Search

An online survey was sent to 248 dairy farms from all four UK nations. The results identified areas to optimise calf health and welfare, with a particular focus on extended colostrum feeding (beyond the first 24 hours of life). Chi squared analysis, Cochran Armitage trend tests and logistic regression were used to investigate biologically plausible associations between variables. Thematic analysis was used to construct and refine thematic maps. There was a significant linear trend between the frequency of blood sampling of calves to monitor serum IgG concentrations and testing of colostrum for IgG concentration (P<0.01). A number of farms (41.53%) pooled colostrum (without pasteurising), which may reduce overall IgG concentration and increase disease transmission risk. Timing of colostrum harvest (within 6 hours of calving) was suboptimal on some (23.39%) farms. Many of the perceived barriers to extended colostrum feeding were human and physical, including tangible commodities such as storage and facilities, labour and procedural issues.

The objective of this study was to explore the relative frequency and seasonality of bovine respiratory pathogens in the UK, based on clinical case submission for laboratory PCR testing. This study used retrospective data generated by a central Scotland laboratory using 407 clinical (pooled) samples collected by 95 veterinary practices located throughout the UK between November 2020 and September 2022. Statistical analyses were performed using descriptive spatial analysis (choropleth maps), chi‐squared analysis, Poisson and logistic regression modelling. The majority (77.6%) of the samples had more than one species of bacteria identified, and 17.7% had multiple viruses identified. In comparison with the colder months of autumn and winter (September to February), the warmer months (March to August) were significantly associated with lower odds of respiratory disease caused by certain pathogens. Poisson models showed small but significant univariable associations between total viruses (coefficient = ‒0.01, standard error [SE] = 0.004, 95% confidence interval [CI] = ‒0.02 to ‒0.003) and total pathogens (coefficient = ‒0.005, SE = 0.002, 95% CI = ‒0.008 to 0.002) and increasing weekly age. This is an inherently biased population because it only comprises clinical samples submitted to a single UK laboratory, and the data were analysed retrospectively. A large majority of clinical bovine respiratory disease (BRD) samples were multipathogenic, and pathogens such as bovine coronavirus (which has generally not been considered a significant contributing pathogen in the BRD complex in the UK) were prevalent.

ObjectiveA network meta-analysis (NMA) usually assesses multiple outcomes across several treatment comparisons. The Vitruvian plotaims to facilitate communication of multiple outcomes from NMAs to patients and clinicians.MethodsWe developed this tool following the recommendations on the communication of benefit–risk information from the available literature. We collected and implemented feedback from researchers, statisticians, methodologists, clinicians and people with lived experience of physical and mental health issues.ResultsWe present the Vitruvian plot, which graphically presents absolute estimates and relative performance of competing interventions against a common comparator for several outcomes of interest. We use two alternative colour schemes to highlight either the strength of statistical evidence or the confidence in the evidence. Confidence in the evidence is evaluated across six domains (within-study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence) using the Confidence in Network Meta-Analysis (CINeMA) system.ConclusionsThe Vitruvian plotallows reporting of multiple outcomes from NMAs, with colourings appropriate to inform credibility of the presented evidence.

Bipolar disorder (BD) is a highly heritable mood disorder with intermittent episodes of mania and depression. Lithium is the first-in-line medication to treat BD, but it is only effective in a subset of individuals. Large-scale human genomic studies have repeatedly linked the ANK3gene (encoding ankyrin-G, AnkG) to BD. Ank3knockout mouse models mimic BD behavioral features and respond positively to lithium treatment. We investigated cellular phenotypes associated with BD, including dendritic arborization of pyramidal neurons and spine morphology in two models: (1) a conditional knockout mouse model which disrupts Ank3expression in adult forebrain pyramidal neurons, and (2) an AnkG knockdown model in cortical neuron cultures. We observed a decrease in dendrite complexity and a reduction of dendritic spine number in both models, reminiscent of reports in BD. We showed that lithium treatment corrected dendrite and spine deficits in vitro and in vivo. We targeted two signaling pathways known to be affected by lithium using a highly selective GSK3β inhibitor (CHIR99021) and an adenylate cyclase activator (forskolin). In our cortical neuron culture model, CHIR99021 rescues the spine morphology defects caused by AnkG knockdown, whereas forskolin rescued the dendrite complexity deficit. Interestingly, a synergistic action of both drugs was required to rescue dendrite and spine density defects in AnkG knockdown neurons. Altogether, our results suggest that dendritic abnormalities observed in loss of function ANK3 variants and BD patients may be rescued by lithium treatment. Additionally, drugs selectively targeting GSK3β and cAMP pathways could be beneficial in BD.

Patients who are seriously ill can benefit from continuous nursing care. Nurses can provide support to patients who are coping with their lack of autonomy and the fearful surroundings of hospice or hospital. Nurses offer patients human contact, reassurance and a sense of calm as well as caring for them medically and physically.

BackgroundThe effects of COVID-19 on the shift to remote consultations remain to be properly investigated.ObjectiveTo quantify the extent, nature and clinical impact of the use of telepsychiatry during the COVID-19 pandemic and compare it with the data in the same period of the 2 years before the outbreak.MethodsWe used deidentified electronic health records routinely collected from two UK mental health Foundation Trusts (Oxford Health (OHFT) and Southern Health (SHFT)) between January and September in 2018, 2019 and 2020. We considered three outcomes: (1) service activity, (2) in-person versus remote modalities of consultation and (3) clinical outcomes using Health of the Nation Outcome Scales (HoNOS) data. HoNOS data were collected from two cohorts of patients (cohort 1: patients with ≥1 HoNOS assessment each year in 2018, 2019 and 2020; cohort 2: patients with ≥1 HoNOS assessment each year in 2019 and 2020), and analysed in clusters using superclasses (namely, psychotic, non-psychotic and organic), which are used to assess overall healthcare complexity in the National Health Service. All statistical analyses were done in Python.FindingsMental health service activity in 2020 increased in all scheduled community appointments (by 15.4% and 5.6% in OHFT and SHFT, respectively). Remote consultations registered a 3.5-fold to 6-fold increase from February to June 2020 (from 4685 to a peak of 26 245 appointments in OHFT and from 7117 to 24 987 appointments in SHFT), with post-lockdown monthly averages of 23 030 and 22 977 remote appointments/month in OHFT and SHFT, respectively. Video consultations comprised up to one-third of total telepsychiatric services per month from April to September 2020. For patients with dementia, non-attendance rates at in-person appointments were higher than remote appointments (17.2% vs 3.9%). The overall HoNOS cluster value increased only in the organic superclass (clusters 18–21, n=174; p<0.001) from 2019 to 2020, suggesting a specific impact of the COVID-19 pandemic on this population of patients.Conclusions and clinical implicationsThe rapid shift to remote service delivery has not reached some groups of patients who may require more tailored management with telepsychiatry.

There is increased industry focus on optimised welfare, productivity and antibiotic usage in cattle youngstock, however, little is known about UK farmers' attitudes and practices in rearing calves. In this cross-sectional study, 479 farmers were surveyed online about their cattle youngstock rearing approach and outcomes. Represented were 174 dairy farmers, 255 beef suckler farmers and 50 calf rearers. Farmers showed awareness of good youngstock rearing practices such as colostrum management and housing facilities. Morbidity and mortality from diarrhoea (82%, 48%) and bovine respiratory disease (BRD) (68%, 48%) were high on farms surveyed but farmers did not frequently consult their veterinary surgeon regarding these diseases. Farmers surveyed were not always aware of the efficacy of preventative methods such as vaccination, and frequently used antibiotic treatments (27% for diarrhoea and 40% for BRD) but not diagnostics when animals had disease. Veterinary surgeons could use these insights to better understand farmers' motivations and priorities, to make communication more efficient and align goals.

Postsynaptic trafficking plays a key role in regulating synapse structure and function. While spiny excitatory synapses can be stable throughout adult life, their morphology and function is impaired in Alzheimer’s disease (AD). However, little is known about how AD risk genes impact synaptic function. Here we used structured superresolution illumination microscopy (SIM) to study the late-onset Alzheimer’s disease (LOAD) risk factor BIN1, and show that this protein is abundant in postsynaptic compartments, including spines. While postsynaptic Bin1 shows colocalization with clathrin, a major endocytic protein, it also colocalizes with the small GTPases Rab11 and Arf6, components of the exocytic pathway. Bin1 participates in protein complexes with Arf6 and GluA1, and manipulations of Bin1 lead to changes in spine morphology, AMPA receptor surface expression and trafficking, and AMPA receptor-mediated synaptic transmission. Our data provide new insights into the mesoscale architecture of postsynaptic trafficking compartments and their regulation by a major LOAD risk factor.

Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAAreceptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAAreceptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAAreceptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.

SUMMARYNetwork meta-analysis (NMA) is a statistical method that allows comparison of multiple treatments against each other. The use of NMA, and its advantages and potential limitations, is discussed here in the context of this issue's Cochrane review of psychological treatments for panic disorder. The review showed benefits for psychological treatment when compared to a waiting list, particularly for cognitive behavioural therapy in both the short and longer term. The findings were limited by the primary studies available, but despite these, this analysis using NMA presents the best evidence to date of the relative benefits of different types of psychological treatments in panic disorder.DECLARATION OF INTERESTNone.

In summer and early autumn, a wildflower grows that can become a winter snowflake. You can find it in fields or along the sides of roadways. It might even be […]

The repertoire and abundance of proteins displayed on the surface of neuronal dendrites are tuned by regulated fusion of recycling endosomes (REs) with the dendritic plasma membrane. While this process is critical for neuronal function and plasticity, how synaptic activity drives RE fusion remains unexplored. We demonstrate a multistep fusion mechanism that requires Ca2+from distinct sources. NMDA receptor Ca2+initiates RE fusion with the plasma membrane, while L-type voltage-gated Ca2+channels (L-VGCCs) regulate whether fused REs collapse into the membrane or reform without transferring their cargo to the cell surface. Accordingly, NMDA receptor activation triggered AMPA-type glutamate receptor trafficking to the dendritic surface in an L-VGCC-dependent manner. Conversely, potentiating L-VGCCs enhanced AMPA receptor surface expression only when NMDA receptors were also active. Thus L-VGCCs play a role in tuning activity-triggered surface expression of key synaptic proteins by gating the mode of RE fusion.

The influence of rotation on the structure and propagation of internal tides around O'ahu, Hawai'i is investigated using in situ observations and a tidally forced, primitive equation model with realistic bathymetry and stratification. Particular attention is given to the diurnal internal tide, which largely has been de-emphasized in previous studies of the region because of the dominance of the semidiurnal internal tide but has been determined by recent studies to be a significant contributor to baroclinic variability. Though both diurnal and semidiurnal internal tides are generated primarily over Ka'ena Ridge to the northwest of the island, the diurnal internal tide propagates clockwise around the island as an imperfectly trapped wave, while the semidiurnal internal tide propagates away from the ridge, unaffected by rotation. The diurnal and semidiurnal internal tides fall into the superinertial frequency range; however, the diurnal frequency apparently is sufficiently close to inertial (~ 1.4f) for rotation to affect internal tide propagation. The in situ observations support the model finding that diurnal trapping provides the primary source of baroclinic variability along the eastern coast of the island, a stretch of coastline otherwise sheltered from the internal tide energy generated over the Hawaiian Ridge. The findings in Hawai'i suggest that coastal trapping of superinertial internal tides may be a significant source of variability and mixing in other nearshore systems around the world. Model and observations show the diurnal internal tide propagates clockwise around O'ahu as an imperfectly trapped waveThis coastal trapping has consequences for the island's nearshore variabilityImperfect trapping of superinertial internal tides may be an overlooked phenomenon at other locations worldwide

SummaryPsychotic depression is a severe condition. Drug treatment (antipsychotics, antidepressants or the combination) or electroconvulsive therapy (ECT) are both effective. However, a 2005 Cochrane review of drug treatments could not find a clear benefit for combination treatment with antidepressant and antipsychotic medication over antidepressants alone. The current updated Cochrane review (2015) incorporated two larger studies and found evidence of superiority for combination treatment. The review was constrained by the small number of available studies and could not address key questions such as the relative merits of antipsychotics and/or antidepressants compared with ECT or ketamine in acute treatment, and which treatments are best for long-term maintenance and prevention of recurrence. However, the methodology used was rigorous and the review gives the best summary to date of the evidence, as well as providing a platform for informing future research.

Digital innovations in mental health offer great potential, but present unique challenges. Using a consensus development panel approach, an expert, international, cross-disciplinary panel met to provide a framework to conceptualise digital mental health innovations, research into mechanisms and effectiveness and approaches for clinical implementation. Key questions and outputs from the group were agreed by consensus, and are presented and discussed in the text and supported by case examples in an accompanying appendix. A number of key themes emerged. (1) Digital approaches may work best across traditional diagnostic systems: we do not have effective ontologies of mental illness and transdiagnostic/symptom-based approaches may be more fruitful. (2) Approaches in clinical implementation of digital tools/interventions need to be creative and require organisational change: not only do clinicians and patients need training and education to be more confident and skilled in using digital technologies to support shared care decision-making, but traditional roles need to be extended, with clinicians working alongside digital navigators and non-clinicians who are delivering protocolised treatments. (3) Designing appropriate studies to measure the effectiveness of implementation is also key: including digital data raises unique ethical issues, and measurement of potential harms is only just beginning. (4) Accessibility and codesign are needed to ensure innovations are long lasting. (5) Standardised guidelines for reporting would ensure effective synthesis of the evidence to inform clinical implementation. COVID-19 and the transition to virtual consultations have shown us the potential for digital innovations to improve access and quality of care in mental health: now is the ideal time to act.

BackgroundWorldwide uptake of telepsychiatry accelerated during the COVID-19 pandemic.ObjectiveTo conduct an evaluation of the opinions, preferences and attitudes to telepsychiatry from service users, carers and clinicians in order to understand how telepsychiatry can be best used in the peri/post-COVID-19 era.MethodsThis mixed-methods, multicentre, international study of telepsychiatry was set in two sites in England and two in Italy. Survey questionnaires and focus group topic guides were co-produced for each participant group (service users, carers and clinicians).FindingsIn the UK, 906 service users, 117 carers and 483 clinicians, and in Italy, 164 service users, 56 carers and 72 clinicians completed the surveys. In all, 17 service users/carers and 14 clinicians participated in focus groups. Overall, telepsychiatry was seen as convenient in follow-ups with a specific purpose such as medication reviews; however, it was perceived as less effective for establishing a therapeutic relationship or for assessing acutely disturbed mental states. In contrast to clinicians, most service users and carers indicated that telepsychiatry had not improved during the COVID-19 pandemic. Most service users and carers reported that the choice of appointment modality was most often determined by the service or clinician.Conclusion and relevanceThere were circumstances in which telepsychiatry was seen as more suitable than others and clear differences in clinician, carer and service user perspectives on telepsychiatry.Clinical implicationsAll stakeholders should be actively engaged in determining a hybrid model of care according to clinical features and service user and carer preferences. Clinicians should be engaged in training programmes on telepsychiatry.

SummaryGlutamate receptor modulators, including ketamine, are possible candidates for new antidepressants with a novel mode of action. The pair of reviews discussed in this month's Round the Corner considered their use in treating unipolar major depression and bipolar depression. Promising results were seen for ketamine, but further studies are needed, in particular to investigate whether the benefits are sustained or can be extended by repeated or adjunctive treatment, whether ketamine is effective in treatment resistance, whether other modes of administration are as effective as the intravenous route and the long-term adverse effects of use.

SummaryKeeping up to date with the best evidence on treatment interventions is an essential part of clinical practice, but it can seem an overwhelming task for busy clinicians. Systematic reviews and meta-analyses provide a useful and convenient summary of knowledge and form an essential part of an evidence-based approach to clinical practice. However, these reviews vary in methodology and therefore in the quality of the recommendations they provide. Clinicians need to feel confident in their skills of critical appraisal, so that they can assess the relative merits of systematic reviews. In this article we discuss the strengths and limitations of different types of evidence synthesis to enable the reader to feel more confident in assessing the scientific information to use in clinical practice.

SummaryThe internet provides access to what is often a bewildering array of medical knowledge on mental health, some (but not all) of which is evidence based. As well as information for clinicians, there has been a dramatic increase in the variety and quality of information available for patients and carers. In this article we discuss the advantages and limitations of the types of information available, with suggested sites and strategies for assessing their relative merits.

SummarySelf-harm is a significant social and healthcare problem, with substantial morbidity and healthcare costs. It has strong links to further self-harm and to suicide. The current review is one of three that investigate interventions in preventing recurrence of self-harm, and it focuses on pharmacological treatment. The conclusions are limited by the small number and size of trials identified, and the low quality of evidence. No benefit on recurrence of self-harm was detected in three small trials of antidepressants, but the types studied are ones that are now less commonly used. A small trial of flupentixol suggested a possible benefit on repetition, but this has not been replicated. One small trial of lithium showed no benefit, but this was in contrast to a recent large meta-analysis showing a significant anti-suicidal effect of lithium when used to treat mood disorder. The review highlights important areas for further research.

IMPORTANCE: Ventilator-induced lung injury may arise from heterogeneous lung microanatomy, whereby some alveoli remain collapsed throughout the breath cycle while their more compliant or surfactant-replete neighbors become overdistended, and this is called dynamic alveolar heterogeneity. OBJECTIVE: To determine how dynamic alveolar heterogeneity is influenced by 2 modes of mechanical ventilation: low tidal-volume ventilation (LTVV) and airway pressure release ventilation (APRV), using in vivo microscopy to directly measure alveolar size distributions. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, nonblinded laboratory animal study conducted between January 2013 and December 2014, 14 rats (450-500 g in size) were randomized to a control group with uninjured lungs (n = 4) and 2 experimental groups with surfactant deactivation induced by polysorbate lavage: the LTVV group (n = 5) and the APRV group (n = 5). For all groups, a thoracotomy and in vivo microscopy were performed. Following lung injury induced by polysorbate lavage, the LTVV group was ventilated with a tidal volume of 6 mL/kg and progressively higher positive end-expiratory pressure (PEEP) (5, 10, 16, 20, and 24 cm H2O). Following lung injury induced by polysorbate lavage, the APRV group was ventilated with a progressively shorter time at low pressure, which increased the ratio of the end-expiratory flow rate (EEFR) to the peak expiratory flow rate (PEFR; from 10% to 25% to 50% to 75%). MAIN OUTCOMES AND MEASURES: Alveolar areas were quantified (using PEEP and EEFR to PEFR ratio) to determine dynamic heterogeneity. RESULTS: Following lung injury induced by polysorbate lavage, a higher PEEP (20-24 cm H2O) with LTVV resulted in alveolar occupancy (reported as percentage of total frame area) at inspiration (39.9%-42.2%) and expiration (35.9%-38.7%) similar to that in the control group (inspiration 53.3%; expiration 50.3%; P > .01). Likewise, APRV with an increased EEFR to PEFR ratio (50%-75%) resulted in alveolar occupancy at inspiration (46.7%-47.9%) and expiration (40.2%-46.6%) similar to that in the control group (P > .01). At inspiration, the distribution of the alveolar area of the control group was similar to that of the APRV group (P > .01) (but not to that of the LTVV group [P &lt; .01]). A lower PEEP (5-10 cm H2O) and a decreased EEFR to PEFR ratio (≤50%) demonstrated dynamic heterogeneity between inspiration and expiration (P &lt; .01 for both) with a greater percentage of large alveoli at expiration. Dynamic alveolar homogeneity between inspiration and expiration occurred with higher PEEP (16-24 cm H2O) (P > .01) and an increased EEFR to PEFR ratio (75%) (P > .01). CONCLUSIONS AND RELEVANCE: Increasing PEEP during LTVV increased alveolar recruitment and dynamic homogeneity but had a significantly different alveolar size distribution compared with the control group. By comparison, reducing the time at low pressure (EEFR to PEFR ratio of 75%) in the APRV group provided dynamic homogeneity and a closer approximation of the dynamics observed in the control group.

SummaryAnxiety disorders are common, often have a chronic course and frequently coexist with other psychiatric disorders. Psychological therapy is recommended as first-line treatment, but equitable access remains a challenge. This month's Cochrane Corner review assesses the evidence for the efficacy of therapist-supported cognitive-behavioural therapy (CBT) for anxiety disorders delivered via the internet. Although internet delivery of therapy is attractive for many reasons, and the results of this preliminary review suggest that it is efficacious, this is a rapidly expanding field. Further updates of this review will include more evidence to support or refute the use of this new method of treatment delivery, either alongside or in preference to standard face-to-face CBT.

Effective inhibitory synaptic transmission requires efficient stabilization of GABAAreceptors (GABAARs) at synapses, which is essential for maintaining the correct excitatory-inhibitory balance in the brain. However, the signaling mechanisms that locally regulate synaptic GABAAR membrane dynamics remain poorly understood. Using a combination of molecular, imaging, and electrophysiological approaches, we delineate a GIT1/βPIX/Rac1/PAK signaling pathway that modulates F-actin and is important for maintaining surface GABAAR levels, inhibitory synapse integrity, and synapse strength. We show that GIT1 and βPIX are required for synaptic GABAAR surface stability through the activity of the GTPase Rac1 and downstream effector PAK. Manipulating this pathway using RNAi, dominant-negative and pharmacological approaches leads to a disruption of GABAAR clustering and decrease in the strength of synaptic inhibition. Thus, the GIT1/βPIX/Rac1/PAK pathway plays a crucial role in regulating GABAAR synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain.

IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714

A biography of American painter and illustrator Ellen Bernard Thompson-Pyle is presented. She was born on November 11, 1876 and pursued her art education at Drexel Institute in Philadelphia, Pennsylvania. During her time at Drexel, she had created drawings and paintings for the whole institute including "Five O'Clock," "The Knife Grinder" and "The Immigrants." Ellen was married to Walter Pyle and had a stepson, Gerald, from the past wife of Walter. Ellen died at Westbrae on August 1, 1936, when she was 60 years old.

Bovine respiratory disease (BRD) is common in cattle youngstock on UK dairy farms. The current diagnostic methods lack sensitivity and specificity. Thoracic ultrasound (TUS) is a relatively new BRD diagnostic tool with increased accuracy. Data were collected from TUS examinations of 347 calves on Scottish dairy farms and compared to farmer BRD treatment rates. A calf health scoring tool was used to collect information on youngstock health and management on these farms. Of 347 ultrasonographic examinations, 53 (15.3%) were classified as abnormal and 294 (84.7%) as normal. Of the 53 calves classified as abnormal, only 13 (24.5%) were treated by the farmer; however, of the 294 classified as normal, 22 (7.5%) were treated. The results indicated farmers were misdiagnosing BRD in youngstock. Use of TUS on UK farms may improve diagnostic rates and accuracy, reduce the unnecessary use of antimicrobials and demonstrate the value of preventive healthcare programmes.

GABAergic synaptic inhibition controls neuronal firing, excitability, and synaptic plasticity to regulate neuronal circuits. Following an acute excitotoxic insult, inhibitory synapses are eliminated, reducing synaptic inhibition, elevating circuit excitability, and contributing to the pathophysiology of brain injuries. However, mechanisms that drive inhibitory synapse disassembly and elimination are undefined. We find that inhibitory synapses are disassembled in a sequential manner following excitotoxicity: GABAARs undergo rapid nanoscale rearrangement and are dispersed from the synapse along with presynaptic active zone components, followed by the gradual removal of the gephyrin scaffold, prior to complete elimination of the presynaptic terminal. GABAAR nanoscale reorganization and synaptic declustering depends on calcineurin signaling, whereas disassembly of gephyrin relies on calpain activation, and blockade of both enzymes preserves inhibitory synapses after excitotoxic insult. Thus, inhibitory synapse disassembly occurs rapidly, with nanoscale precision, in a stepwise manner and most likely represents a critical step in the progression of hyperexcitability following excitotoxicity.

SummaryDrug treatments are commonly used for sleep disturbance in Alzheimer's disease, although none have a specific licence for this indication. This month's Cochrane review assessed the available evidence of benefit or harm in the use of these medications. The review identified two studies of melatonin, which did not show significant improvement in sleep over placebo. One study of trazodone suggested a beneficial effect on sleep, but its small sample size limits the generalisability of the results. Larger studies are needed, with careful assessment of the evidence for possible improvements in sleep but also of important side-effects such as falls and increased confusion.

SummaryIndividuals with severe mental illness have increased rates of physical health problems and reduced life expectancy. As a vulnerable population, they have been identified as needing increased physical health monitoring and treatment. The first of two Cochrane reviews considered here assessed the evidence for the benefit of monitoring but found no studies that could be included. The second reviewed the evidence for provision of general physical healthcare advice. Although the results were suggestive of benefit, the evidence, where available, was of poor quality. These reviews highlight an important area for future research to evaluate the relative health and cost benefits of different types of intervention.

1We have investigated the physiological and structural changes that occur in skeletal muscle vasculature during acclimation to chronic hypoxia in rats exposed to 12% O2in a hypoxic chamber for 7 or 18 days (7CH and 18CH rats, respectively) and in age‐matched normoxic (7N and 18N) rats.2Under anaesthesia and breathing 12% O2, 7CH and 18CH rats had lower arterial blood pressure (ABP) than 7N and 18N rats breathing air, but the haematocrit of the CH rats was increased so that their arterial O2content equalled that of N rats. Blood flow recorded from the iliac or femoral artery and used to compute muscle vascular conductance (MVC: blood flow/ABP) showed that, in 18CH rats, MVC was comparable with that of 18N rats.3Maximal MVC induced by infusion of sodium nitroprusside (SNP) was used as an index of structural vascular conductance and compared with the MVC evoked by acute hypoxia (breathing 8% O2). Hypoxia induced similar increases in MVC in 7N and 7CH rats and in 18N and 18CH rats, even though N rats were switched from air to 8% O2and CH rats were switched from 12 to 8% O2. The MVCs attained with 8% O2and SNP were similar in 7N and 18N rats. However, the MVCs attained with 8% O2in 7CH and 18CH rats were only ≈60% of those evoked by SNP, while the MVC attained with SNP was greater in 18CH than in 18N rats.4Vascular casts of the spinotrapezius muscle analysed ex vivoshowed that interbranch intervals along primary, secondary and terminal arterioles (22–50, 13–18 and 7–13 μm diameter, respectively) were 30–50% shorter in 7CH and 18CH rats than in 7N and 18N rats. Further, the proportions of branches that were of the secondary and terminal arteriolar categories were increased such that the mean diameter of the branches was lower in 7CH than in 7N rats and lower in 18CH than in 18N rats.5These results indicate that arteriolar remodelling and angiogenesis occurs in skeletal muscle during acclimation to chronic hypoxia, beginning by the 7th day and progressing at least until the 18th day, so that the number of small arterioles and the functional size of the vascular bed is increased. We propose that these structural and functional changes enhance the ability of skeletal muscle to respond to acute hypoxia by facilitating the increase in vascular conductance, blood flow and thereby the O2that can be delivered to muscle.

Ninety-three rapid atrial pacing studies were performed in 38 children to compare preoperative and early postoperative function of the sinus and atrioventricular (AV) nodes. The interval between the preoperative and postoperative studies was under 6 months in the majority of patients. Postoperative studies were performed within 48 hours of operation and between 4 and 8 days after operation. Sinus nodal function as measured by sinus nodal recovery time (SNRT) was an unreliable index in determining depression since the number who improved postoperatively (10/55) was nearly equal to the number that worsened (12/55). The majority who had abnormal function postoperatively demonstrated a junctional rather than sinus recovery focus. This finding appears a more definitive and more reproducible indicator of sinus node depression in the postoperative patient. Postoperative AV nodal function was decreased (as measured by the cycle length [CL] at which Wenckebach periodicity occurred) in 15 of 55 studies (27%) of the entire group. There was nearly an equal chance for improvement (24%) in function. This also applied to those patients who had sequential studies. Therefore, this method of assessment for AV nodal function was unreliable, or else the operation did not affect the node significantly. The latter is unlikely in view of late postoperative data. The greatest utility of this test was to determine the capability for AV conduction in certain patients with slow escape rhythms in the absence of surface P waves, and to differentiate complete heart block from AV dissociation when atrial activity was absent. Despite the variability of effects on the sinus and AV nodes in these patients, those who demonstrated depression had a significantly higher incidence of dysrhythmias (80% of patients with sinus nodal depression and 100% of patients with AV nodal depression).

In response to the need for more systematic descriptions of clinical impressions of effeminate boys, particularly at this time of changing social sex-role stereo types, extensive clinical ratings were made on a series of 29 boys, aged 5–13, and their families who had been referred to a project dealing with gender disturbance. Principal component analysis of these ratings indicated 4 orthogonal factors: Factor I, specific effeminate behaviors; Factor II, normalcy of family environment and childhood adjustment; Factor III, family overprotectiveness and associated fearfulness in the child; and Factor IV, social unresponsiveness and aversiveness in the children. Independently of the data analysis, subgroups were formed and t tests between the groups were computed for factor scores. Children judged as noneffeminate or midly effeminate were less effeminate (p<.001), came from more stereo typically normal families (p<.05), and tended to be less overprotected (p<.10) than highly effeminate children. Effeminate children between ages 5 and 7 tended to be more effeminate (p<. 10) and less overprotected (p< 10) than effeminate children between ages 8 and 10. These results are discussed in terms of their implications for clinical assessment of extreme effeminacy, their relationship to previous findings, and their contribution to understanding the meaning of clinical referral for problems of effeminacy.

Ethical decision-making is inherent in nursing practice. Although a definite portion of the nursing literature is devoted to ethics and ethical decision-making, the profession is just beginning to ground its ethics research in the actual experience of nurses. Therefore, the purpose of this phenomenological study was to examine the experience of staff nurses as they engage in ethical decision-making. Interview data were collected from 19 staff nurses in a large, midwestern American metropolitan hospital. Interviews were subse quently transcribed and Giorgi's method of data analysis applied. The emerging descrip tion revealed four common aspects of ethical decision-making among staff nurses: context, trigger, ethical decision-making process (i.e. deliberation and integration), and outcomes. This description provides a foundation for future research regarding a descrip tive theory of ethical decision-making in nursing.

Adult cats with normal renal function were fed a nutritionally balanced, vitamin A-replete, experimental dry diet with or without ammonium chloride (NH4Cl) for 6 mo to study the effects of chronic dietary acidification on acid-base parameters and the metabolism of selected minerals. Dietary balance studies were performed monthly. Blood and urine samples were collected monthly to evaluate acid-base parameters, plasma parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol levels. Ammonium chloride-treated cats had significantly lower blood and urinary pH, and lower blood bicarbonate concentrations. Treated cats also had higher blood ionized calcium concentrations, hypercalciuria and lower intestinal calcium absorption relative to baseline (prior to feeding the experimental diet) and to control cats. This resulted in the development of lower calcium balance in the first several months. PTH levels were unaffected by dietary acidification; however, 1,25-dihydroxycholecalciferol levels were significantly decreased in treated cats. Treated cats had negative potassium balance during 5 mo of dietary acidification. Magnesium, sodium, and phosphorus balances were lower, but positive, in treated cats compared to control cats. Cats consuming the NH4Cl-supplemented diet had increased chloride balance. Thus, chronic dietary acidification with 1.5% NH4Cl produced chronic metabolic acidosis and lower, or negative, calcium and potassium balance.

Effects of dietary potassium restriction, with or without dietary acidification, on acid-base balance, mineral metabolism and renal function were evaluated in 12 adult cats. Six cats were fed a potassium-restricted diet (0.2% potassium) for 8 wk, and six cats were fed the same potassium-restricted diet plus a dietary acidifier (0.8% NH4Cl) for 8 wk. Both groups of cats were then fed the same diet supplemented with potassium gluconate (0.7% dietary potassium) for an additional 4 wk. Renal function was evaluated before treatment and again at 8 and 12 wk. Serum potassium concentration declined in all cats by wk 1 and was also lower in NH4Cl-treated cats at 2, 3, 6 and 8 wk than in control cats. Metabolic acidosis developed in both groups of cats. Dietary balance studies indicated negative potassium balance in NH4Cl-treated cats. Glomerular filtration rate declined significantly in NH4Cl-treated cats after 8 wk but was unchanged in control cats. From the results of this study, we conclude that adding a dietary acidifier to a potassium-restricted diet worsens hypokalemia, possibly by affecting gastrointestinal potassium handling, and induces severe metabolic acidosis and renal dysfunction in adult cats.

This brief report concerns 3 cases of progressive febrile anemia, 2 ending fatally, which were characterized by the presence within the red cells of unidentified coccoid and bacillary bodies. These were stained dark blue or bluish purple with Wright or Giemsa stains (Fig. 1). From one to 20 or more bodies were present in a single cell, and from 10 to 55% of the cells were affected. They were somewhat pleomorphic, but frequently appeared in the form of diploids, tetrads, or short batonnets, straight or slightly curved. The presence of the structures was often associated with a de-hemoglobinization of the cells; in such cases, they were clustered at the margin.In unstained preparations, the bodies were colorless, very slightly refractile and possessed of an oscillatory motion within the cell. Treated with HCl and potassium ferrocyanide, they gave a positive iron reaction; the iron staining persisted in acid solutions, but disappeared after exposure to alkali at about pH 10. The morphology of the bodies was not altered by these procedures. They were not blackened by (NH4)2S, as is hemosiderin, nor by silver nitrate; they gave no histochemical reaction for alkaline phosphatase; the Feulgen reaction was also negative. They were resistant to autolysis, and to tryptic digestion.By laking the blood with distilled water or saponin, it was possible to obtain a very great concentration of the bodies in the centrifuged sediment (Fig. 2). When a suspension of intact red cells containing the bodies was placed in a strong electro-magnetic field, the cells with the inclusions were drawn in a linear streak along the sharp edge of the magnet.In Giemsa stained sections of the spleen, in all 3 cases, minute blue-staining bodies were present within the endothelial cells lining the sinuses. They were found also in reticuloendothelial cells of lymph-nodes and bone marrow, and in Kuppfer cells, in the 2 fatal cases.

The poem "She Shops for New Clothes" by Katharine Smith is presented. First Line: She gages the thread count of cotton; Last Line: under the sparking wheels.

The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines.

Molecular mechanisms underlying plasticity at brain inhibitory synapses remain poorly characterized. Increased postsynaptic clustering of GABAAreceptors (GABAARs) rapidly strengthens inhibition during inhibitory long-term potentiation (iLTP). However, it is unclear how synaptic GABAAR clustering is maintained to sustain iLTP. Here, we identify a role for miR376c in regulating the translation of mRNAs encoding the synaptic α1 and γ2 GABAAR subunits, GABRA1and GABRG2, respectively. Following iLTP induction, transcriptional repression of miR376c is induced through a calcineurin-NFAT-HDAC signaling pathway and promotes increased translation and clustering of synaptic GABAARs. This pathway is essential for the long-term expression of iLTP and is blocked by miR376c overexpression, specifically impairing inhibitory synaptic strength. Finally, we show that local de novosynthesis of synaptic GABAARs occurs exclusively in dendrites and in a miR376c-dependent manner following iLTP. Together, this work describes a local post-transcriptional mechanism that regulates inhibitory synaptic plasticity via miRNA control of dendritic protein synthesis.

Population ageing poses considerable challenges to the provision of quality end-of-life care. The population of the United States is increasingly diverse, making it imperative to design culturally sensitive end-of-life care interventions. We examined participants of the Health and Retirement Study, who died between 2002 and 2014, to examine racial and ethnic differences in end-of-life care utilization and end-of-life planning in the United States. Our study reveals significant disparities in end-of-life care and planning among studied groups. Findings reveal that racial and ethnic minorities are more likely to die in hospital and less likely to engage in end-of-life planning activities. The observed disparities are still significant but have been narrowing between 2002 and 2014. Efforts to reduce these differences should target both medical professionals and diverse communities to ensure that improved models of care acknowledge heterogeneous values and needs of a culturally diverse US population.

Inhibitory synapses mediate the majority of synaptic inhibition in the brain, thereby controlling neuronal excitability, firing, and plasticity. Although essential for neuronal function, the central question of how these synapses are organized at the subsynaptic level remains unanswered. Here, we use three-dimensional (3D) super-resolution microscopy to image key components of the inhibitory postsynaptic domain and presynaptic terminal, revealing that inhibitory synapses are organized into nanoscale subsynaptic domains (SSDs) of the gephyrin scaffold, GABAARs and the active-zone protein Rab3-interacting molecule (RIM). Gephyrin SSDs cluster GABAAR SSDs, demonstrating nanoscale architectural interdependence between scaffold and receptor. GABAAR SSDs strongly associate with active-zone RIM SSDs, indicating an important role for GABAAR nanoscale organization near sites of GABA release. Finally, we find that in response to elevated activity, synapse growth is mediated by an increase in the number of postsynaptic SSDs, suggesting a modular mechanism for increasing inhibitory synaptic strength.