support and empower adjunct faculty.

Research highlights the high rates and deleterious outcomes of teen dating and sexual violence (DSV), underscoring the critical role of prevention. School personnel have an important role in preventing DSV among teens. The purpose of this study was to explore the rates and correlates of school personnel's opportunity and actions to intervene in situations of teen dating and sexual violence. Participants were 1,150 high school personnel from twenty-five schools recruited via e-mails, flyers, and staff meetings. Results showed that 65.4 percent of school personnel had the opportunity to intervene in at least one type of DSV situation during the past year, and 37.4 to 80.9 percent of school personnel (depending on the type of situation) engaged in positive bystander action when given the opportunity. Further, 47.1 percent of school personnel talked to teens about how to get help if they were experiencing DSV, and 72.3 percent talked to teens about how to have healthy relationships. In general, greater DSV knowledge and efficacy and fewer barriers to intervention in situations of DSV were related to greater bystander opportunity and action. However, for some types of situations (e.g., couples physically fighting), few if any correlates emerged, suggesting the need for future research that includes a more comprehensive set of correlates of bystander opportunity and action in situations of DSV. These findings underscore the critical need for DSV-specific bystander intervention training for high school personnel that helps them recognize situations of DSV and equips them with skills to respond effectively.

Abstract Empirical dynamic modelling (EDM) is becoming an increasingly popular method for understanding the dynamics of ecosystems. It has been applied to laboratory, terrestrial, freshwater and marine systems, used to forecast natural populations and has addressed fundamental ecological questions. Despite its increasing use, we have not found full explanations of EDM in the ecological literature, limiting understanding and reproducibility. Here we expand upon existing work by providing a detailed introduction to EDM. We use three progressively more complex approaches. A short verbal explanation of EDM is then explicitly demonstrated by graphically working through a simple example. We then introduce a full mathematical description of the steps involved. Conceptually, EDM translates a time series of data into a path through a multi‐dimensional space, whose axes are lagged values of the time series. A time step is chosen from which to make a prediction. The state of the system at that time step corresponds to a ‘focal point’ in the multi‐dimensional space. The set (called the library) of candidate nearest neighbours to the focal point is constructed, to determine the nearest neighbours that are then used to make the prediction. Our mathematical explanation explicitly documents which points in the multi‐dimensional space should not be considered as focal points. We suggest a new option for excluding points from the library that may be useful for short‐term time series that are often found in ecology. We focus on the core simplex and S‐map algorithms of EDM. Our new R package, pbsEDM, enhances understanding (by outputting intermediate calculations), reproduces our results and can be applied to new data. Our work improves the clarity of the inner workings of EDM, a prerequisite for EDM to reach its full potential in ecology and have wide uptake in the provision of advice to managers of natural resources.

ABSTRACTPertussis (whooping cough) is a reemergent, highly contagious respiratory infection of public health concern. Infants prior to initiation of their primary vaccination series are the most vulnerable to severe infection, and even death. Vaccination during pregnancy is an efficacious means of reducing infection in infants. This approach relies on boosting maternal immunity and passive transfer of antibodies to the infant via placenta and breast milk. Similarly, maternal vaccination post-partum can enhance maternal-infant immunity. To support the analysis of pertussis immunity in the context of maternal-infant immunization, we developed a high throughput multiplex assay for simultaneous quantification of serum IgG antibodies against pertussis vaccine antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM2/3), and against tetanus (TT) and diphtheria toxoids (DT), using the Meso Scale Discovery (MSD) platform. The assay was qualified, and specificity, sensitivity, accuracy, precision, linearity, and robustness were demonstrated. The assay was subsequently adapted for quantification of IgG and IgA in breast milk. Applied to a serological survey of pregnant women living in the United States and sub-Saharan Africa, this method revealed differences in magnitude and breadth of antibody profile, consistent with history of vaccination. A longitudinal analysis of Tdap responses in women vaccinated post-partum demonstrated a rapid increase in serum IgG that remained elevated for up to 24 months. Likewise, high levels of vaccine-specific IgA and IgG antibodies were present in breast milk, although they exhibited faster decay. This multiplex MSD assay is a reliable and practical tool for quantification of pertussis, tetanus, and diphtheria antibodies in serum and breast milk in serosurveys or vaccine studies.IMPORTANCEPertussis (whooping cough) has reemerged in recent years. Vaccination during pregnancy is an effective approach to prevent illness during the first months of life. We developed a multiplex assay for quantification of pertussis, tetanus, and diphtheria serum antibodies using the Meso Scale Discovery (MSD) platform; the method was qualified, and specificity, precision, accuracy, linearity, and limits of quantification were defined. It was also adapted for quantification of antibodies in breast milk. We successfully determined serostatus in women from different regions and with different vaccination histories, as well as responses to Tdap in blood and breast milk post-partum. This is the first description of a multiplex assay for the quantification of pertussis, tetanus, and diphtheria antibodies in breast milk.

Abstract As maternal mortality and morbidity rates stagnate or increase worldwide, there is an urgent need to address health system issues that impede access to high-quality care. Learning from efforts to address the value, safety, and effectiveness of reproductive and maternal health care is essential to advancing quality improvement efforts.

Background: The introduction of endovascular repair provides an alternative to traditional open repair of thoracoabdominal aortic aneurysms (TAAA). Its utility is not well defined, however. Using a national database, we studied the treatment patterns and outcomes of TAAA to gain insight into its contemporary surgical practice in the United States. Methods: Records of TAAA patients who received endovascular and open repair were retrieved from the 2002 to 2018 National Inpatient Sample database. Each cohort was stratified into 4 age groups: ≤50, 51 to 60, 61 to 70, and >70 years. Patient characteristics and in-hospital outcomes were compared between the 2 repair modalities. Temporal trends were investigated. Results: Endovascular repair use increased steadily, whereas open repair volume remained stable until 2012, before declining by 50% by 2018. This appears to be associated with a declining number of open repairs in patients age >60 years. Patients who underwent endovascular repair were older and had a higher Charlson Comorbidity Index (mean, 2.8 ± 1.7 vs 2.5 ± 1.5; P 60 years but not for patients age ≤60 years. Conclusions: There has been a shift in the treatment of TAAA in the United States from open repair–dominant to endovascular repair–dominant. It has increased surgical access for older and more comorbid patients and has led to a decline in the use of open repair while lowering in-hospital mortality.

Abstract Background Surgical site infections (SSIs) represent ~ 20% of all hospital-acquired infections in surgical patients and are associated with prolonged hospital stay, admission to intensive care, and mortality. We conducted a systematic review with economic and environmental models to assess whether triclosan-coated sutures (Plus Sutures) provide benefits over non-coated sutures in the reduction of SSI risk. Methods Searches were conducted in fifteen databases. A total of 1,991 records were retrieved. Following deduplication and screening by two independent reviewers, 31 randomized controlled trials in adults and children were included in the review. Similarity of the studies was assessed by narrative review and confirmed by quantitative assessment. A fixed effects meta-analysis of SSI incidence model including all groups of patients estimated a risk ratio of 0.71 (95% confidence interval: 0.64 to 0.79) indicating those in the Plus Sutures group had a 29% reduction in the risk of developing an SSI compared with those in the control group (p

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.

ABSTRACT The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores the function of the pathogenic mutated CF transmembrane conductance regulator (CFTR) channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in body mass index and percent predicted forced expiratory volume in one second, and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.IMPORTANCECystic fibrosis (CF) is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Recently approved treatments for CF, CF transmembrane conductance regulator (CFTR) modulators, are anticipated to substantially improve the care of people with CF and extend their lifespans. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease.

Abstract Introduction: The value of Source Data Verification (SDV) has been a common theme in the applied Clinical Translational Science literature. Yet, few published assessments of SDV quality exist even though they are needed to design risk-based and reduced monitoring schemes. This review was conducted to identify reports of SDV quality, with a specific focus on accuracy. Methods: A scoping review was conducted of the SDV and clinical trial monitoring literature to identify articles addressing SDV quality. Articles were systematically screened and summarized in terms of research design, SDV context, and reported measures. Results: The review found significant heterogeneity in underlying SDV methods, domains of SDV quality measured, the outcomes assessed, and the levels at which they were reported. This variability precluded comparison or pooling of results across the articles. No absolute measures of SDV accuracy were identified. Conclusions: A definitive and comprehensive characterization of SDV process accuracy was not found. Reducing the SDV without understanding the risk of critical findings going undetected, i.e., SDV sensitivity, is counter to recommendations in Good Clinical Practice and the principles of Quality by Design. Reference estimates (or methods to obtain estimates) of SDV accuracy are needed to confidently design risk-based, reduced SDV processes for clinical studies.

Summary: Induced pluripotent stem cells (iPSCs) are the foundation of cell therapy. Differences in gene expression, DNA methylation, and chromatin conformation, which could affect differentiation capacity, have been identified between iPSCs and embryonic stem cells (ESCs). Less is known about whether DNA replication timing, a process linked to both genome regulation and genome stability, is efficiently reprogrammed to the embryonic state. To answer this, we compare genome-wide replication timing between ESCs, iPSCs, and cells reprogrammed by somatic cell nuclear transfer (NT-ESCs). While NT-ESCs replicate their DNA in a manner indistinguishable from ESCs, a subset of iPSCs exhibits delayed replication at heterochromatic regions containing genes downregulated in iPSCs with incompletely reprogrammed DNA methylation. DNA replication delays are not the result of gene expression or DNA methylation aberrations and persist after cells differentiate to neuronal precursors. Thus, DNA replication timing can be resistant to reprogramming and influence the quality of iPSCs.

Objectives: We examined the association of nasopharyngeal (NP) pneumococcal co-colonization (>1 pneumococcal serotype) and pneumococcal density in young Peruvian children enrolled in a prospective cohort study. Methods: NP swabs collected monthly from children aged

Organonitrates are important species in the atmosphere due to their impacts on NOx, HOx, and O3 budgets, and their potential to contribute to secondary organic aerosol (SOA) mass. This work presents a steady-state modelling approach to assess the impacts of changes in NOx and O3 concentrations on the organonitrates produced from isoprene oxidation. The diverse formation pathways to isoprene organonitrates dictate the responses of different groups of organonitrates to changes in O3 and NOx. For example, organonitrates predominantly formed from the OH-initiated oxidation of isoprene favour formation under lower-ozone and moderate-NOx concentrations, whereas organonitrates formed via daytime NO3 oxidation show the highest formation under high-O3 concentrations with little dependence on NOx concentrations. Investigating the response of total organonitrates reveals complex and nonlinear behaviour with implications that could inform expectations of changes to organonitrate concentrations as efforts are made to reduce NOx and O3 concentrations, including a region of NOx–O3 space where total organonitrate concentration is relatively insensitive to changes in NOx and O3. These conclusions are further contextualised by estimating the volatility of the isoprene organonitrates revealing the potential for high concentrations of low-volatility species under high-ozone conditions.

Influenza A viruses are a One Health threat because they can spill over between host populations, including among humans, swine, and birds. Surveillance of swine influenza virus in Hanoi, Vietnam, during 2013–2019 revealed gene pool enrichment from imported swine from Asia and North America and showed long-term maintenance, persistence, and reassortment of virus lineages. Genome sequencing showed continuous enrichment of H1 and H3 diversity through repeat introduction of human virus variants and swine influenza viruses endemic in other countries. In particular, the North American H1-δ1a strain, which has a triple-reassortant backbone that potentially results in increased human adaptation, emerged as a virus that could pose a zoonotic threat. Co-circulation of H1-δ1a viruses with other swine influenza virus genotypes raises concerns for both human and animal health.

Abstract Researchers in ecology and evolutionary biology are increasingly dependent on computational code to conduct research. Hence, the use of efficient methods to share, reproduce, and collaborate on code as well as document research is fundamental. GitHub is an online, cloud‐based service that can help researchers track, organize, discuss, share, and collaborate on software and other materials related to research production, including data, code for analyses, and protocols. Despite these benefits, the use of GitHub in ecology and evolution is not widespread. To help researchers in ecology and evolution adopt useful features from GitHub to improve their research workflows, we review 12 practical ways to use the platform. We outline features ranging from low to high technical difficulty, including storing code, managing projects, coding collaboratively, conducting peer review, writing a manuscript, and using automated and continuous integration to streamline analyses. Given that members of a research team may have different technical skills and responsibilities, we describe how the optimal use of GitHub features may vary among members of a research collaboration. As more ecologists and evolutionary biologists establish their workflows using GitHub, the field can continue to push the boundaries of collaborative, transparent, and open research.

Abstract Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Here, we present a mathematical model and Bayesian inference implementation to facilitate genome-wide joint parameter estimation and confidence quantification (R package: burstMCMC). We demonstrate that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. We apply our method to published 4sU scRNA-seq data and linked with ChIP-seq data, we uncover previously obscured associations between different parameters and histone modifications.

Abstract Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number (R e ) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy.