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Abstract Background Gastrointestinal bleeding (GIB) is a clinical challenge in kidney failure. INSPIRE group assessed if machine learning could determine a hemodialysis (HD) patient’s 180-day GIB hospitalization risk. Methods An eXtreme Gradient Boosting (XGBoost) and logistic regression model were developed using an HD dataset in United States (2017–2020). Patient data was randomly split (50% training, 30% validation, and 20% testing). HD treatments ≤ 180 days before GIB hospitalization were classified as positive observations; others were negative. Models considered 1,303 exposures/covariates. Performance was measured using unseen testing data. Results Incidence of 180-day GIB hospitalization was 1.18% in HD population (n = 451,579), and 1.12% in testing dataset (n = 38,853). XGBoost showed area under the receiver operating curve (AUROC) = 0.74 (95% confidence interval (CI) 0.72, 0.76) versus logistic regression showed AUROC = 0.68 (95% CI 0.66, 0.71). Sensitivity and specificity were 65.3% (60.9, 69.7) and 68.0% (67.6, 68.5) for XGBoost versus 68.9% (64.7, 73.0) and 57.0% (56.5, 57.5) for logistic regression, respectively. Associations in exposures were consistent for many factors. Both models showed GIB hospitalization risk was associated with older age, disturbances in anemia/iron indices, recent all-cause hospitalizations, and bone mineral metabolism markers. XGBoost showed high importance on outcome prediction for serum 25 hydroxy (25OH) vitamin D levels, while logistic regression showed high importance for parathyroid hormone (PTH) levels. Conclusions Machine learning can be considered for early detection of GIB event risk in HD. XGBoost outperforms logistic regression, yet both appear suitable. External and prospective validation of these models is needed. Association between bone mineral metabolism markers and GIB events was unexpected and warrants investigation. Trial registration This retrospective analysis of real-world data was not a prospective clinical trial and registration is not applicable. Graphical Abstract

Abstract Huntington’s disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin’s polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.

Abstract Background Northern ecosystems are strongly influenced by herbivores that differ in their impacts on the ecosystem. Yet the role of herbivore diversity in shaping the structure and functioning of tundra ecosystems has been overlooked. With climate and land-use changes causing rapid shifts in Arctic species assemblages, a better understanding of the consequences of herbivore diversity changes for tundra ecosystem functioning is urgently needed. This systematic review synthesizes available evidence on the effects of herbivore diversity on different processes, functions, and properties of tundra ecosystems. Methods Following a published protocol, our systematic review combined primary field studies retrieved from bibliographic databases, search engines and specialist websites that compared tundra ecosystem responses to different levels of vertebrate and invertebrate herbivore diversity. We used the number of functional groups of herbivores (i.e., functional group richness) as a measure of the diversity of the herbivore assemblage. We screened titles, abstracts, and full texts of studies using pre-defined eligibility criteria. We critically appraised the validity of the studies, tested the influence of different moderators, and conducted sensitivity analyses. Quantitative synthesis (i.e., calculation of effect sizes) was performed for ecosystem responses reported by at least five articles and meta-regressions including the effects of potential modifiers for those reported by at least 10 articles. Review findings The literature searches retrieved 5944 articles. After screening titles, abstracts, and full texts, 201 articles including 3713 studies (i.e., individual comparisons) were deemed relevant for the systematic review, with 2844 of these studies included in quantitative syntheses. The available evidence base on the effects of herbivore diversity on tundra ecosystems is concentrated around well-established research locations and focuses mainly on the impacts of vertebrate herbivores on vegetation. Overall, greater herbivore diversity led to increased abundance of feeding marks by herbivores and soil temperature, and to reduced total abundance of plants, graminoids, forbs, and litter, plant leaf size, plant height, and moss depth, but the effects of herbivore diversity were difficult to tease apart from those of excluding vertebrate herbivores. The effects of different functional groups of herbivores on graminoid and lichen abundance compensated each other, leading to no net effects when herbivore effects were combined. In turn, smaller herbivores and large-bodied herbivores only reduced plant height when occurring together but not when occurring separately. Greater herbivore diversity increased plant diversity in graminoid tundra but not in other habitat types. Conclusions This systematic review underscores the importance of herbivore diversity in shaping the structure and function of Arctic ecosystems, with different functional groups of herbivores exerting additive or compensatory effects that can be modulated by environmental conditions. Still, many challenges remain to fully understand the complex impacts of herbivore diversity on tundra ecosystems. Future studies should explicitly address the role of herbivore diversity beyond presence-absence, targeting a broader range of ecosystem responses and explicitly including invertebrate herbivores. A better understanding of the role of herbivore diversity will enhance our ability to predict whether and where shifts in herbivore assemblages might mitigate or further amplify the impacts of environmental change on Arctic ecosystems.

Background:The Together for Health-Virginia (T4H-VA) Research Program aimed to advance cancer prevention, education, and outreach in Virginia. Creating a representative and inclusive cohort is critical to the program’s mission and quality of outcomes. The T4H-VA Research Program utilized a multi-modal sampling approach to improve population health assessment. The current study describes the technology-based, non-probability platform developed for this purpose and compares differences between the probability-based (mail-based) and non-probability-based (e-cohort) methods with respect to participant demographics, health characteristics, and health information and technology use.Methods:T4H-VA is a research registry focusing on 54 counties within the Massey Comprehensive Cancer Center (MCCC) catchment area in Richmond, VA. Adult residents proficient in English were eligible. For the probability-based sampling, surveys were mailed to residents within the catchment area. For the non-probability sampling, an online study platform was developed and surveys were completed through the web/mobile app.Result:Both cohorts fell short of recruitment goals. The study yielded 1158 participants (M = 57, SD = 16 years; 55.0% female; 72.1% White); 899 (77.6%) were sampled through the probability, mail-based approach. Participants who identified as ‘other' race were significantly less likely to be sampled by the non-probability method. Significant differences emerged, including health protective (greater moderate and high physical activity) and risk factors (greater alcohol consumption and personal history of cancer) in the non-probability, e-cohort relative to the probability sample. E-Cohort participants were significantly more likely to report using electronic health records.Discussion:Overall difficulties in recruiting were caused, at least in part, by the onset of the COVID-19 pandemic and related factors. The e-cohort, which used exclusively digital recruitment strategies, fell significantly short of recruitment goals. This suggests in-person and mail-based strategies remain important for recruitment. Moreover, instead of favoring a singular approach, a combined approach to survey sampling may capitalize on the strengths of each sampling mode to increase diversity in sociodemographic and health risk characteristics.Abbreviations:ABS: address-based sample; BRFSS: Behavioral Risk Factor Surveillance System; BMI: body mass index; CI: confidence interval; COVID-19: coronavirus disease 2019; e-cohort: electronic cohort; EHR: electronic health record; eConsent: electronic consent; HINTS: Health Information National Trends Survey; HIT: health information technology; HOP: Healthy Oregon Project; MCC: Massey Cancer Center; NCI: National Cancer Institute; NIH: National Institute of Health; OR: odds ratio; REDCap: Research electronic data capture; T4H-VA: Together for Health-Virginia; VCU: Virginia Commonwealth University.

Introduction Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to end-stage kidney disease (ESKD). The objective of this prespecified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial. Methods Patients with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g were randomized to dapagliflozin 10 mg once daily or placebo, along with standard-of-care and followed for median 2.4 years. The primary endpoint was a composite of ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Exploratory efficacy endpoints included eGFR slope and UACR. Results Among DAPA-CKD participants with membranous nephropathy, 19 were randomized to dapagliflozin and 24 to placebo. Mean (SD) age was 59.9 ± 12.1 years; mean eGFR 45.7 ± 12.1 mL/min/1.73m2, and median UACR 1694.5 (25%, 75% range 891–2582.5) mg/g. Two of 19 (11%) patients randomized to dapagliflozin, and five of 24 (21%) randomized to placebo experienced the primary composite endpoint. Total and chronic mean eGFR slopes for dapagliflozin and placebo were −3.87 and −4.29 and −2.66 and −4.22 mL/min/1.73m2/year, respectively; corresponding between-group mean differences were 0.42 and 1.57 mL/min/1.73m2/year. Dapagliflozin reduced geometric mean (SEM) UACR relative to placebo (−29.3% ± 1.2% versus −3.6% ± 1.1%; between-group mean difference [95% CI] −26.7 [−50.4, 8.3]). Four (21%) patients randomized to dapagliflozin and seven (29%) randomized to placebo experienced a serious adverse event. Conclusions In membranous nephropathy, effects of dapagliflozin on kidney disease progression and albuminuria were generally favourable; there was insufficient power to justify formal inference testing.

An expanded CAG repeat in the huntingtin gene (HTT) causes Huntington’s disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and guide RNAs (gRNAs) efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering HTT mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased in the liver by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion strategies in HD and potentially other repeat expansion disorders.

Abstract Background The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. Methods Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. Results A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. Conclusions In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

Abstract This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54–63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18–29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18–45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5–21) sessions. At baseline, 90–100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62–83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants’ reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement. Trial registration NCT04872933. Date of first registration 05/05/2021.

Abstract The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.

Background. In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). Objectives. To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors’ CYP3A5 genotypes, considering both donor and recipient characteristics. Methods. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. Results. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p

Abstract Objective The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]). Methods Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. Results The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. Conclusion Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.

Abstract Background Increased breast density augments breast cancer risk and reduces mammography sensitivity. Supplemental breast MRI screening can significantly increase cancer detection among women with dense breasts. However, few women undergo this exam, and screening is consistently lower among racially minoritized populations. Implementation strategies informed by behavioral economics (“nudges”) can promote evidence-based practices by improving clinician decision-making under conditions of uncertainty. Nudges directed toward clinicians and patients may facilitate the implementation of supplemental breast MRI. Methods Approximately 1600 patients identified as having extremely dense breasts after non-actionable mammograms, along with about 1100 clinicians involved with their care at 32 primary care or OB/GYN clinics across a racially diverse academically based health system, will be enrolled. A 2 × 2 randomized pragmatic trial will test nudges to patients, clinicians, both, or neither to promote supplemental breast MRI screening. Before implementation, rapid cycle approaches informed by clinician and patient experiences and behavioral economics and health equity frameworks guided nudge design. Clinicians will be clustered into clinic groups based on existing administrative departments and care patterns, and these clinic groups will be randomized to have the nudge activated at different times per a stepped wedge design. Clinicians will receive nudges integrated into the routine mammographic report or sent through electronic health record (EHR) in-basket messaging once their clinic group (i.e., wedge) is randomized to receive the intervention. Independently, patients will be randomized to receive text message nudges or not. The primary outcome will be defined as ordering or scheduling supplemental breast MRI. Secondary outcomes include MRI completion, cancer detection rates, and false-positive rates. Patient sociodemographic information and clinic-level variables will be examined as moderators of nudge effectiveness. Qualitative interviews conducted at the trial’s conclusion will examine barriers and facilitators to implementation. Discussion This study will add to the growing literature on the effectiveness of behavioral economics-informed implementation strategies to promote evidence-based interventions. The design will facilitate testing the relative effects of nudges to patients and clinicians and the effects of moderators of nudge effectiveness, including key indicators of health disparities. The results may inform the introduction of low-cost, scalable implementation strategies to promote early breast cancer detection. Trial registration ClinicalTrials.gov NCT05787249. Registered on March 28, 2023.

Tobacco smoke contains a high concentration of oxidants and is the primary cause of chronic obstructive pulmonary disease (COPD). Extracellular superoxide dismutase (EC-SOD) is the major antioxidant enzyme in the extracellular space of the lung and is part of the lung defense against these oxidants. We hypothesized that EC-SOD is a risk factor for COPD. We found that EC-SOD plasma levels were significantly higher (p

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. Methods Fifty-five individuals with AS (aged

Objectives Traditional potassium (K+) binders for treating hyperkalaemia are unpalatable and poorly tolerated. Newer K+ binders are reportedly better tolerated; however, no published data describe their palatability, a determinant of long-term adherence. This study evaluated the palatability of and preference for three K+ binders: sodium and calcium polystyrene sulfonate (S/CPS), sodium zirconium cyclosilicate (SZC) and calcium patiromer sorbitex (patiromer).Design Phase 4, randomised, participant-blinded, cross-over study. Participants were randomised to one of six taste sequences and, using a ‘sip and spit’ approach, tasted each K+ binder before completing a survey.Setting 17 centres across the USA, Canada and European Union.Participants 144 participants with chronic kidney disease, hyperkalaemia and no recent use of K+ binders.Main outcome measures For the primary (USA) and key secondary (Canada and European Union) endpoints, participants rated palatability attributes (taste, texture, smell and mouthfeel) and willingness to take each K+ binder on a scale of 0–10 (rational evaluation). Feelings about each attribute, and the idea of taking the product once daily, were evaluated using a non-verbal, visual measure of emotional response. Finally, participants ranked the K+ binders according to palatability.Results In each region, SZC and patiromer outperformed S/CPS on overall palatability (a composite of taste, texture, smell and mouthfeel), based on rational evaluation and emotional response. Taking the product once daily was more appealing for SZC and patiromer, creating greater receptivity than the idea of taking S/CPS. The emotional response to mouthfeel had the strongest influence on feelings about taking each product. In each region, a numerically greater proportion of participants ranked SZC as the most preferred K+ binder versus patiromer or S/CPS.Conclusions Preference for more palatable K+ binders such as SZC and patiromer may provide an opportunity to improve adherence to long-term treatment of hyperkalaemia.Trial registration number NCT04566653.

We present high-cadence photometric and spectroscopic observations of supernova (SN) 2024ggi, a Type II SN with flash spectroscopy features, which exploded in the nearby galaxy NGC 3621 at ∼7 Mpc. The light-curve evolution over the first 30 hr can be fit by two power-law indices with a break after 22 hr, rising from M _V ≈ −12.95 mag at +0.66 day to M _V ≈ −17.91 mag after 7 days. In addition, the densely sampled color curve shows a strong blueward evolution over the first few days and then behaves as a normal SN II with a redward evolution as the ejecta cool. Such deviations could be due to interaction with circumstellar material (CSM). Early high- and low-resolution spectra clearly show high-ionization flash features from the first spectrum to +3.42 days after the explosion. From the high-resolution spectra, we calculate the CSM velocity to be 37 ± 4 km s ^−1 . We also see the line strength evolve rapidly from 1.22 to 1.49 days in the earliest high-resolution spectra. Comparison of the low-resolution spectra with CMFGEN models suggests that the pre-explosion mass-loss rate of SN 2024ggi falls in the range of 10 ^−3 –10 ^−2 M _☉ yr ^−1 , which is similar to that derived for SN 2023ixf. However, the rapid temporal evolution of the narrow lines in the spectra of SN 2024ggi ( R _CSM ∼ 2.7 × 10 ^14 cm) could indicate a smaller spatial extent of the CSM than in SN 2023ixf ( R _CSM ∼ 5.4 × 10 ^14 cm), which in turn implies a lower total CSM mass for SN 2024ggi.

Background: Pediatric colorectal specialists care for patients with a variety of defecation disorders. Anorectal (AR) manometry testing is a valuable tool in the diagnosis and management of these children. This paper provides a summary of AR manometry techniques and applications as well as a review of AR manometry findings in pediatric patients with severe defecation disorders referred to a pediatric colorectal center. This is the first study describing multi-year experience using a portable AR manometry device in pediatric patients. Methods: An electronic medical record review was performed (1/2018 to 12/2023) of pediatric patients with defecation disorders who had AR manometry testing. Demographics, diagnostic findings, and outcomes are described. Key Results: A total of 297 unique patients (56.9% male, n = 169) had AR manometry testing. Of these, 72% (n = 188) had dyssynergic defecation patterns, of which 67.6% (n = 127) had fecal soiling prior to treatment. Pelvic rehabilitation (PR) was administered to 35.4% (n = 105) of all patients. A total of 79.5% (n = 58) of the 73 patients that had fecal soiling at initial presentation and completed PR with physical therapy and a bowel management program were continent after therapy. AR manometry was well tolerated, with no major complications. Conclusions: AR manometry is a simple test that can help guide the management of pediatric colorectal surgical patients with defecation disorders. As a secondary finding, PR is a useful treatment for patients with dyssynergic stooling.

Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD). The expanded Htt CAG repeats further reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Integrative transcriptomic analyses unveil a network of transcriptionally altered micro-RNAs and RNA-binding proteins (Celf, hnRNPs, Ptbp, Srsf, Upf1, Ythd2) which might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might alter neural fitness, contributing to HD pathogenesis.

In the early months of the COVID-19 pandemic, states enacted multiple policies to reduce in-person interactions. Scholars have speculated that these policies may have contributed to adverse mental health outcomes. This study examines potential associations between states’ COVID-19 physical distancing policies and working-age (18–64) adults’ self-reported mental health. Mental health outcomes (depression, anxiety, worsened mental health, and sought treatment for anxiety or depression) are from the National Wellbeing Survey collected from working-age adults in the United States (U.S.) February 1 to March 18, 2021 (N = 3,804). Data on 12 state policies are from the COVID-19 U.S. State Policy Database. Analyses included logistic regression and Bayesian group index modeling, which identified sets, or “bundles,” of policies that were associated with each mental health outcome. Multiple policies (both separately and in bundles) were associated with adverse mental health outcomes, with certain policies (closures and curfews on retail and other businesses) being particularly important. A one-month increase in exposure to respective model-derived physical distancing policy bundles was associated with a 36% increase in the odds of reporting that COVID-19 worsened one’s mental health (odds ratio [OR] = 1·36; 95% credible interval [CRI] = 1·01 to 1·80), a 6% increase in the odds of meeting the clinical threshold for anxiety (OR = 1·06; CRI = 0·99 to 1·16), and a 15% increase in the odds of seeking treatment for anxiety or depression (OR = 1·15; CRI = 1·02 to 1·49). To accurately understand the role of states’ COVID-19 policies on mental health during the pandemic, researchers must consider how collections of policies might influence outcomes.

Abstract Rewilding is an increasingly common conservation approach, aiming to restore ecosystem processes and minimise human intervention. Rewilding has the potential to profoundly change landscapes and people–nature relations. These issues prompt an ongoing debate about how and if rewilding should be done. Farmers are key stakeholders in this debate; they stand to be both affected by and influence the trajectory of rewilding initiatives developing in the United Kingdom and globally. Despite this, a comprehensive understanding of farmers' perceptions towards rewilding is lacking. Here, we focus on how members of the farming community in England perceive common rewilding scenarios (beaver release, farm‐level rewilding and landscape‐scale rewilding), and how these perceptions shape farmers' attitudinal support for rewilding practices. Using thematic analysis of semi‐structured interviews with 36 farmers and farming representatives, we show that the diversity of famers' attitudes can be understood through the prism of perceptions on five core issues: (a) the perceived need for restoration action, (b) the ecological effectiveness of rewilding, (c) rewilding's compatibility with ensuring food security, (d) rewilding's compatibility with rural lifestyles, livelihoods and economies and (e) multidimensional justice of rewilding initiatives. These issues are rooted in collective farming values, and farmers' perceptions of these issues are influenced by mental models, perceived social impacts and perceived ecological outcomes of rewilding initiatives. Diverse perceptions result in a range of attitudes, from enthusiastic support to strong opposition to different rewilding practices. We argue that the scope to increase support for rewilding varies depending on the type of underlying negative perceptions. Where the negative perceptions are based on objectively verifiable causal beliefs (mental models), opponents' minds may be changed through the provision of positive experiences, social learning, and adhering to good governance principles. However, where negative perceptions are based on values, for example, a preference for traditional rural landscapes, they are unlikely to change easily. Pursuing rewilding ambitions that clash with the values of local farmers may risk social conflicts, but accommodating these values too much may compromise rewilding's own goals. Rewilding initiatives will need dialogue and social engagement to navigate their path around this tension. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Background Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. Main body This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. Conclusion With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.

The Peruvian guanaco (Lama guanicoe cacsilensis) is classified as being “in critical danger of extinction” by the government. In this study, we evaluate how the conflict between farmers and guanacos in the Susapaya and Estique Districts, Tacna Department (Southern Peru) may represent a threat to their survival. To evaluate the situation, we 1. Conducted field surveys to monitor guanaco presence, 2. Used available remote sensing data to map guanaco movement, and 3. interviewed the impacted farmers concerning their losses. Remote sensing data showed that sedentary guanaco family groups located in prime steppe vegetation habitats never entered agricultural areas, while field surveys showed that bachelor bands and solitary individuals did, perhaps seeking forage due to growing population pressure. Interview data found that 90% of community farmers felt that guanacos were a problem best resolved by better fencing (45%), hunting (19%), or increased security (16%), and 92% saw no value in the conservation of the species. Hunting is illegal, given the critically endangered status of guanacos in Peru, so additional efforts are needed to both educate those who feel guanacos are a menace and involve them in efforts to preserve the species.

We present the second and final release of optical spectroscopy of Type Ia supernovae (SNe Ia) obtained during the first and second phases of the Carnegie Supernova Project (CSP-I and CSP-II). The newly released data consist of 148 spectra of 30 SNe Ia observed in the course of CSP-I and 234 spectra of 127 SNe Ia obtained during CSP-II. We also present 216 optical spectra of 46 historical SNe Ia, including 53 spectra of 30 SNe Ia observed by the Calán/Tololo Supernova Survey. We combine these observations with previously published CSP data and publicly available spectra to compile a large sample of measurements of spectroscopic parameters at maximum light, consisting of pseudo-equivalent widths and expansion velocities of selected features for 232 CSP and historical SNe Ia (including more than 1000 spectra). Finally, we review some of the strongest correlations between spectroscopic and photometric properties of SNe Ia. Specifically, we define two samples: one consisting of SNe Ia discovered by targeted searches (most of them CSP-I objects) and the other composed of SNe Ia discovered by untargeted searches, which includes most of the CSP-II objects. The analyzed correlations are similar for both samples. We find a larger incidence of SNe Ia belonging to the cool and broad-line Branch subtypes among the events discovered by targeted searches, shallow-silicon SNe Ia are present with similar frequencies in both samples, while core normal SNe Ia are more frequent in untargeted searches.

We present cosmological analysis of 12 nearby ( z < 0.06) Type IIP supernovae (SNe IIP) observed with the ROTSE-IIIb telescope. To achieve precise photometry, we present a new image-differencing technique that is implemented for the first time on the ROTSE SN photometry pipeline. With this method, we find up to a 20% increase in the detection efficiency and significant reduction in residual rms scatter of the SN lightcurves when compared to the previous pipeline performance. We use the published optical spectra and broadband photometry of well-studied SNe IIP to establish temporal models for ejecta velocity and photospheric temperature evolution for our SNe IIP population. This study yields measurements that are competitive with other methods even when the data are limited to a single epoch during the photospheric phase of SNe IIP. Using the fully reduced ROTSE photometry and optical spectra, we apply these models to the respective photometric epochs for each SN in the ROTSE IIP sample. This facilitates the use of the Expanding Photosphere Method (EPM) to obtain distance estimates to their respective host galaxies. We then perform cosmological parameter fitting using these EPM distances, from which we measure the Hubble constant to be ${72.9}_{-4.3}^{+5.7}\,\mathrm{km}\,{{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$ , which is consistent with the standard ΛCDM model values derived using other independent techniques.

Abstract Background Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. Methods This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3–4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. Results Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) μg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. Conclusion The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. Trial registration EudraCT: 2018–000,144-25 Registered 28/01/2019.

Abstract Background More than a third of the 65,000 people living with kidney failure in the UK attend a dialysis unit 2–5 times a week to have their blood cleaned for 3–5 h. In haemodialysis (HD), toxins are removed by diffusion, which can be enhanced using a high-flux dialyser. This can be augmented with convection, as occurs in haemodiafiltration (HDF), and improved outcomes have been reported in people who are able to achieve high volumes of convection. This study compares the clinical- and cost-effectiveness of high-volume HDF compared with high-flux HD in the treatment of kidney failure. Methods This is a UK-based, multi-centre, non-blinded randomised controlled trial. Adult patients already receiving HD or HDF will be randomised 1:1 to high-volume HDF (aiming for 21+ L of substitution fluid adjusted for body surface area) or high-flux HD. Exclusion criteria include lack of capacity to consent, life expectancy less than 3 months, on HD/HDF for less than 4 weeks, planned living kidney donor transplant or home dialysis scheduled within 3 months, prior intolerance of HDF and not suitable for high-volume HDF for other clinical reasons. The primary outcome is a composite of non-cancer mortality or hospital admission with a cardiovascular event or infection during follow-up (minimum 32 months, maximum 91 months) determined from routine data. Secondary outcomes include all-cause mortality, cardiovascular- and infection-related morbidity and mortality, health-related quality of life, cost-effectiveness and environmental impact. Baseline data will be collected by research personnel on-site. Follow-up data will be collected by linkage to routine healthcare databases — Hospital Episode Statistics, Civil Registration, Public Health England and the UK Renal Registry (UKRR) in England, and equivalent databases in Scotland and Wales, as necessary — and centrally administered patient-completed questionnaires. In addition, research personnel on-site will monitor for adverse events and collect data on adherence to the protocol (monthly during recruitment and quarterly during follow-up). Discussion This study will provide evidence of the effectiveness and cost-effectiveness of HD as compared to HDF for adults with kidney failure in-centre HD or HDF. It will inform management for this patient group in the UK and internationally. Trial registration ISRCTN10997319 . Registered on 10 October 2017

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components.Results HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60–90, 45–59, and 30–44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by −0.24%, −0.14%, and −0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control.Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22

Background The DAPA‐CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end‐stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all‐cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin‐angiotensin‐aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin‐angiotensin‐aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β‐adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid‐lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150.

Abstract Background In recent years there has been an increased focus on the role of large herbivores in ecosystem restoration and climate change mitigation. There are multiple processes by which large herbivores could potentially influence climate feedback and forcing effects, but the evidence has not yet been synthesised in a systematic and accessible format. Grazing, browsing, trampling, defecation, and seed dispersal by large herbivores can influence vegetation and soils in ways that may directly or indirectly contribute to climate change or mitigation. For example, changes in vegetation could impact wildfire regimes, carbon storage, and albedo, with ultimate impacts on climate. These processes may be influenced by herbivore species composition, density, and functional traits. The main aim of this systematic map is to synthesise the range of research on climate feedback and forcing effects from large herbivores (≥ 10 kg) in terrestrial ecosystems. We also aim to identify knowledge clusters and gaps in the research base, as well as assessing the potential for quantitative analyses. Methods A search of peer-reviewed and grey literature will be conducted using a range of bibliographic databases, search engines and websites. The search strategy will involve using a pre-defined search string with Boolean operators. All search results will be screened for relevance according to specific eligibility criteria. Screening will be conducted in two stages: all articles will initially be screened by title and abstract, then those that meet the eligibility criteria will be screened by full text. At both stages, articles will be excluded if they don’t meet all eligibility criteria or if they meet any exclusion criteria. All articles included as eligible after full text screening will be coded. At each stage (of screening and coding) a proportion of articles will be processed independently by two reviewers to assess inter-reviewer reliability and resolve differences. The evidence will be presented in a searchable database with accompanying visual outputs. A narrative synthesis will be provided outlining the range and distribution of evidence, knowledge gaps and clusters, potential bias, and areas for further research.

Abstract X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20–40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington’s disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

Abstract The compound extreme weather event that impacted northern Queensland in February 2019 featured record-breaking rainfall, persistent high wind gusts and relatively cold day-time temperatures. This caused livestock losses numbering around 500,000 in the northwest Queensland Gulf region. In this study, we examine the livestock chill conditions associated with this week-long compound weather event and its potential for prediction from eleven world-leading sub-seasonal to seasonal (S2S) forecast systems. The livestock chill index combines daily rainfall, wind and surface temperature data. Averaged over the event week, the potential heat loss of livestock was in the moderate to high category, with severe conditions on the day of peak rainfall (5 February). Using calibrated forecasts from the Bureau of Meteorology's S2S forecast system, ACCESS-S1, a 1-week lead prediction showed a 20–30% probability of extreme livestock chill conditions over the northwest Queensland Gulf region, however the highest probabilities were located to the west of where the greatest livestock impacts were observed. Of the remaining ten S2S systems, around half predicted a more than 20% chance of extreme conditions, more than twice the climatological probability. It appears that the prediction accuracy arose from the skilful forecasts of extreme rainfall, as opposed to cold day-time temperature and strong wind forecasts. Despite a clear association between the observed extreme weather conditions and an active Madden–Julian Oscillation (MJO) event stalling in the western Pacific, the majority of 1-week lead S2S forecasts showed little indication of a slow-down in the MJO. As the livestock chill index was developed for southern Australian sheep, it may not be the best metric to represent the effects of exposure on tropical cattle breeds. Hence, this study draws attention to the need for tailored diagnostics that better represent the cold effects of summer tropical cyclones and tropical depressions on northern Australian livestock.

ACCESS-S2 is a major upgrade to the Australian Bureau of Meteorology’s multi-week to seasonal prediction system. It was made operational in October 2021, replacing ACCESS-S1. The focus of the upgrade is the addition of a new weakly coupled data assimilation system to provide initial conditions for atmosphere, ocean, land and ice fields. The model is based on the UK Met Office GloSea5-GC2 seasonal prediction system and is unchanged from ACCESS-S1, aside from minor corrections and enhancements. The performance of the assimilation system and the skill of the seasonal and multi-week forecasts have been assessed and compared to ACCESS-S1. There are improvements in the ACCESS-S2 initial conditions compared to ACCESS-S1, particularly for soil moisture and aspects of the ocean, notably the ocean currents. More realistic soil moisture initialisation has led to increased skill for forecasts over Australia, especially those of maximum temperature. The ACCESS-S2 system is shown to have increased skill of El Nino–Southern Oscillation forecasts over ACCESS-S1 during the challenging autumn forecast period. Analysis suggests that ACCESS-S2 will deliver improved operational forecast accuracy in comparison to ACCESS-S1. Assessments of the operational forecasts are underway. ACCESS-S2 represents another step forward in the development of seasonal forecast systems at the Bureau of Meteorology. However, key rainfall and sea surface temperature biases in ACCESS-S1 remain in ACCESS-S2, indicating where future efforts should be focused.

We present the optical spectroscopic evolution of SN 2023ixf seen in subnight cadence spectra from 1.18 to 15 days after explosion. We identify high-ionization emission features, signatures of interaction with material surrounding the progenitor star, that fade over the first 7 days, with rapid evolution between spectra observed within the same night. We compare the emission lines present and their relative strength to those of other supernovae with early interaction, finding a close match to SN 2020pni and SN 2017ahn in the first spectrum and SN 2014G at later epochs. To physically interpret our observations, we compare them to CMFGEN models with confined, dense circumstellar material around a red supergiant (RSG) progenitor from the literature. We find that very few models reproduce the blended N iii ( λλ 4634.0,4640.6)/C iii ( λλ 4647.5,4650.0) emission lines observed in the first few spectra and their rapid disappearance thereafter, making this a unique diagnostic. From the best models, we find a mass-loss rate of 10 ^−3 –10 ^−2 M _⊙ yr ^−1 , which far exceeds the mass-loss rate for any steady wind, especially for an RSG in the initial mass range of the detected progenitor. These mass-loss rates are, however, similar to rates inferred for other supernovae with early circumstellar interaction. Using the phase when the narrow emission features disappear, we calculate an outer dense radius of circumstellar material R _CSM,out ≈ 5 × 10 ^14 cm, and a mean circumstellar material density of ρ = 5.6 × 10 ^−14 g cm ^−3 . This is consistent with the lower limit on the outer radius of the circumstellar material we calculate from the peak H α emission flux, R _CSM,out ≳ 9 × 10 ^13 cm.

This paper provides the detailed protocol for a pilot study testing the feasibility, acceptability, and initial efficacy of a targeted two-phase, remotely delivered early intervention program for infants with neurogenetic conditions (NGC) and their caregivers. The Parent and Infant Inter(X)action Intervention (PIXI) is designed to support parents and infants with a NGC diagnosed in the first year of life. PIXI is implemented in two phases, with the first phase focusing on psychoeducation, parent support, and how to establish routines for supporting infant development. Phase II helps parents learn targeted skills to support their infant's development as symptoms may begin to emerge. The proposed non-randomized feasibility pilot study will establish the feasibility of a year-long virtually implemented intervention program to support new parents of an infant diagnosed with an NGC.

Objectives To establish barriers and motivators underlying research engagement among early-career practitioners in nephrology across the UK, in order to guide potential interventions to enhance research involvement in renal units.Design Cross-sectional online survey employing a range of free-text, Likert scale and binomial/multiple-choice responses, distributed via mailing lists and social media. Topics covered research experience, research involvement and barriers, impact of COVID-19 and strategies to improve research engagement. Thematic analysis was used to assess free-text responses.Setting Renal units throughout the UK.Participants Non-consultant healthcare staff self-identifying as working in nephrology were included (n=211), with responses from non-UK respondents or consultant nephrologists excluded (n=12).Results Responses were received from across the multidisciplinary team (physicians (n=83) and nurses (n=83)) and other allied health professionals (n=45). Most were aware of ongoing local research, but under half of them were actively involved. Multivariate analysis indicated employment as a physician, protected time for research activity and provision of appropriate training were associated with greater research experience and output. There was general enthusiasm to undertake research, but perceived barriers included insufficient staffing, lack of time, funding and encouragement. COVID-19 was felt to have further impacted negatively upon opportunities. Among the suggested strategies to promote engagement, mentorship and an online research resource were felt to be of most interest.Conclusions In the first survey of this type in nephrology, we demonstrate differences across the multidisciplinary spectrum in perceived research experience and accessibility, which have been worsened by COVID-19. Our findings will guide strategies to broaden engagement in early-career practitioners and serve as a baseline to assess the impact of these interventions.

Abstract Background Globally, over 1.2 million people die from chronic kidney disease (CKD) every year. Patients with CKD are up to 10 times more likely to die prematurely than progress to kidney failure requiring kidney replacement therapy. The burden of symptoms and impaired quality of life in CKD may be compounded by comorbidities and treatment side effects. However, patient-important outcomes remain inconsistently and infrequently reported in trials in patients with CKD, which can limit evidence-informed decision-making. The Standardised Outcomes in Nephrology – Chronic Kidney Disease (SONG-CKD) aims to establish a consensus-based core outcome set for trials in patients with CKD not yet requiring kidney replacement therapy to ensure outcomes of relevance to patients, caregivers and health professionals are consistently reported in trials. Methods SONG-CKD involves four phases: a systematic review to identify outcomes (domains and measures) that have been reported in randomised controlled trials involving adults with CKD who do not require kidney replacement therapy; stakeholder key informant interviews with health professionals involved in the care of adults with CKD to ascertain their views on establishing core outcomes in CKD; an international two-round online Delphi survey with patients, caregivers, clinicians, researchers, policy makers and industry representatives to obtain consensus on critically important outcome domains; and stakeholder consensus workshops to review and finalise the set of core outcome domains for trials in CKD. Discussion Establishing a core outcome set to be reported in trials in patients with CKD will enhance the relevance, transparency and impact of research to improve the lives of people with CKD. Trial registration Not applicable. This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database: http://www.comet-initiative.org/Studies/Details/1653 .

An association between adverse childhood experiences (ACEs) and elevated body mass index (BMI) has been found in previous investigations. ACEs’ effects on BMI have been primarily considered via individual-level physiological and behavioral frameworks. Neighborhood factors, such as greenspace, are also associated with BMI and may merit consideration in studies examining ACEs-BMI associations. This exploratory study examined associations of BMI with ACEs and neighborhood greenspace and tested whether greenspace moderated ACEs-BMI associations. Methods entailed secondary analysis of cross-sectional data. ACEs and BMI were captured from 2012/2013 Philadelphia ACE Survey and 2012 Southeastern Household Heath Survey data; greenspace percentage in participants’ (n = 1,679 adults) home neighborhoods was calculated using National Land Cover Database data. Multi-level, multivariable linear regression 1) examined associations between BMI, ACEs, (0 ACEs [reference], 1–3 ACEs, 4 + ACEs), and neighborhood greenspace levels (high [reference], medium, low) and 2) tested whether greenspace moderated the ACEs-BMI association (assessed via additive interaction) before and after controlling for sociodemographic and health-related covariates. Experiencing 4 + ACEs (β = 1.21; 95 %CI: 0.26, 2.15; p = 0.01), low neighborhood greenspace (β = 1.51; 95 %CI: 0.67, 2.35; p

Chronic kidney disease (CKD) related cardiovascular disease (CVD) is characterized by vascular remodelling with well-established structural and functional changes in the vascular wall such as arterial stiffness, matrix deposition, and calcification. These phenotypic changes resemble pathology seen in ageing, and are likely to be mediated by sustained alterations in gene expression, which may be caused by epigenetic changes such as tissue-specific DNA methylation. We aimed to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD. Genome-wide DNA methylation changes were examined in bisulphite converted genomic DNA isolated from the vascular media of CKD and healthy arteries. Methylation-specific PCR was used to validate the array data, and the association between DNA methylation and gene and protein expression was examined. The DNA methylation age was compared to the chronological age in both cases and controls. Three hundred and nineteen differentially methylated regions (DMR) were identified spread across the genome. Pathway analysis revealed that DMRs associated with genes were involved in embryonic and vascular development, and signalling pathways such as TGFβ and FGF. Expression of top differentially methylated gene HOXA5 showed a significant negative correlation with DNA methylation. Interestingly, DNA methylation age and chronological age were highly correlated, but there was no evidence of accelerated age-related DNA methylation in the arteries of CKD patients. In conclusion, we demonstrated that differential DNA methylation in the arterial tissue of CKD patients represents a potential mediator of arterial pathology and may be used to uncover novel pathways in the genesis of CKD-associated complications.

Objectives Identifying the prevalence of neuropathic pain components in patients with chronic tendinopathy conditions using the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire.Methods Patients with chronic tendinopathy and ‘tendon-like’ conditions treated within a single hospital outpatient clinic specialising in tendinopathy were identified. Pain scores, plus global function patient-reported outcome measures (5-Level version of EuroQol-5 Dimension and Musculoskeletal Health Questionnaire (MSK-HQ)), were completed and compared with the S-LANSS questionnaireResults 341 suitable patients with chronic tendinopathy and potentially similar conditions were identified. Numbers: lateral elbow tendinopathy (39), greater trochanteric pain syndrome (GTPS; 112), patellar tendinopathy (11), non-insertional Achilles tendinopathy (40), insertional Achilles tendinopathy (39), plantar fasciopathy (100). 68% were female, with a mean age of 54.0±11.3 years and a mean symptom duration of 38.1±33.7 months.There was a mean S-LANSS score of 11.4±6.4. Overall, 47% of patients scored 12 or greater points on S-LANSS, indicating the possible presence of neuropathic pain. The highest proportion was in patients with plantar fasciopathy (61%), the lowest in those with GTPS (33%). Weak correlations were found between the S-LANSS score and MSK-HQ score, the numerical rating scale (0–10) values for ‘average pain’ and for ‘worst pain’, but not with the MSK-HQ %health value.Conclusion S-LANSS identified nearly half of patients with chronic tendinopathy as possibly having a neuropathic pain component. This is of unclear clinical significance but worth further study to see if/how this may relate to treatment outcomes. These results are from a single hospital clinic dealing with patients with chronic tendinopathy, without a control group or those with shorter symptom duration. However, this reinforces the probability of neuropathic pain components in at least some patients with chronic tendinopathy.

Abstract Meeting recruitment targets for clinical trials and health research studies is a notable challenge. Unsuccessful efforts to recruit participants from traditionally underserved populations can limit who benefits from scientific discovery, thus perpetuating inequities in health outcomes and access to care. In this study, we evaluated direct mail and email outreach campaigns designed to recruit women who gave birth in North Carolina for a statewide research study offering expanded newborn screening for a panel of rare health conditions. Of the 54,887 women who gave birth in North Carolina from September 28, 2018, through March 19, 2019, and were eligible to be included on the study’s contact lists, we had access to a mailing address for 97.9% and an email address for 6.3%. Rural women were less likely to have sufficient contact information available, but this amounted to less than a one percentage point difference by urbanicity. Native American women were less likely to have an email address on record; however, we did not find a similar disparity when recruitment using direct‐mail letters and postcards was concerned. Although we sent letters and emails in roughly equal proportion by urbanicity and race/ethnicity, we found significant differences in enrollment across demographic subgroups. Controlling for race/ethnicity and urbanicity, we found that direct‐mail letters and emails were effective recruitment methods. The enrollment rate among women who were sent a recruitment letter was 4.1%, and this rate increased to 5.0% among women who were also sent an email invitation. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Under‐representation by traditionally underserved populations in clinical trials and health research is a challenge that may in part reflect inequitable opportunities to participate. WHAT QUESTION DID THIS STUDY ADDRESS? Are direct‐mail and email outreach strategies effective for reaching and recruiting women from traditionally underserved and rural populations to participate in large‐scale, population‐based research? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Despite sending recruitment letters and email invitations in roughly equal proportion by urbanicity and race/ethnicity, women living in rural areas were less likely to enroll (2.8%) than women from urban areas (4.2%). Additionally, enrollment rates decreased as the probability that women were members of a racial or ethnic minority group increased. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Results from this study might encourage researchers to take a holistic and participant‐centered view of barriers to study enrollment that may disproportionately affect underserved communities, including differences in willingness to participate, trust, and access to resources needed for uptake.

Aims: This systematic review examines the available evidence on the use of medical stretching devices to treat knee arthrofibrosis, it suggests a focus for future studies addressing limitations in current research and identifies gaps in the published literature to facilitate future works. Materials and methods: Articles were identified using the Cochrane Library, MEDLINE, PubMed and SCOPUS databases. Articles from peer reviewed journals investigating the effectiveness of medical stretching devices to increase range of movement when treating arthrofibrosis of the knee were included. Results: A total of 13 studies (558 participants) met the inclusion criteria with the devices falling into the following categories; CPM, load control or displacement control stretching devices. A statistically significant increase in range of movement was demonstrated in CPM, load-control and displacement-control studies (p ​

Abstract Evolutionary genetic studies have uncovered abundant evidence for genomic hotspots of phenotypic evolution, as well as biased patterns of mutations at those loci. However, the theoretical basis for this concentration of particular types of mutations at particular loci remains largely unexplored. In addition, historical contingency is known to play a major role in evolutionary trajectories, but has not been reconciled with the existence of such hotspots. For example, do the appearance of hotspots and the fixation of different types of mutations at those loci depend on the starting state and/or on the nature and direction of selection? Here, we use a computational approach to examine these questions, focusing the anthocyanin pigmentation pathway, which has been extensively studied in the context of flower color transitions. We investigate two transitions that are common in nature, the transition from blue to purple pigmentation and from purple to red pigmentation. Both sets of simulated transitions occur with a small number of mutations at just four loci and show strikingly similar peaked shapes of evolutionary trajectories, with the mutations of the largest effect occurring early but not first. Nevertheless, the types of mutations (biochemical vs. regulatory) as well as their direction and magnitude are contingent on the particular transition. These simulated color transitions largely mirror findings from natural flower color transitions, which are known to occur via repeated changes at a few hotspot loci. Still, some types of mutations observed in our simulated color evolution are rarely observed in nature, suggesting that pleiotropic effects further limit the trajectories between color phenotypes. Overall, our results indicate that the branching structure of the pathway leads to a predictable concentration of evolutionary change at the hotspot loci, but the types of mutations at these loci and their order is contingent on the evolutionary context.

Summary: We performed a comparative analysis of human and 12 non-human primates to identify sequence variations in known cancer genes. We identified 395 human-specific fixed non-silent substitutions that emerged during evolution of human. Using bioinformatics analyses for functional consequences, we identified a number of substitutions that are predicted to alter protein function; one of these mutations is located at the most evolutionarily conserved domain of human BRCA2.

Background. The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. Methods. Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. Results. Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88–2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01–1.06), female sex (HR 2.49, CI 1.70–3.65), previous fracture (HR 2.30, CI 1.58–3.34), Asian race (HR 1.74, CI 1.09–2.78), vitamin D therapy requirement (HR 2.05, CI 1.31–3.21), HbA1c (HR 1.14, CI 1.00–1.32), prior cardiovascular event (HR 1.60, CI 1.10–2.33), and serum albumin (HR 0.41, CI 0.23–0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92–1849.51, SBC range 1875.60–1948.04). Conclusion. Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors.

The purpose of this study was to determine whether interventions could improve peroneal reaction time in both healthy and those with injured ankle participants based on a systematic review and meta-analysis. An electronic search of the following database was carried out: MEDLINE, ScienceDirect and SPORTDiscus (1965–2020). Studies utilising sudden ankle inversion to measure peroneal reaction times were selected. 28 studies were included for the systematic review, and 18 studies for the meta-analysis. The peroneal reaction time for pre-and post-intervention were compared into two groups, Group 1 was therapeutic exercise intervention, and Group 2 was prophylactic devices. The results showed a statistically significant difference in reduced peroneal reaction time in favour of participants in the exercise group (SMD ​= ​0.74, 95%CI [1.09,0.39], p ​

Summary: Cartilaginous fishes possess gel-filled tubular sensory organs called Ampullae of Lorenzini (AoL) that are used to detect electric fields. Although recent studies have identified various components of AoL gel, it has remained unclear how the molecules are structurally arranged and how their structure influences the function of the organs. Here we describe the structure of AoL gel by microscopy and small-angle X-ray scattering and infer that the material is colloidal in nature. To assess the relative function of the gel's protein constituents, we compared the microscopic structure, X-ray scattering, and proton conductivity properties of the gel before and after enzymatic digestion with a protease. We discovered that while proteins were largely responsible for conferring the viscous nature of the gel, their removal did not diminish proton conductivity. The findings lay the groundwork for more detailed studies into the specific interactions of molecules inside AoL gel at the nanoscale.