The multigenerational impact of long QT syndrome: A Gitxsan perspective.

Long QT syndrome (LQTS), a rare cardiac condition that can lead to sudden death, is highly prevalent in First Nations communities of northern British Columbia. In the Gitxsan community of 5500, an estimated 1 in 125 individuals are affected, primarily due to the novel pathogenic variant p.V205M in KCNQ1. Over the past decade, more than 800 Gitxsan individuals received genetic testing and counseling for LQTS through a community-based study. Despite the substantial research characterizing the biological underpinnings of LQTS, there are few studies exploring the lived experiences of families with LQTS, especially those of Indigenous peoples. The goal of this study was to gain a greater understanding of the impact of the genetic confirmation of LQTS in this community, and the impact the condition has on individuals, their families, and the community. A qualitative study was developed in consultation with a local research advisory board and a Talking Circle, a traditional Indigenous format for discussion, was held. Four people who belonged to the same kindred group attended the Talking Circle. This article presents the multigenerational impact that LQTS and genetic diagnosis have through the reflections of one Gitxsan family. LQTS affects identity and family relationships, including those between parents and children, siblings, and even extended family members. Laughter and humor played an important part in coping. The role of family relationships for this Gitxsan family was seen to be critical in managing an LQTS diagnosis. This multigenerational perspective provides key insights into family structure and dynamics which can inform genetic counseling and clinical care. As cultural safety is experienced and therefore defined by the person receiving services, listening to the perspectives and preferences of Indigenous peoples is essential to the delivery of culturally informed care.

Cold indoor temperatures and their association with health and well-being: a systematic literature review.

OBJECTIVE: The study aimed to identify, appraise and update evidence on the association between cold temperatures (i.e. <18°C) within homes (i.e. dwellings) and health and well-being outcomes. STUDY DESIGN: This study was a systematic review. METHODS: Seven databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews, CINAHL, APA PsycInfo, Applied Social Sciences Index and Abstracts, Coronavirus Research Database) were searched for studies published between 2014 and 2022, which explored the association between cold indoor temperatures and health and well-being outcomes. Studies were limited to those conducted in temperate and colder climates due to the increased risk of morbidity and mortality during winter in those climatic zones. Studies were independently quality assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Of 1209 studies, 20 were included for review. Study outcomes included cardiovascular (blood pressure, electrocardiogram abnormalities, blood platelet count), respiratory (chronic obstructive pulmonary disease symptoms, respiratory viral infection), sleep, physical performance and general health. Seventeen studies found exposure to cold indoor temperatures was associated with negative effects on health outcomes studied. Older individuals and those with chronic health problems were found to be more vulnerable to negative health outcomes. CONCLUSION: Evidence suggests that indoor temperatures <18°C are associated with negative health effects. However, the evidence is insufficient to allow clear conclusions regarding outcomes from specific temperature thresholds for different population groups. Significant gaps in the current evidence base are identified, including research on the impacts of cold indoor temperatures on mental health and well-being, studies involving young children, and the long-term health effects of cold indoor temperatures.

The missing link in gravitational-wave astronomy: A summary of discoveries waiting in the decihertz range.

Since 2015 the gravitational-wave observations of LIGO and Virgo have transformed our understanding of compact-object binaries. In the years to come, ground-based gravitational-wave observatories such as LIGO, Virgo, and their successors will increase in sensitivity, discovering thousands of stellar-mass binaries. In the 2030s, the space-based LISA will provide gravitational-wave observations of massive black holes binaries. Between the ∼ 10 -103 Hz band of ground-based observatories and the ∼ 1 0 - 4 -10- 1 Hz band of LISA lies the uncharted decihertz gravitational-wave band. We propose a Decihertz Observatory to study this frequency range, and to complement observations made by other detectors. Decihertz observatories are well suited to observation of intermediate-mass ( ∼ 1 0 2 -104 M ⊙) black holes; they will be able to detect stellar-mass binaries days to years before they merge, providing early warning of nearby binary neutron star mergers and measurements of the eccentricity of binary black holes, and they will enable new tests of general relativity and the Standard Model of particle physics. Here we summarise how a Decihertz Observatory could provide unique insights into how black holes form and evolve across cosmic time, improve prospects for both multimessenger astronomy and multiband gravitational-wave astronomy, and enable new probes of gravity, particle physics and cosmology.

Candidate Electromagnetic Counterpart to the Binary Black Hole Merger Gravitational-Wave Event S190521g.

We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus [B. McKernan, K. E. S. Ford, I. Bartos et al., Astrophys. J. Lett. 884, L50 (2019)AJLEEY2041-821310.3847/2041-8213/ab4886] and is unlikely [

Investigating Wilms' Tumours Worldwide: A Report of the OxPLORE Collaboration-A Cross-Sectional Observational Study.

BACKGROUND: Childhood cancer is neglected within global health. Oxford Pediatrics Linking Oncology Research with Electives describes early outcomes following collaboration between low- and high-income paediatric surgery and oncology centres. The aim of this paper is twofold: to describe the development of a medical student-led research collaboration; and to report on the experience of Wilms' tumour (WT). METHODS: This cross-sectional observational study is reported as per STROBE guidelines. Collaborating centres included three tertiary hospitals in Tanzania, Rwanda and the UK. Data were submitted by medical students following retrospective patient note review of 2 years using a standardised data collection tool. Primary outcome was survival (point of discharge/death). RESULTS: There were 104 patients with WT reported across all centres over the study period (Tanzania n = 71, Rwanda n = 26, UK n = 7). Survival was higher in the high-income institution [87% in Tanzania, 92% in Rwanda, 100% in the UK (X2 36.19, p < 0.0001)]. Given the short-term follow-up and retrospective study design, this likely underestimates the true discrepancy. Age at presentation was comparable at the two African sites but lower in the UK (one-way ANOVA, F = 0.2997, p = 0.74). Disease was more advanced in Tanzania at presentation (84% stage III-IV cf. 60% and 57% in Rwanda and UK, respectively, X2 7.57, p = 0.02). All patients had pre-operative chemotherapy, and a majority had nephrectomy. Post-operative morbidity was higher in lower resourced settings (X2 33.72, p < 0.0001). Methodology involving medical students and junior doctors proved time- and cost-effective. This collaboration was a valuable learning experience for students about global research networks. CONCLUSIONS: This study demonstrates novel research methodology involving medical students collaborating across the global south and global north. The comparison of outcomes advocates, on an institutional level, for development in access to services and multidisciplinary treatment of WT.

Hierarchical Black Hole Mergers in Active Galactic Nuclei.

The origins of the stellar-mass black hole mergers discovered by LIGO/Virgo are still unknown. Here we show that if migration traps develop in the accretion disks of active galactic nuclei (AGNs) and promote the mergers of their captive black holes, the majority of black holes within disks will undergo hierarchical mergers-with one of the black holes being the remnant of a previous merger. 40% of AGN-assisted mergers detected by LIGO/Virgo will include a black hole with mass ≳50M_{⊙}, the mass limit from stellar core collapse. Hierarchical mergers at traps in AGNs will exhibit black hole spins (anti)aligned with the binary's orbital axis, a distinct property from other hierarchical channels. Our results suggest, although not definitively (with odds ratio of ∼1), that LIGO's heaviest merger so far, GW170729, could have originated from this channel.

Low-fidelity Paediatric Surgical Simulation: Description of Models in Low-Resource Settings.

BACKGROUND: Surgical simulation is an important aspect of competency-based training. Recent trends in paediatric surgical simulations have migrated towards high-fidelity simulation with advanced technology resulting in models which are expensive and largely inaccessible in low- and middle-income countries. METHODS: This article describes four wet simulation models of common surgical procedures in paediatric population created with animal tissue from local abattoir. The models are designed to provide a framework for others to make the models and benefit from the training opportunity they provide especially in low-middle-income countries. RESULTS: The models created in the wet laboratory are neonatal bowel anastomosis, duodenoduodenostomy for discrepancy anastomosis, gastrostomy and pyeloplasty. These models are easily reproducible in resource-challenged healthcare setting as they are low cost, utilise locally available resources and require only a basic set of surgical instruments with which to perform the procedures. CONCLUSION: These models provide locally accessible material for sustainable training programmes which are fundamental in developing safe and affordable surgical care worldwide.

Measuring the relationships between adverse childhood experiences and educational and employment success in England and Wales: findings from a retrospective study.

OBJECTIVES: Educational and employment outcomes are critical elements in determining the life course of individuals, yet through health and other mechanisms, those who suffer adverse childhood experiences (ACEs) may experience barriers to achieve in these domains. This study examines the association between ACEs and poor educational outcomes, before considering the impact of ACEs and education on employment in adulthood. STUDY DESIGN: Retrospective cross-sectional surveys were conducted in England and Wales using a random stratified sampling methodology. METHODS: During face-to-face household interviews (n = 2881), data were collected on demographic factors, ACEs, self-rated childhood affluence, the highest qualification level attained and the current employment status. RESULTS: While respondents with ≥4 ACEs were significantly more likely to have no formal qualifications (adjusted odds ratio [AOR] = 2.18; P < 0.001), among those who did achieve secondary level qualifications, the presence of ACEs did not further impact subsequent likelihood of going on to attain college or higher qualifications. However, results suggest a persisting independent impact of high (≥4) ACEs, which were found to be significantly associated with both current unemployment (AOR = 2.52, P < 0.001) and long-term sickness and disability (AOR = 3.94, P < 0.001). Modelled levels of not being in employment ranged from as little as 3% among those with 0 or 1 ACE and higher qualifications to 62% among those with no qualifications and ≥4 ACEs (adjusted for age, gender and childhood affluence effects). CONCLUSIONS: Compulsory education may play a pivotal role in mitigating the effects of adversity, supporting the case for approaches within schools that build resilience and tackle educational inequalities. However, adults with ACEs should not be overlooked and efforts should be considered to support them in achieving meaningful employment.

The good, the bad and the tasty: The many roles of mushrooms.

Fungi are often inconspicuous in nature and this means it is all too easy to overlook their importance. Often referred to as the "Forgotten Kingdom", fungi are key components of life on this planet. The phylum Basidiomycota, considered to contain the most complex and evolutionarily advanced members of this Kingdom, includes some of the most iconic fungal species such as the gilled mushrooms, puffballs and bracket fungi. Basidiomycetes inhabit a wide range of ecological niches, carrying out vital ecosystem roles, particularly in carbon cycling and as symbiotic partners with a range of other organisms. Specifically in the context of human use, the basidiomycetes are a highly valuable food source and are increasingly medicinally important. In this review, seven main categories, or 'roles', for basidiomycetes have been suggested by the authors: as model species, edible species, toxic species, medicinal basidiomycetes, symbionts, decomposers and pathogens, and two species have been chosen as representatives of each category. Although this is in no way an exhaustive discussion of the importance of basidiomycetes, this review aims to give a broad overview of the importance of these organisms, exploring the various ways they can be exploited to the benefit of human society.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Feasibility of two levels of protein intake in patients with colorectal cancer: findings from the Protein Recommendation to Increase Muscle (PRIMe) randomized controlled pilot trial.

BACKGROUND: Low muscle mass (MM) predicts unfavorable outcomes in cancer. Protein intake supports muscle health, but oncologic recommendations are not well characterized. The objectives of this study were to evaluate the feasibility of dietary change to attain 1.0 or 2.0 g/kg/day protein diets, and the preliminary potential to halt MM loss and functional decline in patients starting chemotherapy for stage II-IV colorectal cancer. PATIENTS AND METHODS: Patients were randomized to the diets and provided individualized counseling. Assessments at baseline, 6 weeks, and 12 weeks included weighed 3-day food records, appendicular lean soft tissue index (ALSTI) by dual-energy X-ray absorptiometry to estimate MM, and physical function by the Short Physical Performance Battery (SPPB) test. RESULTS: Fifty patients (mean ± standard deviation: age, 57 ± 11 years; body mass index, 27.3 ± 5.6 kg/m2; and protein intake, 1.1 ± 0.4 g/kg/day) were included at baseline. At week 12, protein intake reached 1.6 g/kg/day in the 2.0 g/kg/day group and 1.2 g/kg/day in the 1.0 g/kg/day group (P = 0.012), resulting in a group difference of 0.4 g/kg/day rather than 1.0 g/kg/day. Over one-half (59%) of patients in the 2.0 g/kg/day group maintained or gained MM compared with 44% of patients in the 1.0 g/kg/day group (P = 0.523). Percent change in ALSTI did not differ between groups [2.0 g/kg/day group (mean ± standard deviation): 0.5% ± 4.6%; 1.0 g/kg/day group: -0.4% ± 6.1%; P = 0.619]. No differences in physical function were observed between groups. However, actual protein intake and SPPB were positively associated (ß = 0.37; 95% confidence interval 0.08-0.67; P = 0.014). CONCLUSION: Individualized nutrition counselling positively impacted protein intake. However, 2.0 g/kg/day was not attainable using our approach in this population, and group contamination occurred. Increased protein intake suggested positive effects on MM and physical function, highlighting the potential for nutrition to attenuate MM loss in patients with cancer. Nonetheless, muscle anabolism to any degree is clinically significant and beneficial to patients. Larger trials should explore the statistical significance and clinical relevance of protein interventions.

A New Era of Morphological Investigations: Reviewing Methods for Comparative Anatomical Studies.

The increased use of imaging technology in biological research has drastically altered morphological studies in recent decades and allowed for the preservation of important collection specimens alongside detailed visualization of bony and soft-tissue structures. Despite the benefits associated with these newer imaging techniques, there remains a need for more "traditional" methods of morphological examination in many comparative studies. In this paper, we describe the costs and benefits of the various methods of visualizing, examining, and comparing morphological structures. There are significant differences not only in the costs associated with these different methods (monetary, time, equipment, and software), but also in the degree to which specimens are destroyed. We argue not for any one particular method over another in morphological studies, but instead suggest a combination of methods is useful not only for breadth of visualization, but also for the financial and time constraints often imposed on early-career research scientists.

Climate determines upper, but not lower, altitudinal range limits of Pacific Northwest conifers.

Does climate determine species' ranges? Rapid rates of anthropogenic warming make this classic ecological question especially relevant. We ask whether climate controls range limits by quantifying relationships between climatic variables (precipitation, temperature) and tree growth across the altitudinal ranges of six Pacific Northwestern conifers on Mt. Rainier, Washington, USA. Results for three species (Abies amabilis, Callitropsis nootkatensis, Tsuga mertensiana) whose upper limits occur at treeline (> 1600 m) imply climatic controls on upper range limits, with low growth in cold and high snowpack years. Annual growth was synchronized among individuals at upper limits for these high-elevation species, further suggesting that stand-level effects such as climate constrain growth more strongly than local processes. By contrast, at lower limits climatic effects on growth were weak for these high-elevation species. Growth-climate relationships for three low-elevation species (Pseudotsuga menziesii, Thuja plicata, Tsuga heterophylla) were not consistent with expectations of climatic controls on upper limits, which are located within closed-canopy forest (< 1200 m). Annual growth of these species was poorly synchronized among individuals. Our results suggest that climate controls altitudinal range limits at treeline, while local drivers (perhaps biotic interactions) influence growth in closed-canopy forests. Climate-change-induced range shifts in closed-canopy forests will therefore be difficult to predict accurately.

Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis.

Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: DeltaFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of DeltaFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, DeltaFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that DeltaFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.

Sex differences in force attenuation: a clinical assessment of single-leg hop performance on a portable force plate.

OBJECTIVE: Impaired biomechanics and neuromuscular control have been suggested as probable links to female sex bias in the onset of patellofemoral pain syndrome. There are limited objective, clinical measures for assessment of impaired biomechanics and neuromuscular control. The primary objective of this investigation was to examine sex differences in vertical ground reaction force (vGRF) and force loading rate in young athletes performing maximum, repeated vertical single-leg hops (RVSHs). The authors hypothesised that females would demonstrate greater vGRF and force loading rate than males and show interlimb differences in force attenuation. DESIGN: Cross-sectional study. SETTING: Paediatric sports medicine clinic. PARTICIPANTS: 109 Healthy high school, soccer and basketball athletes. ASSESSMENT OF RISK FACTORS: Participants performed RVSHs for 15 seconds on a portable force plate with a sampling rate of 400 Hz (Accupower; AMTI, Watertown, Massachusetts, USA). MAIN OUTCOME MEASUREMENTS: Raw vGRF was filtered with a generalised cross-validation spline using a 50-Hz cutoff frequency and then normalised to potential energy. Force loading rate was calculated by dividing normalised vGRF by time-to-peak force. Group means were compared using analysis of variance. RESULTS: The females demonstrated significantly greater normalised vGRF (p<0.001) and force loading rate (p<0.001) during landing than their male counterparts. Neither sex demonstrated significant interlimb differences in force attenuation (p>0.05). CONCLUSIONS: The female athletes may have altered force attenuation capability during RVSHs as identified by increased vGRF and force loading rate compared with the male athletes. Portable force plates may be potential tools to identify altered force attenuation in clinical settings.

Multiple risk factors related to familial predisposition to anterior cruciate ligament injury: fraternal twin sisters with anterior cruciate ligament ruptures.

OBJECTIVE: A multifactorial combination of predictors may increase anterior cruciate ligament (ACL) injury risk in athletes. The objective of this twin study was to examine these risk factors to identify commonalities in risk factors that predisposed female fraternal twins to ACL injury. METHODS: Female twins in high-risk sports were prospectively measured prior to an injury for neuromuscular control using three-dimensional motion analysis during landing, hamstrings and quadriceps muscular strength on a dynamometer and joint laxity using a modified Beighton-Horan index and a Compu-KT arthrometer. Intraoperative measures of femoral intercondylar notch width were recorded during ACL reconstruction. RESULTS: Abduction angles were increased at one knee in both of the twin sister athletes relative to uninjured controls at initial contact and at maximum displacement during landing. The twin female athletes that went on to ACL injury also demonstrated decreased peak knee flexion motion at both knees than uninjured females during landing. The twin athletes also had increased joint laxity and decreased hamstrings to quadriceps (H/Q) torque ratios compared to controls. Femoral intercondylar notch widths were also below the control mean in the twin siblings. CONCLUSIONS: Prescreened mature female twins that subsequently experienced ACL injury demonstrated multiple potential risk factors including: increased knee abduction angles, decreased knee flexion angles, increased general joint laxity, decreased H/Q ratios and femoral intercondylar notch width.

Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis.

Improvise, Adapt, Overcome: mobile phone LED used as a light source for cystoscopy and resection of posterior urethral valves in a low-cost setting.

We describe use of an improvised light source to perform cystoscopy and PUV resection while working in a resource poor setting. The light emitted from a mobile telephone LED (iPhone 6) was sufficient to perform the procedure and there was an excellent surgical outcome. We hope that this report may prove to be helpful to colleagues working in similar circumstances with limited resources.

Quantitative data analysis methods for bead-based DNA hybridization assays using generic flow cytometry platforms.

Bead-based assays are in demand for rapid genomic and proteomic assays for both research and clinical purposes. Standard quantitative procedures addressing raw data quality and analysis are required to ensure the data are consistent and reproducible across laboratories independent of flow platform. Quantitative procedures have been introduced spanning raw histogram analysis through to absolute target quantitation. These included models developed to estimate the absolute number of sample molecules bound per bead (Langmuir isotherm), relative quantitative comparisons (two-sided t-tests), and statistical analyses investigating the quality of raw fluorescence data. The absolute target quantitation method revealed a concentration range (below probe saturation) of Cy5-labeled synthetic cytokeratin 19 (K19) RNA of c.a. 1 x 10(4) to 500 x 10(4) molecules/bead, with a binding constant of c.a. 1.6 nM. Raw hybridization frequency histograms were observed to be highly reproducible across 10 triplex assay replicates and only three assay replicates were required to distinguish overlapping peaks representing small sequence mismatches. This study provides a quantitative scheme for determining the absolute target concentration in nucleic acid hybridization reactions and the equilibrium binding constants for individual probe/target pairs. It is envisaged that such studies will form the basis of standard analytical procedures for bead-based cytometry assays to ensure reproducibility in inter- and intra-platform comparisons of data between laboratories.