Alkene Isomerization Using a Heterogeneous Nickel-Hydride Catalyst.

Transition metal-catalyzed alkene isomerization is an enabling technology used to install an alkene distal to its original site. Due to their well-defined structure, homogeneous catalysts can be fine-tuned to optimize reactivity, stereoselectivity, and positional selectivity, but they often suffer from instability and nonrecyclability. Heterogeneous catalysts are generally highly robust but continue to lack active-site specificity and are challenging to rationally improve through structural modification. Known single-site heterogeneous catalysts for alkene isomerization utilize precious metals and bespoke, expensive, and synthetically intense supports. Additionally, they generally have mediocre reactivity, inspiring us to develop a heterogeneous catalyst with an active site made from readily available compounds made of Earth-abundant elements. Previous work demonstrated that a very active homogeneous catalyst is formed upon protonation of Ni[P(OEt)3]4 by H2SO4, generating a [Ni-H]+ active site. This catalyst is incredibly active, but also decomposes readily, which severely limits its utility. Herein we show that by using a solid acid (sulfated zirconia, SZO300), not only is this decomposition prevented, but high activity is maintained, improved selectivity is achieved, and a broader scope of functional groups is tolerated. Preliminary mechanistic experiments suggest that the catalytic reaction likely goes through an intermolecular, two-electron pathway. A detailed kinetic study comparing the state-of-the-art Ni and Pd isomerization catalysts reveals that the highest activity and selectivity is seen with the Ni/SZO300 system. The reactivity of Ni/SZO300, is not limited to alkene isomerization; it is also a competent catalyst for hydroalkenylation, hydroboration, and hydrosilylation, demonstrating the broad application of this heterogeneous catalyst.

Vessel wall imaging in the diagnosis of antiphospholipid syndrome presenting as Moyamoya syndrome-A case report.

Objectives: We describe a case of anti-phospholipid syndrome (APLS) vasculopathy presenting with Moyamoya syndrome (MMS) and show the associated intracranial vessel wall MRI (VWI) findings. Methods: A 37-year-old-woman presented with acute onset dizziness and left-sided weakness. Neurologic exam revealed a left facial droop and left hemiparesis. She underwent a comprehensive laboratory work-up for stroke. Neuroimaging included a CT head, CT angiogram, VWI, and digital subtraction angiography. Results: Work-up revealed a triple-positive APLS antibody profile. CT of the head showed an acute right basal ganglia infarction and right frontal subarachnoid hemorrhage. CT angiogram revealed severe stenosis of the right internal carotid artery terminus in a Moyamoya pattern. Intracranial VWI showed long-segment concentric vessel wall thickening and homogeneous vessel wall enhancement and T2-hyperintense wall edema of the stenotic right ICA terminus, M1 middle cerebral artery, and A1 anterior cerebral artery. She was treated with long-term anticoagulation with warfarin and a right superficial temporal artery to middle cerebral artery bypass. Discussion: We present intracranial VWI features of vessel wall pathology in a patient with primary APLS presenting with MMS.

First Contact Physiotherapy: An evaluation of clinical effectiveness and costs.

BACKGROUND: First Contact Physiotherapy Practitioners (FCPPs) are embedded within general practice, providing expert assessment, diagnosis and management plans for patients with musculoskeletal disorders (MSKDs), without the prior need for GP consultation. AIM: To determine the clinical effectiveness and costs of FCPP-led compared to GP-led models of care. DESIGN AND SETTING: Multiple site case study design. UK GP practices. METHOD: General Practice sites were recruited representing three models: 1. GP-led care; 2. FCPPs who could not prescribe/inject (Standard (St)); 3. FCPPs who could prescribe/inject (Additional Qualifications (AQ)). Patient participants from each site completed clinical outcome data at baseline, 3 and 6 months. The primary outcome was the SF-36v.2 Physical Component Score (PCS). Healthcare usage was collected for 6 months. RESULTS: N=426 adults were recruited from 46 practices across the UK. Non-inferiority analysis showed no significant difference in physical function (SF36-PCS) across all three arms at 6 months (p=0.999). At 3 months a significant difference in numbers improving was seen between arms: 54.7% GP consultees; 72.4% FCPP-St, 66.4% FCPP-AQ; (p=0.037). No safety issues were identified. Following initial consultation, a greater proportion of patients received medication (including opioids) in the GP-led arm (44.7%) compared with FCPP-St (17.5%) and FCPP-AQ (22.8%); (p<0.001). NHS costs (initial consultation and over 6 months follow up) were significantly higher in the GP-led model (median £105.50) vs FCPP-St (£41) and FCPP-AQ (£44); (p<0.001). CONCLUSION: FCPP led models provide safe, clinically effective and cost-beneficial management for patients with MSKDs in general practice and reduced opioid use in this cohort.

The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gß5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.

Cognitive and Emotional Responses to Chronic Obstructive Pulmonary Disease Exacerbations and Patterns of Care Seeking.

Rationale: Cognitive and emotional responses associated with care seeking for chronic obstructive pulmonary disease (COPD) exacerbations are not well understood.Objectives: We sought to define care-seeking profiles based on whether and when U.S. veterans seek care for COPD exacerbations and compare cognitive and emotional responses with exacerbation symptoms across the profiles.Methods: This study analyzes data from a 1-year prospective observational cohort study of individuals with COPD. Cognitive and emotional responses to worsening symptoms were measured with the Response to Symptoms Questionnaire, adapted for COPD. Seeking care was defined as contacting or visiting a healthcare provider or going to the emergency department. Participants were categorized into four care-seeking profiles based on the greatest delay in care seeking for exacerbations when care was sought: 0-3 days (early), 4-7 days (short delay), >7 days (long delay), or never sought care for any exacerbation. The proportion of exacerbations for which participants reported cognitive and emotional responses was estimated for each care-seeking profile, stratified by the timing of when care was sought.Results: There were 1,052 exacerbations among 350 participants with Response to Symptoms Questionnaire responses. Participants were predominantly male (96%), and the mean age was 69.3 ± 7.2 years. For the 409 (39%) exacerbations for which care was sought, the median delay was 3 days. Those who sought care had significantly more severe COPD (forced expiratory volume in 1 s, modified Medical Research Council dyspnea scale) than those who never sought care. Regardless of the degree of delay until seeking care at one exacerbation, participants consistently reported experiencing serious symptoms if they sought care compared with events for which participants did not seek care (e.g., among early care seekers when care was sought, 36%; when care was not sought, 25%). Similar findings were seen in participants' assessment of the importance of getting care (e.g., among early care seekers when care was sought, 90%; when care was not sought, 52%) and their assessment of anxiety about the symptoms (e.g., among early care seekers when care was sought, 33%; when care was not sought, 17%).Conclusions: Delaying or not seeking care for COPD exacerbations was common. Regardless of care-seeking profile, cognitive and emotional responses to symptoms when care was sought differed from responses when care was not sought. Emotional and cognitive response to COPD exacerbations should be considered when developing individualized strategies to encourage seeking care for exacerbations.Clinical trial registered with www.clinicaltrials.gov (NCT02725294).

Gender differences in prosthesis-related outcomes among veterans: Results of a national survey of U.S. veterans.

BACKGROUND: Women with lower extremity amputations (LEAs) tend to have poorer prosthesis-related outcomes than men, although the literature is sparse. To our knowledge, there are no prior studies examining prosthesis-related outcomes of women veterans with LEAs. OBJECTIVE: To examine gender differences (overall and by type of amputation) among veterans who underwent LEAs between 2005 and 2018, received care at the Veterans Health Administration (VHA) prior to undergoing amputation, and were prescribed a prosthesis. It was hypothesized that compared to men, women would report lower satisfaction with prosthetic services, poorer prosthesis fit, lower prosthesis satisfaction, less prosthesis use, and worse self-reported mobility. Furthermore, it was hypothesized that gender differences in outcomes would be more pronounced among individuals with transfemoral than among those with transtibial amputations. DESIGN: Cross-sectional survey. Linear regressions were used to assess overall gender differences in outcomes and gender differences based on type of amputation in a national sample of veterans. SETTING: VHA medical centers. PARTICIPANTS: The sample consisted of 449 veterans who self-identified their gender (women = 165, men = 284) with transtibial (n = 236), transfemoral (n = 135), and bilateral LEAs (n = 68) including all amputation etiologies. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Orthotics and Prosthetics User's Survey, Trinity Amputation and Prosthesis Experiences Scale, and Prosthetic Limb Users Survey of Mobility-Short Form were used to assess satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, prosthesis use, and self-reported mobility. RESULTS: Women had poorer self-reported mobility than men (d = -0.26, 95% confidence interval -0.49 to -0.02, p < .05); this difference was small. There were no statistically significant gender differences in satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, daily hours of prosthesis use, or by amputation type. CONCLUSIONS: Contrary to the hypothesis, prosthesis-related outcomes were similar between men and women with LEAs. Minimal differences may in part be due to receiving care from the VHA's integrated Amputation System of Care.

Outcomes of newly referred patients with suspected angle closure: do we need to redefine the clinical pathways?

BACKGROUND/OBJECTIVES: To investigate outcomes of referrals for suspected angle closure and explore whether anterior segment optical coherence tomography (AS-OCT) can be used to tighten triaging criteria in a glaucoma virtual clinic. SUBJECTS/METHODS: Retrospectively collected data. The first audit (04/2018-03/2019) identified referrals for suspected angle closure without other glaucoma-related findings (primary angle closure suspect (PACS) referrals). All patients underwent gonioscopy. The second audit (04-08/2019) identified patients with suspected angle closure in a virtual clinic. Management outcomes were assessed, using gonioscopy as reference standard. The outcomes of the second audit were re-audited after changing the triaging criterion from angle width <10° to iridotrabecular contact (ITC) in ≥1 quadrants on AS-OCT. RESULTS: Out of 1754 glaucoma referrals (first audit), 24.6% (431/1754) were PACS referrals. Of these, only 10.7% (42/393) had an occludable angle on gonioscopy, with 97.6% (41/42) being PACS. Of these, 78% (32/41) underwent laser peripheral iridotomy. Out of 137 referrals in the virtual clinic (second audit), 66.4% (91/137) were triaged to the face-to-face clinic. Of these, 31.9% (29/91) were discharged. AS-OCT had positive and negative predictive value of 74.3% (95% confidence intervals (CI) 57.8-86.0) and 82.1% (95% CI 70.0-90.2%), respectively, in detecting ITC in ≥1 quadrants. In the re-audit 45.9% (45/98) of those with suspected angle closure were triaged for gonioscopy, with 24.4% (11/45) of them being discharged. CONCLUSION: PACS referrals represent a substantial burden to hospital-based services and their accuracy is low. ITC in ≥1 quadrants on AS-OCT can be useful in triaging those who need further evaluation with gonioscopy.

Plasma von Willebrand Factor Is Elevated Hyperacutely After Mild Traumatic Brain Injury.

Each year in the United States, ∼2.7 million persons seek medical attention for traumatic brain injury (TBI), of which ∼85% are characterized as being mild brain injuries. Many different cell types in the brain are affected in these heterogeneous injuries, including neurons, glia, and the brain vasculature. Efforts to identify biomarkers that reflect the injury of these different cell types have been a focus of ongoing investigation. We hypothesized that von Willebrand factor (vWF) is a sensitive biomarker for acute traumatic vascular injury and correlates with symptom severity post-TBI. To address this, blood was collected from professional boxing athletes (n = 17) before and within 30 min after competition. Plasma levels of vWF and neuron-specific enolase were measured using the Meso Scale Discovery, LLC. (MSD) electrochemiluminescence array-based multi-plex format (MSD, Gaithersburg, MD). Additional symptom and outcome data from boxers and patients, such as the Rivermead symptom scores (Rivermead Post Concussion Symptoms Questionnaire [RPQ-3]), were collected. We found that, subsequent to boxing bouts, there was a 1.8-fold increase in vWF levels within 30 min of injury (p < 0.0009). Moreover, fold-change in vWF correlates moderately (r = 0.51; p = 0.03) with the number of head blows. We also found a positive correlation (r = 0.69; p = 0.002) between fold-change in vWF and self-reported post-concussive symptoms, measured by the RPQ-3. The receiver operating curve analysis of vWF plasma levels and RPQ-3 scoring yielded a sensitivity of 94.12% and a specificity of 76.5% with an area under the curve of 83% for boxers after a fight compared to the pre-bout baseline. This study suggests that vWF is a potential blood biomarker measurable in the hyperacute period after blunt mild TBI. This biomarker may prove to be useful in diagnosing and monitoring traumatic vascular injury.

Delaminated Patellar Tendon Rupture in a Pediatric Patient: A Case Report.

CASE: We present a 12-year-old boy with partial delamination of the patellar tendon in the coronal plane and bipolar avulsion fracture of the tibial tubercle and patella after a planting injury while skateboarding. Pediatric patellar tendon rupture with associated bipolar avulsion fractures is rare. Furthermore, to the best of our knowledge, a delamination injury pattern of the patellar tendon has not been described. CONCLUSION: This type of extensor mechanism injury has not been reported in the literature. Repair with Krackow sutures and suture-bone tunnel technique, with consideration of the proximal tibial physis, is a safe and effective way to fix this unique pathology.

Treatment of intestinal and liver features in cystic fibrosis mice by the osmotic laxative polyethylene glycol.

BACKGROUND: Cystic Fibrosis (CF) is a genetic disease affecting multiple organs, primarily the lungs and digestive system. Improved pulmonary management significantly improved life expectancy of CF patients. As a result, extrapulmonary manifestations, including gastrointestinal and liver-related symptoms, have become more relevant. We previously reported that the osmotic laxative polyethylene glycol (PEG), which hydrates the CF gut, decreased fecal bile acid loss in a CF knockout mouse model. In the current study we investigated the effect of PEG on intestinal fat and cholesterol absorption and on CF-related liver features in a CF mouse model with the most common CF-causing mutation. METHODS: CftrΔF508/ΔF508 (n=13) and wild-type (WT) (n=12) mice were treated with PEG for 2 weeks. The intestinal and hepatic effects of PEG were assessed by analysis of intestinal bile acid, cholesterol, and fat fluxes, transcriptome analysis as well as histology. RESULTS: PEG improved intestinal malabsorption of bile acids, fat, and cholesterol in CftrΔF508/ΔF508 mice. Transcriptome analysis showed that PEG partially restored the intestinal signaling of nuclear receptors RXR, FXR, and CAR/PXR, which are involved in bile acid and xenobiotic metabolism. PEG also reduced liver inflammation in CF mice as assessed by transcriptome and histological analyses. CONCLUSIONS: PEG, a non-absorbable osmotic laxative, improved intestinal nutrient absorption, intestinal bile acid and xenobiotic signaling, as well as CF-related liver features. These findings highlight the potential for osmotic laxation to improve gastrointestinal complications of CF in humans.

Screening for Hypertensive Disorders of Pregnancy: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Hypertensive disorders of pregnancy are a leading cause of pregnancy-related morbidity and mortality in the US. Objective: To conduct a targeted systematic review to update the evidence on the effectiveness of screening for hypertensive disorders of pregnancy to inform the US Preventive Services Task Force. Data Sources: MEDLINE and the Cochrane Central Register of Controlled Trials for relevant studies published between January 1, 2014, and January 4, 2022; surveillance through February 21, 2023. Study Selection: English-language comparative effectiveness studies comparing screening strategies in pregnant or postpartum individuals. Data Extraction and Synthesis: Two reviewers independently appraised articles and extracted relevant data from fair-or good-quality studies; no quantitative synthesis was conducted. Main outcomes and measures: Morbidity or mortality, measures of health-related quality of life. Results: The review included 6 fair-quality studies (5 trials and 1 nonrandomized study; N = 10 165) comparing changes in prenatal screening practices with usual care, which was routine screening at in-person office visits. No studies addressed screening for new-onset hypertensive disorders of pregnancy in the postpartum period. One trial (n = 2521) evaluated home blood pressure measurement as a supplement to usual care; 3 trials (total n = 5203) evaluated reduced prenatal visit schedules. One study (n = 2441) evaluated proteinuria screening conducted only for specific clinical indications, compared with a historical control group that received routine proteinuria screening. One additional trial (n = 80) only addressed the comparative harms of home blood pressure measurement. The studies did not report statistically significant differences in maternal and infant complications with alternate strategies compared with usual care; however, estimates were imprecise for serious, rare health outcomes. Home blood pressure measurement added to prenatal care visits was not associated with earlier diagnosis of a hypertensive disorder of pregnancy (104.3 vs 106.2 days), and incidence was not different between groups in 3 trials of reduced prenatal visit schedules. No harms of the different screening strategies were identified. Conclusions and Relevance: This review did not identify evidence that any alternative screening strategies for hypertensive disorders of pregnancy were more effective than routine blood pressure measurement at in-person prenatal visits. Morbidity and mortality from hypertensive disorders of pregnancy can be prevented, yet American Indian/Alaska Native persons and Black persons experience inequitable rates of adverse outcomes. Further research is needed to identify screening approaches that may lead to improved disease detection and health outcomes.

Applications of near-infrared spectroscopy in neurocritical care.

Significance: Acute brain injuries are commonly encountered in the intensive care unit. Alterations in cerebrovascular physiology triggered by the initial insult can lead to neurological worsening, further brain injury, and poor outcomes. Robust methods for assessing cerebrovascular physiology continuously at the bedside are limited. Aim: In this review, we aim to assess the potential of near-infrared spectroscopy (NIRS) as a bedside tool to monitor cerebrovascular physiology in critically ill patients with acute brain injury as well as those who are at high risk for developing brain injury. Approach: We first review basic principles of cerebral blood flow regulation and how these are altered after brain injury. We then discuss the potential role for NIRS in different acute brain injuries. We pay specific attention to the potential for NIRS to (1) identify new brain injuries and clinical worsening, (2) non-invasively measure intracranial pressure (ICP) and cerebral autoregulation, and (3) identify optimal blood pressure (BP) targets that may improve patient outcomes. Results: A growing body of work supports the use of NIRS in the care of brain injured patients. NIRS is routinely used during cardiac surgeries to identify acute neurologic events, and there is some evidence that treatment algorithms using cerebral oximetry may result in improved outcomes. In acute brain injury, NIRS can be used to measure autoregulation to identify an "optimum" BP where autoregulation status is best preserved. Finally, NIRS has been utilized to identify oximetry thresholds that correlate with poor outcome as well as identify new focal intracranial hemorrhages. Conclusions: NIRS is emerging as a tool that can non-invasively measure brain function in critically ill patients. Future work will be aimed at technical refinements to improve diagnostic accuracy, as well as larger scale clinical trials that can establish a definitive impact on patient outcomes.

Anxiety Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Anxiety is commonly seen in primary care and associated with substantial burden. Objective: To review the benefits and harms of screening and treatment for anxiety and the accuracy of instruments to detect anxiety among primary care patients. Data Sources: MEDLINE, PsychINFO, Cochrane library through September 7, 2022; references of existing reviews; ongoing surveillance for relevant literature through November 25, 2022. Study Selection: English-language original studies and systematic reviews of screening or treatment compared with control conditions and test accuracy studies of a priori-selected screening instruments were included. Two investigators independently reviewed abstracts and full-text articles for inclusion. Two investigators independently rated study quality. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Meta-analysis results were included from existing systematic reviews where available; meta-analyses were conducted on original research when evidence was sufficient. Main Outcomes and Measures: Anxiety and depression outcomes; global quality of life and functioning; sensitivity and specificity of screening tools. Results: Of the 59 publications included, 40 were original studies (N = 275 489) and 19 were systematic reviews (including ≈483 studies [N≈81 507]). Two screening studies found no benefit for screening for anxiety. Among test accuracy studies, only the Generalized Anxiety Disorder (GAD) GAD-2 and GAD-7 screening instruments were evaluated by more than 1 study. Both screening instruments had adequate accuracy for detecting generalized anxiety disorder (eg, across 3 studies the GAD-7 at a cutoff of 10 had a pooled sensitivity of 0.79 [95% CI, 0.69 to 0.94] and specificity of 0.89 [95% CI, 0.83 to 0.94]). Evidence was limited for other instruments and other anxiety disorders. A large body of evidence supported the benefit of treatment for anxiety. For example, psychological interventions were associated with a small pooled standardized mean difference of -0.41 in anxiety symptom severity in primary care patients with anxiety (95% CI, -0.58 to -0.23]; 10 RCTs [n = 2075]; I2 = 40.2%); larger effects were found in general adult populations. Conclusions and Relevance: Evidence was insufficient to draw conclusions about the benefits or harms of anxiety screening programs. However, clear evidence exists that treatment for anxiety is beneficial, and more limited evidence indicates that some anxiety screening instruments have acceptable accuracy to detect generalized anxiety disorder.

Depression and Suicide Risk Screening: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Depression is common and associated with substantial burden. Suicide rates have increased over the past decade, and both suicide attempts and deaths have devastating effects on individuals and families. Objective: To review the benefits and harms of screening and treatment for depression and suicide risk and the accuracy of instruments to detect these conditions among primary care patients. Data Sources: MEDLINE, PsychINFO, Cochrane library through September 7, 2022; references of existing reviews; ongoing surveillance for relevant literature through November 25, 2022. Study Selection: English-language studies of screening or treatment compared with control conditions, or test accuracy of screening instruments (for depression, instruments were selected a priori; for suicide risk, all were included). Existing systematic reviews were used for treatment and test accuracy for depression. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Findings were synthesized qualitatively, including reporting of meta-analysis results from existing systematic reviews; meta-analyses were conducted on original research when evidence was sufficient. Main Outcomes and Measures: Depression outcomes; suicidal ideation, attempts, and deaths; sensitivity and specificity of screening tools. Results: For depression, 105 studies were included: 32 original studies (N=385 607) and 73 systematic reviews (including ≈2138 studies [N ≈ 9.8 million]). Depression screening interventions, many of which included additional components beyond screening, were associated with a lower prevalence of depression or clinically important depressive symptomatology after 6 to 12 months (pooled odds ratio, 0.60 [95% CI, 0.50-0.73]; reported in 8 randomized clinical trials [n=10 244]; I2 = 0%). Several instruments demonstrated adequate test accuracy (eg, for the 9-item Patient Health Questionnaire at a cutoff of 10 or greater, the pooled sensitivity was 0.85 [95% CI, 0.79-0.89] and specificity was 0.85 [95% CI, 0.82-0.88]; reported in 47 studies [n = 11 234]). A large body of evidence supported benefits of psychological and pharmacologic treatment of depression. A pooled estimate from trials used for US Food and Drug Administration approval suggested a very small increase in the absolute risk of a suicide attempt with second-generation antidepressants (odds ratio, 1.53 [95% CI, 1.09-2.15]; n = 40 857; 0.7% of antidepressant users had a suicide attempt vs 0.3% of placebo users; median follow-up, 8 weeks). Twenty-seven studies (n = 24 826) addressed suicide risk. One randomized clinical trial (n=443) of a suicide risk screening intervention found no difference in suicidal ideation after 2 weeks between primary care patients who were and were not screened for suicide risk. Three studies of suicide risk test accuracy were included; none included replication of any instrument. The included suicide prevention studies generally did not demonstrate an improvement over usual care, which typically included specialty mental health treatment. Conclusions and Relevance: Evidence supported depression screening in primary care settings, including during pregnancy and postpartum. There are numerous important gaps in the evidence for suicide risk screening in primary care settings.

Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK.

Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise.

The Histopathological Characteristic of Gastric Carcinoma in the Belgian Tervueren and Groenendael Dog: A Comparison of Two Classification Methods.

Gastric carcinoma is generally considered to be a rare disease in dogs, carrying a grave prognosis. However, in the Tervueren and Groenendael varieties of the Belgian Shepherd dog breed, the disease is highly prevalent. While histopathology is the gold standard for diagnosing gastric carcinoma, there is no general consensus on the methods for histological classification in these cases. Biopsies of a group of 61 dogs with confirmed gastric carcinoma (45 Tervueren and 16 Groenendael) were examined and classified according to World Health Organization (WHO) and Laurén classifications. Kaplan-Meier curves were used to compare survival between the different subtypes and simple and multiple linear regression were used to analyse the association between age of onset and breed variant, sex, neuter status, location of the tumour, inflammation score, and Laurén and WHO classifications. Mean age at diagnosis was significantly different in Groenendael (10.1 ± 2.01) and Tervueren dogs (8.5 ± 1.90). The Laurén classification resulted in 29 (48%) diffuse- and 32 (52%) intestinal-type tumours. Applying the WHO classification resulted in 30 (49%) tubular carcinoma growth patterns and 31 (51%) others. Median survival time was significantly reduced for the diffuse type as compared to the intestinal type according to the Laurén classification, with the same median survival time results for tubular compared to non-tubular subtypes according to the WHO classification (median survival time of 61 vs. 182 days, respectively). Using the WHO and Lauren classification on tumour biopsies may help the practising clinician in the prognostication of gastric carcinoma in Tervueren and Groenendael dogs.

Specific regulation of mechanical nociception by Gß5 involves GABA-B receptors.

Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gß5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gß5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gß5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gß5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gß5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist ß-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gß5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.

Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.

BACKGROUND: Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia. METHODS: Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. RESULTS: Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged. CONCLUSIONS: In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.

The dogs of Chernobyl: Demographic insights into populations inhabiting the nuclear exclusion zone.

The 1986 Chernobyl nuclear disaster initiated a series of catastrophic events resulting in long-term and widespread environmental contamination. We characterize the genetic structure of 302 dogs representing three free-roaming dog populations living within the power plant itself, as well as those 15 to 45 kilometers from the disaster site. Genome-wide profiles from Chernobyl, purebred and free-breeding dogs, worldwide reveal that the individuals from the power plant and Chernobyl City are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression. Kinship analysis reveals 15 families, with the largest spanning all collection sites within the radioactive exclusion zone, reflecting migration of dogs between the power plant and Chernobyl City. This study presents the first characterization of a domestic species in Chernobyl, establishing their importance for genetic studies into the effects of exposure to long-term, low-dose ionizing radiation.