Search

Abstract Background The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. Methods We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. Results We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Conclusion Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

Abstract The interest in recirculating aquaculture systems (RAS) is growing due to their benefits such as increased productivity, better control over animal care, reduced environmental effects, and less water consumption. However, in some regions of the world, traditional aquaculture methods remain prevalent, and selective breeding has often been designed for performance within these systems. Therefore, it is important to evaluate how current fish populations fare in RAS to guide future breeding choices. In a commercial setting, we explore the genetic structure of growth characteristics, measure genotype–environment interactions (GxE) in salmon smolts, and examine genetic markers related to growth in freshwater lochs and RAS. Young salmon were raised together until they reached the parr stage, after which they were divided equally between freshwater net‐pens and RAS. After an 8‐week period, we sampled fish from each environment and genotyped them. Our findings revealed that fish reared in RAS were generally smaller in weight and length but exhibited a higher condition factor and uniformity. We found a notably smaller component of unexplained variance in the RAS, leading to higher heritability estimates. We observed a low GxE effect for length and condition factor, but significant re‐ranking for whole‐body weight, as well as noticeable differences in trait associations across environments. Specifically, a segment of chromosome 22 was found to be linked with the condition factor in the RAS population only. Results suggests that if the use of RAS continues to expand, the efficiency of existing commercial populations may not reach its full potential unless breeding programs specific to RAS are implemented.

Abstract Dacryoadenitis in the setting of linear scleroderma en coup de sabre (LScs) is an association that has not previously been described in the scientific literature. The purpose of this case report is to describe the co‐existence of LScs and chronic dacryoadenitis and how it was managed. We report the case of a 42‐year‐old woman who presented with a 4‐month history of left upper eyelid swelling with radiological enlargement of the left lacrimal gland on orbital CT and MRI imaging. Clinical examination revealed a left erythematous, swollen upper eyelid with lateral conjunctival injection and a palpable left lacrimal gland. An ipsilateral band‐like cutaneous depression in the fronto‐temporal region was also noted, which extended to the ipsilateral upper eyelid and brow. Serology revealed nucleolar antinuclear antibodies. A further incisional biopsy of the lacrimal gland confirmed chronic inflammatory changes and fibrous tissue. Based on both the histological and clinical findings, a diagnosis of dacryoadenitis in association with LScs was made. Oral methotrexate was commenced. The patient responded well with less frequent episodes of eyelid swelling and reduced periocular pain. This case describes for the first time, the ophthalmological manifestation of chronic dacryoadenitis in association with linear scleroderma en coup de sabre.

Abstract The objective of our study was to reanalyse the Ethiopia STEPwise approach to Surveillance Noncommunicable Disease Risk Factors survey (NCD STEPS), using causal path diagrams constructed using expert subject matter knowledge in conjunction with graphical model theory to map the underlying causal network of modifiable factors associated with prediabetes/diabetes and hypertension. We used data from the 2015 Ethiopia NCD STEPS representative cross‐sectional survey (males; n = 3977 and females; n = 5823 aged 15–69 years) and performed directed acyclic graph‐informed logistic regression analyses. In both sexes, a 1‐unit higher in body mass index (BMI) and waist circumference (WC) were positively associated with prediabetes/diabetes (BMI: males: adjusted odds ratio [aOR]: 1.07 [95% confidence interval: 1.0, 1.1], females aOR: 1.03 [1.0, 1.1]; WC: males: aOR: 1.1 [0.9, 1.2], females: aOR: 1.2 [1.1, 1.3]) and hypertension (BMI: males: aOR: 1.2 [1.1, 1.2], females aOR: 1.1 [1.0, 1.1]; WC: males: aOR: 1.6 [1.4, 1.8], females: aOR: 1.3 [1.2, 1.5]). Although residing in urban settings was associated with higher odds of hypertension in both males (aOR: 1.79 [1.49, 2.16]) and females (aOR: 1.70 [1.49, 1.95]), it was only associated with prediabetes/diabetes in males (aOR: 1.56 [1.25, 1.96]). Males and females in pastoralist areas had lower odds of prediabetes/diabetes compared with their agrarian counterparts (males: aOR: 0.27 [0.14, 0.52], females: aOR: 0.31 [0.16, 0.58]). Physical activity was associated with lower odds of prediabetes/diabetes among females (aOR: 0.75 [0.58, 0.97]). Other diet‐related modifiable factors such as consumption of fruit and vegetable, alcohol or salt were not associated with either prediabetes/diabetes or hypertension. Our findings highlight the need to implement interventions that prevent overweight/obesity and nutrition‐related NCDs, particularly in urban areas.

Abstract Ethiopia faces a rising problem of overweight and obesity alongside a high prevalence of undernutrition; a double burden of malnutrition (DBM). This study aimed to quantify the magnitude and trends of household‐level DBM—defined as the coexistence of maternal overweight/obesity and child undernutrition (i.e., stunting or anaemia)—in Ethiopia between 2005, 2011 and 2016 and understand the potential drivers influencing DBM and the change in DBM over time. Data come from the Ethiopian Demographic and Health Surveys. National and regional prevalence estimates of the DBM were calculated (n = 13,107). Equiplots were produced to display inequalities in the distribution of DBM. Factors associated with DBM were explored using pooled multivariable logistic regression analyses for 2005, 2011 and 2016 (n = 9358). These were also included in a logistic regression decomposition analysis to understand their contribution to the change in DBM between 2005 and 2016 (n = 5285). The prevalence of household‐level DBM at the national level was low, with a modest increase from 2.4% in 2005% to 3.5% in 2016. This masks important within‐country variability, with substantially higher prevalence in Addis Ababa (22.8%). Factors positively associated with DBM were maternal age (odds ratio [OR] = 1.04 [1.02, 1.06]), urban residence (OR = 3.12 [2.24, 4.36]), wealth (OR = 1.14 [1.06, 1.24]) and the number of children

Abstract Inadequate safe water supply and poor sanitation and hygiene continue to be important risk factors for diarrhoea and stunting globally. We used data from the four rounds of the Ethiopian Demographic and Health Survey and applied the new World Health Organization (WHO)/UNICEF Joint Monitoring Program (JMP) service standards to assess progress in water, sanitation and hygiene (WASH) coverage between 2000 and 2016. We also performed an age‐disaggregated pooled linear probability regression analysis followed by a decomposition analysis to determine whether changes in WASH practices have contributed to the changing prevalence of diarrhoea and stunting in children under 5 years of age. We observed a significant increase in the coverage of safe drinking water and adequate sanitation facilities over the period. At the national level, the use of a basic water source increased from 18% in 2000 to 50% in 2016. Open defecation declined from 82% to 32% over the same period. However, in 2016, only 6% of households had access to a basic sanitation facility, and 40% of households had no handwashing facilities. The reduction in surface water use between 2000 and 2016 explained 6% of the decline in diarrhoea observed among children aged 0–5 months. In children aged 6–59 months, between 7% and 9% of the reduction in stunting were attributable to the reduction in open defecation over this period. Despite progress, improvements are still needed to increase basic WASH coverage in Ethiopia. Our findings showed that improvements in water and sanitation only modestly explained reductions in diarrhoea and stunting.

Abstract During mammalian terrestrial locomotion, body flexibility facilitated by the vertebral column is expected to be correlated with observed modes of locomotion, known as gait (e.g., sprawl, trot, hop, bound, gallop). In small‐ to medium‐sized mammals (average weight up to 5 kg), the relationship between locomotive mode and vertebral morphology is largely unexplored. Here we studied the vertebral column from 46 small‐ to medium‐sized mammals. Nine vertebrae across cervical, thoracic, and lumbar regions were chosen to represent the whole vertebral column. Vertebra shape was analysed using three‐dimensional geometric morphometrics with the phylogenetic comparative method. We also applied the multi‐block method, which can consider all vertebrae as a single structure for analysis. We calculated morphological disparity, phylogenetic signal, and evaluated the effects of allometry and gait on vertebral shape. We also investigated the pattern of integration in the column. We found the cervical vertebrae show the highest degree of morphological disparity, and the first thoracic vertebra shows the highest phylogenetic signal. A significant effect of gait type on vertebrae shape was found, with the lumbar vertebrae having the strongest correlation; but this effect was not significant after taking phylogeny into account. On the other hand, allometry has a significant effect on all vertebrae regardless of the contribution from phylogeny. The regions showed differing degrees of integration, with cervical vertebrae most strongly correlated. With these results, we have revealed novel information that cannot be captured from study of a single vertebra alone: although the lumbar vertebrae are the most correlated with gait, the cervical vertebrae are more morphologically diverse and drive the diversity among species when considering whole column shape.

Abstract Objective Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single‐ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. Methods We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Results Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single‐ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. Interpretation We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Abstract Polarization surrounding bias correction (BC) in creating climate projections arises from its lack of physicality. Here, we perform and analyze 18 dynamical downscaling simulations (with and without BC) to better understand the physical impacts of BC, applied before downscaling, on regional climate output across the western United States. Without BC, downscaled precipitation is systematically and unrealistically wet biased compared to a hierarchy of observationally based datasets over the 1980–2014 period due to cascading mean‐state Global Climate Model (GCM) biases: (a) overly strong lower‐tropospheric lapse rates (5 K/km), (b) overly cold (2 K) tropospheric temperatures, and (c) anomalous mid‐tropospheric cyclonic vorticity advection. With BC, downscaled precipitation (snow) biases are virtually eliminated (halved). Identified GCM biases are common to the broader Coupled Model Intercomparison Project ensemble. Physical effects of BC on the quality of the regionalized projections, pending an evaluation of BC's distortion of the downscaled climate response, may motivate its broader application by dynamical downscalers.

Background Exercise‐associated secondary amenorrhea results in estrogen deficiency, which may lead to dysfunction in estrogen's normal cardioprotective pathways. Estrogen may be essential in a woman's endothelial adaptations to exercise. The objective of this review was to assess the association between secondary amenorrhea in physically active women and cardiovascular disease (CVD) risk. Methods and Results A literature search was performed in January 2023 and updated in August 2023 of the Cumulative Index to Nursing and Allied Health Literature (EBSCOhost), Cochrane Library, Embase (Ovid), MEDLINE (Ovid), SPORTDiscus (EBSCOhost), and Scopus from inception to present with no date or language limitations. Citation chaining was done to screen for additional studies. Eight sources were searched for gray literature. Studies that compared physically active women with amenorrhea to physically active women with eumenorrhea aged 18 to 35 years with evidence of CVD, alterations to cardiovascular physiology, or CVD risks were included. Eighteen observational studies from 3 countries were included. Overall, the quality of evidence was good. A meta‐analysis was performed. Physically active women with secondary amenorrhea had significantly lower estradiol, flow‐mediated dilation, resting heart rate, systolic blood pressure, and diastolic blood pressure and higher total cholesterol, triglycerides, high‐density lipoprotein, and low‐density lipoprotein cholesterol. Conclusions Estrogen deficiency resulting from exercise‐associated secondary amenorrhea in physically active women may impact cardiovascular physiology and certain CVD risk factors. The research in this area is observational; therefore, findings should be interpreted cautiously. However, as exercise‐associated secondary amenorrhea is reversible and the primary prevention of CVD is important for public health, it may be important to treat secondary amenorrhea and restore estrogen levels.

Abstract Recently promulgated Draft Guidance from the US Food and Drug Administration Oncology Center of Excellence (OCE) recommends randomized, parallel dose–response trials for “dose optimization,” but with vaguely stated aims that engage none of the statistical principles which typically attend randomization. Here, I advance a criterion for reasonable precision of such trials, and examine its implications for minimum enrollment, within a utility‐based framework that acknowledges interindividual heterogeneity simultaneously in pharmacokinetics/pharmacodynamics and in the subjective evaluation of efficacy‐toxicity trade‐offs. Even when designed and conducted under ideal circumstances, reasonably sized trials of the kind advocated by OCE may need to enroll many hundreds of participants.

Abstract Tominersen is an intrathecally administered antisense oligonucleotide targeting huntingtin mRNA which leads to a dose‐dependent, reversible lowering of cerebrospinal fluid (CSF) mutant huntingtin protein concentration in individuals with Huntington's disease. Nonlinear mixed‐effect population pharmacokinetic (PopPK) modeling was conducted to characterize the CSF and plasma pharmacokinetics (PK) of tominersen, and to identify and quantify the covariates that affect tominersen PKs. A total of 750 participants from five clinical studies with a dose range from 10 to 120 mg contributed CSF (n = 6302) and plasma (n = 5454) PK samples. CSF PK was adequately described by a three‐compartment model with first‐order transfer from CSF to plasma. Plasma PK was adequately described by a three‐compartment model with first‐order elimination from plasma. Baseline total CSF protein, age, and antidrug antibodies (ADAs) were the significant covariates for CSF clearance. Body weight was a significant covariate for clearances and volumes in plasma. ADAs and sex were significant covariates for plasma clearance. The developed PopPK model was able to describe tominersen PK in plasma and CSF after intrathecal administration across a range of dose levels, and relevant covariate relationships were identified. This model has been applied to guide dose selection for future clinical trials of tominersen in patients with Huntington's disease.

Abstract Background Nucleoside analog GS‐441524 is effective in treating cats with feline infectious peritonitis (FIP). Investigation into the use of parent nucleotide analog remdesivir (GS‐5734) is needed. Objectives To assess efficacy and tolerability of remdesivir with or without transition to GS‐441524 in cats with FIP and document clinical and clinicopathologic progression over 6 months. Animals Twenty‐eight client‐owned cats with FIP. Methods Cats were prospectively recruited between May 2021 and May 2022. An induction dosage of remdesivir 10 to 15 mg/kg intravenously or subcutaneously q24h was utilized for 4 doses, with a maintenance dosage of remdesivir (6‐15 mg/kg SC) or GS‐441524 (10‐15 mg/kg per os) every 24 hours continued for at least 84 days. Laboratory testing, veterinary, and owner assessments were recorded. Results Twenty‐four cats survived to 6 months (86%). Three cats died within 48 hours. Excluding these, survival from 48 hours to 6 months was 96% (24/25). Remission was achieved by day 84 in 56% (14/25). Three cats required secondary treatment for re‐emergent FIP. Remission was achieved in all 3 after higher dosing (15‐20 mg/kg). Adverse reactions were occasional site discomfort and skin irritation with remdesivir injection. Markers of treatment success included resolution of pyrexia, effusions, and presenting signs of FIP in the first half of treatment and normalization of globulin concentration, and continued body weight gains in the latter half of the treatment period. Conclusions and Clinical Importance Parenteral administration of remdesivir and oral administration of GS‐441524 are effective and well‐tolerated treatments for FIP. Early emphasis on clinical, and later emphasis on clinicopathologic response, appears prudent when monitoring treatment efficacy.

Abstract Background In oestrogen‐receptor positive breast cancer, daily oral adjuvant endocrine therapy (ET) for at least 5 years significantly reduces risks of recurrence and breast cancer‐specific mortality. However, many women are poorly adherent to ET. Development of effective adherence support requires comprehensive understanding of influences on adherence. We undertook an umbrella review to identify determinants of ET adherence. Methods We searched PubMed, Embase, CINAHL, PsycINFO, Cochrane and PROSPERO (inception to 08/2022) to identify systematic reviews on factors influencing ET adherence. Abstracted determinants were mapped to the World Health Organization's dimensions of adherence. Reviews were quality appraised and overlap assessed. Results Of 5732 citations screened, 17 reviews were eligible (9 quantitative primary studies; 4 qualitative primary studies; 4 qualitative or quantitative studies) including 215 primary papers. All five WHO dimensions influenced ET non‐adherence: The most consistently identified non‐adherence determinants were patient‐related factors (e.g. lower perceived ET necessity, more treatment concerns, perceptions of ET ‘cons’ vs. ‘pros’). Healthcare system/healthcare professional‐related factors (e.g. perceived lower quality health professional interaction/relationship) were also important and, to a somewhat lesser extent, socio‐economic factors (e.g. lower levels of social/economic/material support). Evidence was more mixed for medication‐related and condition‐related factors, but several may be relevant (e.g. experiencing side‐effects, cost). Potentially modifiable factors are more influential than non‐modifiable/fixed factors (e.g. patient characteristics). Conclusions The evidence‐base on ET adherence determinants is extensive. Future empirical studies should focus on less well‐researched areas and settings. The determinants themselves are numerous and complex in indicating that adherence support should be multifaceted, addressing multiple determinants.

Abstract Objective Obesity and many of its comorbidities can be improved by nutritional therapy, lifestyle modification, pharmacotherapy, and surgical intervention. Relatively little is known about patients' preferences for the range of obesity treatments. The present study was undertaken to identify factors that may influence these preferences. By evaluating patient‐preferred treatment options and factors influencing patients, treatment adherence and efficacy may be improved. Our objective was to identify factors that influence patient preferences and subsequent choice of obesity treatment among those seeking treatment for obesity‐related complications. Methods Participatory action research, using purposeful sampling, was used to recruit 33 patients with obesity complications. Recruitment took place in specialist clinics for non‐alcoholic fatty liver disease, diabetes, hypertension, and chronic kidney disease. Sixteen males and 17 females aged 18–70 years with a BMI>35 kg/m2 were recruited. Prior to the interview, participants watched a 60‐min video explaining nutritional therapies, pharmacotherapies, and surgical therapies in equipoise. Data were collected in one‐to‐one semi‐structured interviews using zoom or the telephone; reflective thematic analysis was used. Results Four themes emerged: 1) structural factors, 2) autonomy, 3) interaction with formal care, and 4) the emotional and physical consequences of obesity. 39% of participants preferred nutritional therapy with support from medical professionals. 27% chose bariatric surgery. 24% chose pharmacotherapy alone, while 6% chose pharmacotherapy combined with nutritional therapy, 3% of participants wanted no intervention. Conclusion The challenges can be addressed by increasing support for healthcare professionals toward enhancing both their knowledge and the health literacy of patients. Future research should focus on improving access to treatment pathways for patients as well as developing health literacy programs and educational programs for healthcare professionals.

Abstract Objectives Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B‐cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array. Methods IgG responses to S. pneumoniae were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole‐cell ELISA, a flow cytometry opsonisation assay and an S. pneumoniae protein array. For the RA patients, results were compared before and after B‐cell depletion therapy. Results Compared to a well‐characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen‐specific responses also correlated with reduced IgG opsonisation of S. pneumoniae. Although B‐cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre‐existing IgG repertoire to protein antigens in individual patients. Conclusion These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.

Background Untreated intracranial aneurysms can rupture and result in high rates of morbidity and mortality. Although there are numerous approved endovascular aneurysm treatment devices, most require dual anti‐platelet therapy, are minimally biocompatible, or are prone to recanalization. Neurovascular Controlled Uniform Rapid Embolic (NeuroCURE) is an innovative polymer gel material with long‐term stability, biocompatibility, and hemocompatibility developed for the treatment of large, wide‐neck aneurysms. Methods Sidewall aneurysms were surgically created in 10 canines and NeuroCURE was injected through a 0.025 microcatheter under a single balloon inflation period. Aneurysm treatment was angiographically assessed post‐embolization and pre‐term with Raymond–Roy occlusion classification and a qualitative flow grade scale. Aneurysm neck stability and biocompatibility was histologically assessed to grade platelet/fibrin thrombus, percent endothelialization, and neointimal formation. Aneurysm sac stability was assessed by NeuroCURE sac content, inflammation, and neo‐angiogenesis scales. Results Explanted aneurysms exhibited a smooth surface at the aneurysm neck with nearly complete neointimal coverage at 3‐months. By 6‐months, neck endothelialization was 100% in all animals (average Raymond–Roy occlusion classification of 1.2), with no instances of aneurysm recanalization or parent vessel flow compromise. Biocompatibility assessments verified a lack of inflammatory response, neo‐angiogenesis, and platelet/fibrin thrombus formation. Conclusion The NeuroCURE material promotes progressive occlusion of wide‐necked side wall aneurysms over time without the need for dual antiplatelet agents. NeuroCURE also promotes neointimal tissue infill without dependence on thrombus formation and thus resists aneurysm recanalization. NeuroCURE remains a compelling investigational device for the treatment of intracranial aneurysms.

Abstract In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor. This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an “at‐risk” status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at‐risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production, which should normally be transient, but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations, ultimately driving the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial “checkpoints” that in principle should constrain or resolve autoimmunity; however, instead, the checkpoints “fail” and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt, or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at‐risk state, or approaches that target novel pathways.

Background Gender‐related factors are psycho‐socio‐cultural characteristics and are associated with adverse clinical outcomes in acute myocardial infarction, independent of sex. Whether sex‐ and gender‐related factors contribute to the substantial heterogeneity in hospital length of stay (LOS) among patients with non–ST‐segment–elevation myocardial infarction remains unknown. Methods and Results This observational cohort study combined and analyzed data from the GENESIS‐PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary Syndrome study), EVA (Endocrine Vascular Disease Approach study), and VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI [Acute Myocardial Infarction] Patients study) cohorts of adults hospitalized across Canada, the United States, Switzerland, Italy, Spain, and Australia for non–ST‐segment–elevation myocardial infarction. In total, 5219 participants were assessed for eligibility. Sixty‐three patients were excluded for missing LOS, and 2938 were excluded because of no non–ST‐segment–elevation myocardial infarction diagnosis. In total, 2218 participants were analyzed (66% women; mean±SD age, 48.5±7.9 years; 67.8% in the United States). Individuals with longer LOS (51%) were more likely to be White race, were more likely to have diabetes, hypertension, and a lower income, and were less likely to be employed and have completed secondary education. No univariate association between sex and LOS was observed. In the adjusted multivariable model, age (0.62 d/10 y; P

Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning‐induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10‐ to 14‐week‐old male wild‐type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane‐induced changes in iNOS expression were measured. N‐(3‐(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1‐way ANOVA and 2‐way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P

Abstract Objective Adipose tissue is a central regulator of metabolic health and a contributor to systemic inflammation. Patterns of adiposity deposition are important to understand for optimizing health. This study aimed to asses relationships between adiposity deposition and metabolic and inflammatory biomarkers in South African women prior to conception. Methods Non‐pregnant, healthy women (n = 298) were recruited for this cross‐sectional study via home visits. Body composition was measured by Dual X‐ray Absorptiometry. Inflammation markers C‐reactive protein (CRP), alpha1‐acid glycoprotein (AGP), hemoglobin A1c (HbA1c), and blood pressure were scored according to risk. A summative metabolic health risk score was created for women with obesity. Generalized regression models assessed relationships between adiposity deposition and outcomes with adjustment for potential confounders. Results Obesity was present in 22% of women (mean age = 20.93 years). Fat mass index was associated with inflammation and metabolic health risk (β = 0.58; p

Abstract How to best track species as they rapidly alter their distributions in response to climate change has become a key scientific priority. Information on species distributions is derived from biological records, which tend to be primarily sourced from traditional recording schemes, but increasingly also by citizen science initiatives and social media platforms, with biological recording having become more accessible to the general public. To date, however, our understanding of the respective potential of social media and citizen science to complement the information gathered by traditional recording schemes remains limited, particularly when it comes to tracking species on the move with climate change. To address this gap, we investigated how species occurrence observations vary between different sources and to what extent traditional, citizen science, and social media records are complementary, using the Banded Demoiselle (Calopteryx splendens) in Britain as a case study. Banded Demoiselle occurrences were extracted from citizen science initiatives (iRecord and iNaturalist) and social media platforms (Facebook, Flickr, and Twitter), and compared with traditional records primarily sourced from the British Dragonfly Society. Our results showed that species presence maps differ between record types, with 61% of the citizen science, 58% of the traditional, and 49% of the social media observations being unique to that data type. Banded Demoiselle habitat suitability maps differed most according to traditional and social media projections, with traditional and citizen science being the most consistent. We conclude that (i) social media records provide insights into the Banded Demoiselle distribution and habitat preference that are different from, and complementary to, the insights gathered from traditional recording schemes and citizen science initiatives; (ii) predicted habitat suitability maps that ignore information from social media records can substantially underestimate (by over 3500 km2 in the case of the Banded Demoiselle) potential suitable habitat availability.

Abstract Background Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. Methods We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. Results Forty‐five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69–84). At baseline, the median BMI was 26 kg/m2 (IQR: 22–29), and median weight loss in the previous 6 months was 5% (IQR: −12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count − median % change from baseline to endpoint, per trial arm (experimental −18.5% [IQR: −61 to 65], control 5% [IQR: −32 to 50], P = 0.548); weight − median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: −3 to 3], control −0.5% [IQR: −3 to 1], P = 0.184); overall quality of life − median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: −20 to 19], control 0% [IQR: −23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £‐319.51 [CI −7593.53 to 6581.91], suggesting the experimental arm was less costly. Conclusions An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Abstract Estimating the contribution of demographic parameters to changes in population growth is essential for understanding why populations fluctuate. Integrated population models (IPMs) offer a possibility to estimate the contributions of additional demographic parameters, for which no data have been explicitly collected—typically immigration. Such parameters are often subsequently highlighted as important drivers of population growth. Yet, accuracy in estimating their temporal variation, and consequently their contribution to changes in population growth rate, has not been investigated. To quantify the magnitude and cause of potential biases when estimating the contribution of immigration using IPMs, we simulated data (using northern wheatear Oenanthe oenanthe population estimates) from controlled scenarios to examine potential biases and how they depend on IPM parameterization, formulation of priors, the level of temporal variation in immigration and sample size. We also used empirical data on populations with known rates of immigration: Soay sheep Ovis aries and Mauritius kestrel Falco punctatus with zero immigration and grey wolf Canis lupus in Scandinavia with near‐zero immigration. IPMs strongly overestimated the contribution of immigration to changes in population growth in scenarios when immigration was simulated with zero temporal variation (proportion of variance attributed to immigration = 63% for the more constrained formulation and real sample size) and in the wild populations, where the true number of immigrants was zero or near‐zero (kestrel 19.1%–98.2%, sheep 4.2%–36.1% and wolf 84.0%–99.2%). Although the estimation of the contribution of immigration in the simulation study became more accurate with increasing temporal variation and sample size, it was often not possible to distinguish between an accurate estimation from data with high temporal variation versus an overestimation from data with low temporal variation. Unrealistically, large sample sizes may be required to estimate the contribution of immigration well. To minimize the risk of overestimating the contribution of immigration (or any additional parameter) in IPMs, we recommend to: (a) look for evidence of variation in immigration before investigating its contribution to population growth, (b) simulate and model data for comparison to the real data and (c) use explicit data on immigration when possible.

Abstract Elucidating factors (“drivers”) that influence succession after disturbance can explain ecological phenomena, including why communities vary spatiotemporally. To gain insight on drivers related to habitat availability, species availability, and species performance during succession, we conducted two field experiments on infaunal communities in intertidal mudflats, one on each of the Atlantic and Pacific coasts of Canada, that had disturbances of different type, size, and frequency. Related to habitat availability drivers, we observed that disturbance type and size, which differed between experiments, did not change end patterns of succession; however, disturbance frequency, directly assessed in one experiment, did. Dispersal of species from surrounding mudflat and water column (species availability) was the primary driver of succession, whereas local interactions between species after colonization (species performance drivers) did not have a detectable effect. We suggested that ample space and resources diffused competition and predation effects, and so species replacements did not occur in our systems, resulting in a lack of “traditional” successional dynamics as observed in other ecosystems. Our findings that community composition in intertidal mudflats is strongly influenced by species availability on two different coasts suggest that this driver may be key to variation in intertidal mudflat communities elsewhere.

Approximately 25% of human neuroblastoma is caused by amplification of the MYCN oncogene, which leads to overexpression of N‐Myc oncoprotein. The survival rate for this patient subtype is