Mathematical modeling of exercise fatigability in the severe domain: A unifying integrative framework in isokinetic condition.

Muscle fatigue is the decay in the ability of muscles to generate force, and results from neural and metabolic perturbations. This article presents an integrative mathematical model that describes the decrease in maximal force capacity (i.e. fatigue) over exercises performed at intensities above the critical force Fc (i.e. severe domain). The model unifies the previous Critical Power Model and All-Out Model and can be applied to any exercise described by a changing force F over time. The assumptions of the model are (i) isokinetic conditions, an intensity domain of Fc

KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.

Mental health support across the sight loss pathway: a qualitative exploration of eye care patients, optometrists, and ECLOs.

BACKGROUND: The process of becoming visually impaired or blind is undoubtedly a highly emotional experience, requiring practical and psychological support. Information on mental health support provision in the UK across the sight-loss pathway, however, is largely unknown, especially amongst healthcare practitioners that are often sought after for advice: the referring optometrist and eye clinic liaison officer (ECLO). This study aims to ascertain the perceived accessibility and quality of mental health support across the sight-loss pathway. METHODS: Semi-structured individual interviews were conducted with patients with a diagnosed eye condition who had received care from a hospital eye service, referring optometrists, and ECLOs. Following interview transcription, results were synthesised in a narrative analysis. RESULTS: A total of 28 participants were included in the analysis, of which 17 were participants with various eye conditions, five were referring optometrists, and five were ECLOs. After analysis, three broad themes emerged: (1) The emotional trauma of diagnosis (2) Availability of mental health support; (3) The point where mental health support is most needed across the sight-loss pathway. Several patients reporting that they had received no offer of support nor were they signposted to any possible sources. Referring optometrists and ECLO's agreed. CONCLUSION: It is important that referring optometrists are aware of the need for mental health support services and can signpost to local support services including the third sector anytime during the referral process. Future large-scale, UK-wide research into referral practice and signposting for mental health support for patients is warranted, to identify how services can be improved in order to ensure that the wellbeing of patients is maintained.

Does lesion type or severity predict outcome of therapy for horses with equine glandular gastric disease? - A retrospective study.

BACKGROUND: Equine glandular gastric disease (EGGD) is a common condition of the horse. Misoprostol is reported to be superior to oral omeprazole and sucralfate for treatment. Long-acting intramuscular injectable omeprazole (LAIOMEP) is a novel treatment shown to be effective in a small population. OBJECTIVES: This study aimed to determine LAIOMEP efficacy compared to misoprostol and oral omeprazole and identify characteristics that predict treatment outcome. METHODS: All horses that underwent gastroscopy between 2012 and 2019 were reviewed. Lesions were characterised by 4 blinded observers, all of whom are diplomates in equine internal medicine, using established descriptors from the ECEIM consensus statement and subjective severity. Treatment outcome was ranked as worsened, improved or healed. Consensus lesion type, lesion severity and treatment choice were compared to outcome and data screened using univariate analysis (chi-squared) to determine whether each predicted outcome. Lesion types where univariate analysis predicted a trend (p<0.2) were included in a multiple-regression analysis to identify predictors of outcome irrespective of treatment. RESULTS: Only severity significantly predicted final outcome (p = 0.025) with severe lesions being more likely to improve. Treatment choice did not significantly predict outcome. Overall healing rate was 29% (24 horses), and 43% (44 horses) improved. Treatment healing rates were 23% (10), 12% (7) and 27% (7) for LAIOMEP, misoprostol and oral omeprazole, respectively, with improvement in 69% (14), 76% (21) and 61% (9). 64% of the latter group received sucralfate. Worsening occurred in 7% (6). Treatment length varied with a median of 4 weeks (range 4-20 weeks). CONCLUSIONS: This study showed poorer therapy outcome compared to previous studies. The only initial lesion descriptor to predict outcome was severity and treatment choice did not affect outcome.

Neuromuscular fatigability during repeated sprints assessed with an innovative cycle ergometer.

PURPOSE: Repeated sprint ability is an integral component of team sports. This study aimed to evaluate fatigability development and its aetiology during and immediately after a cycle repeated sprint exercise performed until a given fatigability threshold. METHODS: On an innovative cycle ergometer, 16 healthy males completed an RSE (10-s sprint/28-s recovery) until task failure (TF): a 30% decrease in sprint mean power (Pmean). Isometric maximum voluntary contraction of the quadriceps (IMVC), central alterations [voluntary activation (VA)], and peripheral alterations [twitch (Pt)] were evaluated before (pre), immediately after each sprint (post), at TF and 3 min after. Sprints were expressed as a percentage of the total number of sprints to TF (TSTF). Individual data were extrapolated at 20, 40, 60, and 80% TSTF. RESULTS: Participants completed 9.7 ± 4.2 sprints before reaching a 30% decrease in Pmean. Post-sprint IMVCs were decreased from pre to 60% TSTF and then plateaued (pre: 345 ± 56 N, 60% 247 ± 55 N, TF: 233 ± 57 N, p < 0.001). Pt decreased from 20% and plateaued after 40% TSTF (p < 0.001, pre-TF = - 45 ± 13%). VA was not significantly affected by repeated sprints until 60% TSTF (pre-TF = - 6.5 ± 8.2%, p = 0.036). Unlike peripheral parameters, VA recovered within 3 min (p = 0.042). CONCLUSION: During an RSE, Pmean and IMVC decreases were first concomitant to peripheral alterations up to 40% TSTF and central alterations was only observed in the second part of the test, while peripheral alterations plateaued. The distinct recovery kinetics in central versus peripheral components of fatigability further confirm the necessity to reduce traditional delays in neuromuscular fatigue assessment post-exercise.

An assessment of the spatial extent of polar dust using satellite thermal data.

The effect of mineral dust aerosols and subsequent deposition in polar regions has historically been underestimated in climate models. Dust aerosols increase melt rates by reducing surface albedo and modifying atmospheric radiative properties. In this study 127,413 satellite images covering the Arctic and Antarctic from 2007 to 2019 were assessed for dust content using thermal infrared wavelengths. The results show a strong linear trend in which the relative spatial extent of dust (RSED) increased annually by 0.31% in the Arctic (8.5% to 12.1%) and 0.19% in the Antarctic (5.2% to 7.5%). Seasonally, the maximum aggregated average RSED occurred in the Arctic during boreal winter (11.2%), while the Antarctic peaked in austral spring (9.5%). Maximum RSED rates occurred in boreal winter/austral summer (Dec-Jan-Feb) for both polar regions. The data suggests that finer dust particles are more efficiently distributed by aeolian processes leading to higher RSED values that are not necessarily reflective of polar dust loading models.

COVID-19-related intracranial imaging findings: a large single-centre experience.

AIM: To describe the neuroradiological changes in patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: A retrospective review was undertaken of 3,403 patients who were confirmed positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and admitted to Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK between 1 March 2020 and 31 May 2020, and who underwent neuroimaging. Abnormal brain imaging was evaluated in detail and various imaging patterns on magnetic resonance imaging MRI were identified. RESULTS: Of the 3,403 patients with COVID-19, 167 (4.9%) had neurological signs or symptoms warranting neuroimaging. The most common indications were delirium (44/167, 26%), focal neurology (37/167, 22%), and altered consciousness (34/167, 20%). Neuroimaging showed abnormalities in 23% of patients, with MRI being abnormal in 20 patients and computed tomography (CT) in 18 patients. The most consistent neuroradiological finding was microhaemorrhage with a predilection for the splenium of the corpus callosum (12/20, 60%) followed by acute or subacute infarct (5/20, 25%), watershed white matter hyperintensities (4/20, 20%), and susceptibility changes on susceptibility-weighted imaging (SWI) in the superficial veins (3/20, 15%), acute haemorrhagic necrotising encephalopathy (2/20, 10%), large parenchymal haemorrhage (2/20, 10%), subarachnoid haemorrhage (1/20, 5%), hypoxic-ischaemic changes (1/20, 5%), and acute disseminated encephalomyelitis (ADEM)-like changes (1/20, 5%). CONCLUSION: Various imaging patterns on MRI were observed including acute haemorrhagic necrotising encephalopathy, white matter hyperintensities, hypoxic-ischaemic changes, ADEM-like changes, and stroke. Microhaemorrhages were the most common findings. Prolonged hypoxaemia, consumption coagulopathy, and endothelial disruption are the likely pathological drivers and reflect disease severity in this patient cohort.

Diversity of Rotavirus Strains Circulating in Botswana before and after introduction of the Monovalent Rotavirus Vaccine.

BACKGROUND: Globally, rotavirus is the leading cause of acute gastroenteritis (AGE) in children aged <5 years. Botswana introduced the monovalent rotavirus vaccine (Rotarix) in July 2012. To study the impact of this vaccine on rotavirus genotypes circulating in Botswana, a comparison of the genotypes pre-vaccination (2011-2012) and post-vaccination (2013-2018) periods was conducted. SUBJECTS AND METHODS: Residual samples from 284 children <5 years of age that tested positive for rotavirus by enzyme immunoassay were genotyped. One hundred and five samples were from the pre-vaccination period and 179 were from the post-vaccination period. Genotyping was performed using two multiplexed one-step reverse transcription polymerase chain reaction (RT-PCR) assays for the amplification and genotyping of rotavirus VP7 (G) and VP4 (P) genes. RESULTS: Prior to vaccine introduction, the predominant rotavirus circulating genotypes were G9P[8] (n = 63, 60%) and G1P[8] (n = 22, 21%). During the vaccine period, G2P[4] was the predominant genotype (n = 49, 28%), followed by G9P[8] (n = 40, 22%) and G1P[8] (n = 33, 18.5%). There was a significant decline in the prevalence of G9P[8] (p = 0.001) in the post-vaccination period. There was also a notable decline in G1P[8]. A spike in G2P[4] was observed in 2013, one year post-vaccine introduction. Rotavirus strain G3P[4] (n = 8) was only detected in the post-vaccine introduction period. In 2018 there was a marked increase in genotype G3P[8] (p = 0.0003). CONCLUSIONS: The distribution of circulating rotavirus genotypes in Botswana changed after vaccine implementation. Further studies are needed to examine whether these changes are related to vaccination or simply represent natural secular variation.

Stigma: a linguistic analysis of the UK red-top tabloids press' representation of schizophrenia.

AIMS: Media representations of mental health problems may influence readers' understanding of, and attitude towards, people who have received psychiatric diagnoses. Negative beliefs and attitudes may then lead to discriminatory behaviour, which is understood as stigma. This study explored the language used in popular national newspapers when writing about schizophrenia and considered how this may have contributed to the processes of stigmatisation towards people with this diagnosis. METHODS: Using corpus linguistic methods, a sample of newspaper articles over a 24-month period that mentioned the word 'schizophrenia' was compared with a similar sample of articles about diabetes. This enabled a theory-driven exploration of linguistic characteristics to explore stigmatising messages, while supported by statistical tests (log-likelihood) to compare the data sets and identify words with a high relative frequency. RESULTS: Analysis of the 'schizophrenia' data set identified that overtly stigmatising language (e.g. 'schizo') was relatively infrequent, but that there was frequent use of linguistic signatures of violence. Articles frequently used graphic language referring to acts of violence, descriptions of violent acts, implements used in violence, identity labels and exemplars of well-known individuals who had committed violent acts. The word 'schizophrenic' was used with a high frequency ( n = 108) and most commonly to name individuals who had committed acts of violence. DISCUSSION: The study suggests that while the press has largely avoided the use of words that press guidance has steered them away from (e.g. 'schizo' and 'psycho'), they still use a range of graphic language to present people with a diagnosis of schizophrenia as frighteningly 'other' and as prone to violence. This repetition of negative stereotypical messages may well contribute to the processes of stigmatisation many people who experience psychosis have to contend with.

Trends in utilization and costs of BRCA testing among women aged 18-64 years in the United States, 2003-2014.

PurposeWe examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors.MethodsWe estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18-64 years using private claims data and publicly reported revenues from the primary BRCA testing provider.ResultsThe percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013-2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013-2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity.ConclusionThe observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity.

From public health genomics to precision public health: a 20-year journey.

In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.

BRCA Genetic Testing and Receipt of Preventive Interventions Among Women Aged 18-64 Years with Employer-Sponsored Health Insurance in Nonmetropolitan and Metropolitan Areas - United States, 2009-2014.

PROBLEM/CONDITION: Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined. PERIOD COVERED: 2009-2014. DESCRIPTION OF SYSTEM: Medical claims data from Truven Health Analytics MarketScan Commercial Claims and Encounters databases were used to estimate rates of BRCA testing and receipt of preventive interventions after BRCA testing among women aged 18-64 years with employer-sponsored health insurance in metropolitan and nonmetropolitan areas of the United States, both nationally and regionally. RESULTS: From 2009 to 2014, BRCA testing rates per 100,000 women aged 18-64 years with employer-sponsored health insurance increased 2.3 times (102.7 to 237.8) in metropolitan areas and 3.0 times (64.8 to 191.3) in nonmetropolitan areas. The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased from 37% in 2009 (102.7 versus 64.8) to 20% in 2014 (237.8 versus 191.3). The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased more over time in younger women than in older women and decreased in all regions except the West. Receipt of preventive services 90 days after BRCA testing in metropolitan versus nonmetropolitan areas throughout the period varied by service: the percentage of women who received a mastectomy was similar, the percentage of women who received magnetic resonance imaging of the breast was lower in nonmetropolitan areas (as low as 5.8% in 2014 to as high as 8.2% in 2011) than metropolitan areas (as low as 7.3% in 2014 to as high as 10.3% in 2011), and the percentage of women who received mammography was lower in nonmetropolitan areas in earlier years but was similar in later years. INTERPRETATION: Possible explanations for the 47% decrease in the relative difference in BRCA testing rates over the study period include increased access to genetic services in nonmetropolitan areas and increased demand nationally as a result of publicity. The relative differences in metropolitan and nonmetropolitan BRCA testing rates were smaller among women at younger ages compared with older ages. PUBLIC HEALTH ACTION: Improved data sources and surveillance tools are needed to gather comprehensive data on BRCA testing in the United States, monitor adherence to evidence-based guidelines for BRCA testing, and assess receipt of preventive interventions for women with BRCA mutations. Programs can build on the recent decrease in geographic disparities in receipt of BRCA testing while simultaneously educating the public and health care providers about U.S. Preventive Services Task Force recommendations and other clinical guidelines for BRCA testing and counseling.

Fluorescence-Based Assays to Analyse Phosphatidylinositol 5-Phosphate in Autophagy.

Autophagosome formation is stimulated by VPS34-dependent PI(3)P formation and by alternative VPS34-independent pathways. We recently described that PI(5)P regulates autophagosome biogenesis and rescues autophagy in VPS34-inactivated cells, suggesting that PI(5)P contributes to canonical autophagy. Our analysis revealed a hitherto unknown functional interplay between PIKfyve and PIPK type II in controlling PI(5)P levels in the context of autophagy. Among phosphoinositides, visualization of PI(5)P in intact cells has remained difficult. While PI(5)P has been implicated in signaling pathways, chromatin organization, bacterial invasion, and cytoskeletal remodeling, our study is the first report showing PI(5)P localization on autophagosomes and early autophagosomal structures when autophagy is induced by nutrient deprivation (amino acids or glucose starvation). We provided a detailed analysis of PI(5)P distribution by the use of super-resolution structured illuminated microscopy. Here, we present a set of tools for detection of PI(5)P during autophagy by confocal microscopy, live-cell imaging, and super-resolution microscopy.

Foster home integration as a temporal indicator of relational well-being.

This study sought to identify factors that contribute to the relational well-being of youth in substitute care. Using data from the [BLIND] study, youth responded to a 9-item measure of positive home integration, a scale designed to assess the relational experiences of youth to their caregivers and their integration into the foster home. Data were collected from youth in six month intervals, for an 18-month period of time. Latent growth curve modeling procedures were employed to determine if child, family, and case characteristics influenced youth's home integration trajectories. Results suggest stability in youth reports of home integration over time; however, children who were older at the time of study enrollment and youth who experienced placement changes during the period of observation experienced decreased home integration during the 18-month period. Results suggest youth's perspectives of home integration may in part be a function of the child's developmental stage and their experiences with foster care placement instability. Implications for practice and future research are discussed.

Body Temperature Modulates Infarction Growth following Endovascular Reperfusion.

BACKGROUND AND PURPOSE: The neuronal substrate is highly sensitive to temperature elevation; however, its impact on the fate of the ischemic penumbra has not been established. We analyzed interactions between temperature and penumbral expansion among successfully reperfused patients with acute ischemic stroke, hypothesizing infarction growth and worse outcomes among patients with fever who achieve full reperfusion. MATERIALS AND METHODS: Data from 129 successfully reperfused (modified TICI 2b/3) patients (mean age, 65 ± 15 years) presenting within 12 hours of onset were examined from a prospectively collected acute ischemic stroke registry. CT perfusion was analyzed to produce infarct core, hypoperfusion, and penumbral mismatch volumes. Final DWI infarction volumes were measured, and relative infarction growth was computed. Systemic temperatures were recorded throughout hospitalization. Correlational and logistic regression analyses assessed the associations between fever (>37.5°C) and both relative infarction growth and favorable clinical outcome (90-day mRS of ≤2), corrected for NIHSS score, reperfusion times, and age. An optimized model for outcome prediction was computed by using the Akaike Information Criterion. RESULTS: The median presentation NIHSS score was 18 (interquartile range, 14-22). Median (interquartile range) CTP-derived volumes were: core = 9.6 mL (1.5-25.3 mL); hypoperfusion = 133 mL (84.2-204 mL); and final infarct volume = 9.6 mL (8.3-45.2 mL). Highly significant correlations were observed between temperature of >37.5°C and relative infarction growth (Kendall τ correlation coefficient = 0.24, P = .002). Odds ratios for favorable clinical outcome suggested a trend toward significance for fever in predicting a 90-day mRS of ≤2 (OR = 0.31, P = .05). The optimized predictive model for favorable outcomes included age, NIHSS score, procedure time to reperfusion, and fever. Likelihood ratios confirmed the superiority of fever inclusion (P < .05). Baseline temperature, range, and maximum temperature did not meet statistical significance. CONCLUSIONS: These findings suggest that imaging and clinical outcomes may be affected by systemic temperature elevations, promoting infarction growth despite reperfusion.

Phthalocyanine based molecular spintronic devices.

Molecular spintronics is an effervescent field of research, which aims at combining spin physics and molecular nano-objects. In this article, we show that phthalocyanine molecules integrated in magnetic tunnel junctions (MTJs) can lead to magnetoresistance effects of different origins. We have investigated cobalt and manganese phthalocyanine molecule based magnetic tunnel junctions. CoPc MTJs exhibit both tunneling magnetoresistance (TMR) and tunneling anisotropic magnetoresistance (TAMR) effects of similar magnitude. However, for MnPc MTJs, a giant TAMR dominates with ratios up to ten thousands of percent. Strong features visible in the conductance suggest that spin-flip inelastic electron tunneling processes occur through the Mn atomic chain formed by the MnPc stacks. These results show that metallo-organic molecules could be used as a template to connect magnetic atomic chains or even a single magnetic atom in a solid-state device.

Versatile variable temperature insert at the DEIMOS beamline for in situ electrical transport measurements.

The design and the first experiments are described of a versatile cryogenic insert used for its electrical transport capabilities. The insert is designed for the cryomagnet installed on the DEIMOS beamline at the SOLEIL synchrotron dedicated to magnetic characterizations through X-ray absorption spectroscopy (XAS) measurements. This development was spurred by the multifunctional properties of novel materials such as multiferroics, in which, for example, the magnetic and electrical orders are intertwined and may be probed using XAS. The insert thus enables XAS to in situ probe this interplay. The implementation of redundant wiring and careful shielding also enables studies on operating electronic devices. Measurements on magnetic tunnel junctions illustrate the potential of the equipment toward XAS studies of in operando electronic devices.