A Headset Method for Measuring the Visual Temporal Discrimination Threshold in Cervical Dystonia

Background: The visual temporal discrimination threshold (TDT) is the shortest time interval at which one can determine two stimuli to be asynchronous and meets criteria for a valid endophenotype in adult‐onset idiopathic focal dystonia, a poorly penetrant disorder. Temporal discrimination is assessed in the hospital laboratory; in unaffected relatives of multiplex adult‐onset dystonia patients distance from the hospital is a barrier to data acquisition. We devised a portable headset method for visual temporal discrimination determination and our aim was to validate this portable tool against the traditional laboratory‐based method in a group of patients and in a large cohort of healthy controls. Methods: Visual TDTs were examined in two groups 1) in 96 healthy control participants divided by age and gender, and 2) in 33 cervical dystonia patients, using two methods of data acquisition, the traditional table‐top laboratory‐based system, and the novel portable headset method. The order of assessment was randomized in the control group. The results obtained by each technique were compared. Results: Visual temporal discrimination in healthy control participants demonstrated similar age and gender effects by the headset method as found by the table‐top examination. There were no significant differences between visual TDTs obtained using the two methods, both for the control participants and for the cervical dystonia patients. Bland–Altman testing showed good concordance between the two methods in both patients and in controls. Discussion: The portable headset device is a reliable and accurate method for visual temporal discrimination testing for use outside the laboratory, and will facilitate increased TDT data collection outside of the hospital setting. This is of particular importance in multiplex families where data collection in all available members of the pedigree is important for exome sequencing studies

Beyond the COVID-19 Pandemic: Tips for Players and Athletes COVID-RECOVER

First paragraph: The aim of this guidance is to provide a framework for athletes to cope, thrive and engage in personal growth during the current pandemic. The COVID-19 pandemic has likely led to wide-scale disruption of your sporting trajectories for 2020. This has included the cancellation or postponement of sporting events, limits to group training due to social distancing, restrictions on use of sporting facilities and loss of face-to-face access to coaches and support personnel. In the context of a threat to public health, arguably sports competition sinks into lesser importance, but for athletes like you, for whom sport is a fulltime job or major life goal, or for those who identify sports competition as a key part of their identity, it is important to share recommendations based on evidence and theory on how to support athletes and players through this time. The unprecedented situation means that evidence from similar or related contexts and relevant theories needs to be used to extrapolate to COVID-19 and all its challenges. Each of the guidelines below should be viewed like a menu to choose from and try, test and review, and be seen as a road to discovery instead of passive prescription of activities. Our team of practitioners and researchers have collated the knowledge below based on four premises: 1. Psychological Strengths: As a performer on the sporting stage, you have, in all likelihood, developed many skills and habits to support your on-field performance. Pre-performance routines for penalty taking, for example, may include relaxation and focusing components which aid emotional regulation. This can be also applied to help you cope in world outside of sport (i.e. outside the bubble). Awareness of your repertoire of psychological skills and the ability to use them across different contexts is highly important. 2. Resilience: The capacity to mobilise resources both in advance and after a major challenge, is developed through our sporting challenges. In the face of a trauma, it is likely that resilience is the default rather than the exception. As an athlete, you have the ability to respond in an optimistic way to major stressors and engage in post-traumatic growth. Further, you have successful experiences from memory to call upon on which By doing this, you build a firm foundation on which to build your beliefs that you have sufficient resources to cope with COVID-19. 3. Individual Responses: It is important to acknowledge that athletes in different sports and at different levels of competition have developed diverse sets of abilities and competencies. Dual-career athletes (e.g. student-athletes) may have invested much of their effort in their sport despite study or work commitments, and injured athletes may be over-identifying with their sport as a predictable response to injury, in both cases making these athletes very vulnerable to major stressors. 4. Perception of Control: Loss of control is a major source of anxiety in a pandemic (see Mansell, 2020). Developing autonomy and a sense of control is a key part to feeling safe and secure. With COVID-19, the new habits that could help protect you such as physical isolation, hand hygiene, and avoiding touching your face can help you gain control in an uncertain world. And finding new ways to exercise, to work and to interact can open up a world of exciting possibilities. Athletes have shown an ability to develop positive habits and maintain self-control, skills transferable to meeting the present challenging circumstances

Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma

Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes

Beyond the COVID-19 Pandemic: Tips for Players and Athletes COVID-RECOVER

First paragraph: The aim of this guidance is to provide a framework for athletes to cope, thrive and engage in personal growth during the current pandemic. The COVID-19 pandemic has likely led to wide-scale disruption of your sporting trajectories for 2020. This has included the cancellation or postponement of sporting events, limits to group training due to social distancing, restrictions on use of sporting facilities and loss of face-to-face access to coaches and support personnel. In the context of a threat to public health, arguably sports competition sinks into lesser importance, but for athletes like you, for whom sport is a fulltime job or major life goal, or for those who identify sports competition as a key part of their identity, it is important to share recommendations based on evidence and theory on how to support athletes and players through this time. The unprecedented situation means that evidence from similar or related contexts and relevant theories needs to be used to extrapolate to COVID-19 and all its challenges. Each of the guidelines below should be viewed like a menu to choose from and try, test and review, and be seen as a road to discovery instead of passive prescription of activities. Our team of practitioners and researchers have collated the knowledge below based on four premises: 1. Psychological Strengths: As a performer on the sporting stage, you have, in all likelihood, developed many skills and habits to support your on-field performance. Pre-performance routines for penalty taking, for example, may include relaxation and focusing components which aid emotional regulation. This can be also applied to help you cope in world outside of sport (i.e. outside the bubble). Awareness of your repertoire of psychological skills and the ability to use them across different contexts is highly important. 2. Resilience: The capacity to mobilise resources both in advance and after a major challenge, is developed through our sporting challenges. In the face of a trauma, it is likely that resilience is the default rather than the exception. As an athlete, you have the ability to respond in an optimistic way to major stressors and engage in post-traumatic growth. Further, you have successful experiences from memory to call upon on which By doing this, you build a firm foundation on which to build your beliefs that you have sufficient resources to cope with COVID-19. 3. Individual Responses: It is important to acknowledge that athletes in different sports and at different levels of competition have developed diverse sets of abilities and competencies. Dual-career athletes (e.g. student-athletes) may have invested much of their effort in their sport despite study or work commitments, and injured athletes may be over-identifying with their sport as a predictable response to injury, in both cases making these athletes very vulnerable to major stressors. 4. Perception of Control: Loss of control is a major source of anxiety in a pandemic (see Mansell, 2020). Developing autonomy and a sense of control is a key part to feeling safe and secure. With COVID-19, the new habits that could help protect you such as physical isolation, hand hygiene, and avoiding touching your face can help you gain control in an uncertain world. And finding new ways to exercise, to work and to interact can open up a world of exciting possibilities. Athletes have shown an ability to develop positive habits and maintain self-control, skills transferable to meeting the present challenging circumstances

Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

Genetic analysis in budding yeast and in cultured human astrocytes reveals that specific histone deacetylase complexes accelerate expansion mutations in DNA triplet repeats

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570