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Objectives: The purpose of this study was to evaluate the incidence of great saphenous vein (GSV) thrombosis in symptomatic patients and its possible relationship to complications usually attributed to deep venous thrombosis (DVT). Methods: To quantitate the frequency of GSV thrombosis and evaluate its possible morbidity, we reviewed all the venous studies, both inpatient and outpatient, at a Level I Trauma Center over one year. The charts of all patients who had a thrombus in the GSV, either alone or in combination with a DVT, were examined. Results: A total of 2646 lower extremity venous scans were done in the year studied. In this group, there were 388 (14.5%) positive studies for a DVT. There were 36 (9.3%) patients in this group who had a DVT of the lower extremity and a thrombus in the GSV. In the total group, there were 30 patients (1.1%) with a superficial thrombophlebitis of the GSV alone. In these patients, 22 (73%) either showed cephalad progression of the thrombus, symptoms of shortness of breath, a mobile tip in the thrombus or extension of the thrombus into the common femoral vein. Five patients (16.6%), after failing medical therapy (heparin, bed rest and antibiotics), underwent surgical treatment. Conclusions: Thrombophlebitis of the GSV, although not very common, needs to be carefully followed with a repeat duplex scan to determine if there is propagation of the thrombus. This study shows that thrombophlebitis of the GSV can cause many of the complications attributed to deep venous thrombi and, therefore, must be thoroughly evaluated, followed, and, if necessary, treated. [ABSTRACT FROM AUTHOR]

Purpose-In the context of changes in the priority given to ensuring that health care is evidence-based, and that service quality should be maximised, there is a new emphasis on quality improvement programmes in the UK National Health Service (NHS). It is not clear how far these programmes can be categorised using the paradigms of research and audit. Making a distinction between what constitutes audit, quality improvement and research is important in the context of enhanced clinical and research governance requirements and in an environment of both sensitivity in relation to the ethics of research and concern about the efficacy of ethics committees. This study aims to address this issue.Design/methodology/approach-This article reviews the literature on how quality improvement differs from audit and research. It considers different ways of considering ethics in research and questions how far one can rely on professional judgement as an alternative to formal ethics committee procedures. The factors that characterise different sorts of activity are reworked to enable a template to be devised. The template, presented in the form of a flow-chart, enables health care workers to better categorise a variety of activities and highlights the necessary procedural requirements that follow.Findings-Key factors are identified in the existing literature that help differentiate between quality improvement, audit and research. These factors range from intent in undertaking the activity, through sample/site selection, choice of methodology, analysis, patterns and speed of dissemination.Originality/value-If quality improvement is to continue to be a central theme in the NHS agenda, it is important that both the Central Office for Ethical Review and NHS organisations review the categorisation system to include quality improvement in their clinical effectiveness structures. [ABSTRACT FROM AUTHOR]

Background: Fosamax (alendronate sodium, Merck & Co., Inc., Whitehouse Station, NJ, USA) is an effective oral bisphosphonate widely used to treat and prevent osteoporosis, with a safety and tolerability profile similar to placebo in clinical trials. It has been evaluated in clinical trials with over 20,000 participants and up to 10 years duration. Oral bisphosphonates have been associated with esophagitis, which involves events that occur prior to absorption and depends on factors such as the frequency of administration, dose, and formulation. Data on non- Fosamax alendronate (NFA) preparations, which contain a form of alendronate with differing excipients, are typically derived from small, single-dose, bioavailability studies. While these studies provide information on systemic effects, they do not address the risk of local esophageal irritation and may, therefore, inadequately characterize safety profiles.Objective: To compare the esophageal irritation potential of NFA preparations to that of the innovator medication, Fosamax.Methods: Two preclinical models of irritation were used. In the first, 24 rabbits were randomized to a single, subcutaneous injection of saline, 10.6 mg of Fosamax in saline, or 10.6 mg NFA in saline. Blinded measurements of skin thickness (a measure of inflammation), wet weight, and histopathology of injection site tissues were performed. In the second study, 16 dogs were anesthetized and a placebo tablet, a 10-mg Fosamax tablet, or a 10-mg NFA tablet was placed by endoscopy in the caudal third of the esophagus for 1 hour, followed by a saline rinse, daily for 5 days. After the final dose, the dogs were sacrificed and esophageal morphology was examined.Results: In the rabbit injection study, the NFA suspension elicited a significantly greater irritant response than an equivalent suspension of Fosamax. The mean wet weight increase at injection site tissues was 70% greater (P < 0.01) for NFA than Fosamax. Fosamax treatment induced smaller, predominantly foreign-body granuloma type lesions, while NFA induced larger, encapsulated cystic lesions containing the injected material, consistent with a post-inflammatory process. In the esophagus study, all 4 dogs (100%) treated with NFA for 5 days exhibited marked ulcerative esophagitis, whereas only 1 of the 5 dogs treated with Fosamax (20%) had marked ulceration; the remaining 4 dogs had more moderate esophageal changes than those observed in dogs treated with NFA.Conclusions: Generic drugs are expected to have similar efficacy and safety to innovator drugs; however, the greater irritant responses of NFA in rabbits and dogs suggest that important differences may exist between the effects of Fosamax and NFA preparations in the clinical setting. These findings, along with other data demonstrating differences in the disintegration/dissolution profiles of NFA preparations relative to Fosamax, suggest that bioavailability studies may not be adequate for meaningful assessment of the safety and efficacy of NFA or other bisphosphonate preparations. [ABSTRACT FROM AUTHOR]

The carbon sequestration potential of open-ocean pelagic ecosystems is vastly under-reported compared to coastal vegetation 'blue carbon' systems. Here we show that just a single pelagic harvested species, Antarctic krill, sequesters a similar amount of carbon through its sinking faecal pellets as marshes, mangroves and seagrass. Due to their massive population biomass, fast-sinking faecal pellets and the modest depths that pellets need to reach to achieve sequestration (mean is 381 m), Antarctic krill faecal pellets sequester 20 MtC per productive season (spring to early Autumn). This is equates USD$ 4 - 46 billion depending on the price of carbon, with krill pellet carbon stored for at least 100 years and with some reaching as far as the North Pacific. Antarctic krill are being impacted by rapid polar climate change and an expanding fishery, thus krill populations and their habitat warrant protection to preserve this valuable carbon sink., (© 2024. The Author(s).)

Objective: To understand the CD8+ tumour infiltrating lymphocyte (TIL) compartment of oesophageal adenocarcinoma (OAC) with regards to markers of lymphocyte exhaustion, tissue residency and to identify possible reasons behind differential responses to therapy., Design: Tumour samples from 44 patients undergoing curative resection for OAC were assessed by flow cytometry for presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of PD-1 and CD39 positive OAC TILs were sorted, and bulk RNA sequencing undertaken using a modified SmartSeq2 protocol. Flow cytometric assessment of functionality was completed., Results: A higher proportion of antigen experienced CD8+ OAC TILs was associated with improved survival following surgery; while, high double positivity (DP) for PD-1 and CD39 among these TILs also correlated significantly with outcome. These DP TILs possess a minority population which is positive for the markers of exhaustion TIM3 and LAG3. Transcriptomic assessment of the PD-1 and CD39 DP TILs demonstrated enrichment for a tissue resident memory T lymphocyte (TRM) phenotype associated with improved survival in other cancers, reinforced by positivity for the canonical TRM marker CD103 by flow cytometry. This population demonstrated maintained functional capacity both in their transcriptomic profile, and on flow cytometric assessment, as well as preserved proliferative capacity., Conclusion: Resected OAC are variably infiltrated by PD-1 and CD39 DP TILs, an abundance of which among lymphocytes is associated with improved survival. This DP population has an increased, but still modest, frequency of TIM3 and LAG3 positivity compared to DN, and is in keeping with a functionally competent TRM phenotype., (© 2024. The Author(s).)

A primary response of many marine ectotherms to warming is a reduction in body size, to lower the metabolic costs associated with higher temperatures. The impact of such changes on ecosystem dynamics and stability will depend on the resulting changes to community size-structure, but few studies have investigated how temperature affects the relative size of predators and their prey in natural systems. We utilise >3700 prey size measurements from ten Southern Ocean lanternfish species sampled across >10° of latitude to investigate how temperature influences predator-prey size relationships and size-selective feeding. As temperature increased, we show that predators became closer in size to their prey, which was primarily associated with a decline in predator size and an increase in the relative abundance of intermediate-sized prey. The potential implications of these changes include reduced top-down control of prey populations and a reduction in the diversity of predator-prey interactions. Both of these factors could reduce the stability of community dynamics and ecosystem resistance to perturbations under ocean warming., (© 2024. The Author(s).)

Chronic enteropathies (CE) are common disorders in cats and the differentiation between the two main underlying diseases, inflammatory bowel disease (IBD) and low-grade intestinal T-cell lymphoma (LGITL), can be challenging. Characterization of the serum metabolome could provide further information on alterations of disease-associated metabolic pathways and may identify diagnostic or therapeutic targets. Unbiased metabolomics analysis of serum from 28 cats with CE (14 cats with IBD, 14 cats with LGITL) and 14 healthy controls identified 1,007 named metabolites, of which 129 were significantly different in cats with CE compared to healthy controls at baseline. Random Forest analysis revealed a predictive accuracy of 90% for differentiating controls from cats with chronic enteropathy. Metabolic pathways found to be significantly altered included phospholipids, amino acids, thiamine, and tryptophan metabolism. Several metabolites were found to be significantly different between cats with IBD versus LGITL, including several sphingolipids, phosphatidylcholine 40:7, uridine, pinitol, 3,4-dihydroxybenzoic acid, and glucuronic acid. However, random forest analysis revealed a poor group predictive accuracy of 60% for the differentiation of IBD from LGITL. Of 129 compounds found to be significantly different between healthy cats and cats with CE at baseline, 58 remained different following treatment., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Sleep and depression have a complex, bidirectional relationship, with sleep-associated alterations in brain dynamics and structure impacting a range of symptoms and cognitive abilities. Previous work describing these relationships has provided an incomplete picture by investigating only one or two types of sleep measures, depression, or neuroimaging modalities in parallel. We analyze the correlations between brainwide neural signatures of sleep, cognition, and depression in task and resting-state data from over 30,000 individuals from the UK Biobank and Human Connectome Project. Neural signatures of insomnia and depression are negatively correlated with those of sleep duration measured by accelerometer in the task condition but positively correlated in the resting-state condition. Our results show that resting-state neural signatures of insomnia and depression resemble that of rested wakefulness. This is further supported by our finding of hypoconnectivity in task but hyperconnectivity in resting-state data in association with insomnia and depression. These observations dispute conventional assumptions about the neurofunctional manifestations of hyper- and hypo-somnia, and may explain inconsistent findings in the literature., (© 2023. The Author(s).)

Introduction: Around the world, many organisations are working on ways to increase the use, sharing, and reuse of person-level data for research, evaluation, planning, and innovation while ensuring that data are secure and privacy is protected. As a contribution to broader efforts to improve data governance and management, in 2020 members of our team published 12 minimum specification essential requirements (min specs) to provide practical guidance for organisations establishing or operating data trusts and other forms of data infrastructure., Approach and Aims: We convened an international team, consisting mostly of participants from Canada and the United States of America, to test and refine the original 12 min specs. Twenty-three (23) data-focused organisations and initiatives recorded the various ways they address the min specs. Sub-teams analysed the results, used the findings to make improvements to the min specs, and identified materials to support organisations/initiatives in addressing the min specs., Results: Analyses and discussion led to an updated set of 15 min specs covering five categories: one min spec for Legal, five for Governance, four for Management, two for Data Users, and three for Stakeholder & Public Engagement. Multiple changes were made to make the min specs language more technically complete and precise. The updated set of 15 min specs has been integrated into a Canadian national standard that, to our knowledge, is the first to include requirements for public engagement and Indigenous Data Sovereignty., Conclusions: The testing and refinement of the min specs led to significant additions and improvements. The min specs helped the 23 organisations/initiatives involved in this project communicate and compare how they achieve responsible and trustworthy data governance and management. By extension, the min specs, and the Canadian national standard based on them, are likely to be useful for other data-focused organisations and initiatives., Competing Interests: Statement of conlficts of interest: No conflicts to declare.

Chronic enteropathy (CE) in cats encompasses food-responsive enteropathy, chronic inflammatory enteropathy (or inflammatory bowel disease), and low-grade intestinal T-cell lymphoma. While alterations in the gut metabolome have been extensively studied in humans and dogs with gastrointestinal disorders, little is known about the specific metabolic profile of cats with CE. As lipids take part in energy storage, inflammation, and cellular structure, investigating the lipid profile in cats with CE is crucial. This study aimed to measure fecal concentrations of various fatty acids, sterols, and bile acids. Fecal samples from 56 cats with CE and 77 healthy control cats were analyzed using gas chromatography-mass spectrometry, targeting 12 fatty acids, 10 sterols, and 5 unconjugated bile acids. Fecal concentrations of nine targeted fatty acids and animal-derived sterols were significantly increased in cats with CE. However, fecal concentrations of plant-derived sterols were significantly decreased in cats with CE. Additionally, an increased percentage of primary bile acids was observed in a subset of cats with CE. These findings suggest the presence of lipid maldigestion, malabsorption, and inflammation in the gastrointestinal tract of cats with CE. Understanding the lipid alterations in cats with CE can provide insights into the disease mechanisms and potential future therapeutic strategies.

Background: CD8 + T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8 + specificities and TCR avidity of naturally arising tumor-specific T cells, where both high and low avidity T cells recognizing the same peptide-major histocompatibility complex (pMHC) coexist in the same tumor, are crucial for understanding T cell exhaustion and resistance to PD-1 immunotherapy., Methods: CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8 + T cells targeting the tumor-specific epitope GSW11 and confirmed with tetramer competition assays. Functional characterization of high and low avidity GSW11-specific CD8 + T cells was conducted using flow cytometry and bulk RNA-seq. In vitro cytotoxicity assays and in vivo adoptive transfer experiments were performed to determine the cytotoxicity of high and low avidity populations., Results: Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tet lo ) GSW11-specific CD8 + T cells with Vβ TCR expressing clonotypes. High avidity T cells (Tet hi ), if present, were only found in progressing PD-1 refractory tumors. Tet lo demonstrated precursor exhausted or progenitor T cell phenotypes marked by higher expression of Tcf-1 and T-bet, and lower expression of the exhaustion markers CD39, PD-1 and Eomes compared with Tet hi , whereas Tet hi cells were terminally exhausted. Transcriptomics analyses showed pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly enriched in Tet lo found in both regressing and progressing tumors compared with Tet hi , whereas genes related to DNA damage, apoptosis and autophagy were downregulated. In vitro studies showed that Tet lo exhibits higher cytotoxicity than Tet hi . Adoptive transfer of Tet lo showed more effective tumor control than Tet hi , and curative responses were achieved when Tet lo was combined with two doses of anti-PD-1., Conclusions: Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Advancements in artificial intelligence (AI) are enabling the development of clinical support tools (CSTs) in psychiatry to facilitate the review of patient data and inform clinical care. To promote their successful integration and prevent over-reliance, it is important to understand how psychiatrists will respond to information provided by AI-based CSTs, particularly if it is incorrect. We conducted an experiment to examine psychiatrists' perceptions of AI-based CSTs for treating major depressive disorder (MDD) and to determine whether perceptions interacted with the quality of CST information. Eighty-three psychiatrists read clinical notes about a hypothetical patient with MDD and reviewed two CSTs embedded within a single dashboard: the note's summary and a treatment recommendation. Psychiatrists were randomised to believe the source of CSTs was either AI or another psychiatrist, and across four notes, CSTs provided either correct or incorrect information. Psychiatrists rated the CSTs on various attributes. Ratings for note summaries were less favourable when psychiatrists believed the notes were generated with AI as compared to another psychiatrist, regardless of whether the notes provided correct or incorrect information. A smaller preference for psychiatrist-generated information emerged in ratings of attributes that reflected the summary's accuracy or its inclusion of important information from the full clinical note. Ratings for treatment recommendations were also less favourable when their perceived source was AI, but only when recommendations were correct. There was little evidence that clinical expertise or familiarity with AI impacted results. These findings suggest that psychiatrists prefer human-derived CSTs. This preference was less pronounced for ratings that may have prompted a deeper review of CST information (i.e. a comparison with the full clinical note to evaluate the summary's accuracy or completeness, assessing an incorrect treatment recommendation), suggesting a role of heuristics. Future work should explore other contributing factors and downstream implications for integrating AI into psychiatric care., (© 2023. The Author(s).)

Introduction: Managing violence or aggression is an ongoing challenge in emergency psychiatry. Many patients identified as being at risk do not go on to become violent or aggressive. Efforts to automate the assessment of risk involve training machine learning (ML) models on data from electronic health records (EHRs) to predict these behaviours. However, no studies to date have examined which patient groups may be over-represented in false positive predictions, despite evidence of social and clinical biases that may lead to higher perceptions of risk in patients defined by intersecting features (eg, race, gender). Because risk assessment can impact psychiatric care (eg, via coercive measures, such as restraints), it is unclear which patients might be underserved or harmed by the application of ML., Methods and Analysis: We pilot a computational ethnography to study how the integration of ML into risk assessment might impact acute psychiatric care, with a focus on how EHR data is compiled and used to predict a risk of violence or aggression. Our objectives include: (1) evaluating an ML model trained on psychiatric EHRs to predict violent or aggressive incidents for intersectional bias; and (2) completing participant observation and qualitative interviews in an emergency psychiatric setting to explore how social, clinical and structural biases are encoded in the training data. Our overall aim is to study the impact of ML applications in acute psychiatry on marginalised and underserved patient groups., Ethics and Dissemination: The project was approved by the research ethics board at The Centre for Addiction and Mental Health (053/2021). Study findings will be presented in peer-reviewed journals, conferences and shared with service users and providers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The surgery for dialysis access has changed over the past 38 years. In the 1980s and 1990s, prosthetic grafts were the most common form of access. Then, autogenous fistulae had a rebirth due to their durability and decreased complications. The continued expansion of the dialysis population, coupled with the paucity of adequate superficial veins in many patients, required other techniques of dialysis access such as tunneled dialysis catheters, and more complex surgery on deeper veins., Methods: This study of one surgeon's practice over 38 years mirrors the extensive changes in dialysis access. The changes in surgical technique, interventional procedures, and approaches were documented and evaluated., Results: During the 38-year period, there were 1531 autogenous fistulae, 409 prosthetic grafts, and 1624 tunneled dialysis catheters placed for access. The first 20 years had 130 autogenous fistulae with 302 prosthetic grafts, while in the last 10 years there were 740 fistulae and only 17 prosthetic grafts. Prosthetic grafts were not salvageable for a long term with exposure, infection, and persistent bleeding. Autogenous fistulae were best salvaged with autogenous tissue rather than prosthetic material. Interventional procedures were most valuable in stenting high-grade stenosis centrally and dilating areas of recurrent stenosis. They were not helpful in treatment of large aneurysms or as a long-term solution for persistent and/or massive bleeding., Conclusion: Dialysis access has progressed back to autogenous fistula. This may require longer use of tunneled dialysis catheters, and more surgical procedures, but the construction of an autogenous fistula can be achieved in many dialysis patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Thalamoreticular circuitry plays a key role in arousal, attention, cognition, and sleep spindles, and is linked to several brain disorders. A detailed computational model of mouse somatosensory thalamus and thalamic reticular nucleus has been developed to capture the properties of over 14,000 neurons connected by 6 million synapses. The model recreates the biological connectivity of these neurons, and simulations of the model reproduce multiple experimental findings in different brain states. The model shows that inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness. We find that thalamic interactions are responsible for the characteristic waxing and waning of spindle oscillations. In addition, we find that changes in thalamic excitability control spindle frequency and their incidence. The model is made openly available to provide a new tool for studying the function and dysfunction of the thalamoreticular circuitry in various brain states., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Our understanding of major depression is complicated by substantial heterogeneity in disease presentation, which can be disentangled by data-driven analyses of depressive symptom dimensions. We aimed to determine the clinical portrait of such symptom dimensions among individuals in the community., Methods: This cross-sectional study consisted of 25 261 self-reported White UK Biobank participants with major depression. Nine questions from the UK Biobank Mental Health Questionnaire encompassing depressive symptoms were decomposed into underlying factors or 'symptom dimensions' via factor analysis, which were then tested for association with psychiatric diagnoses and polygenic risk scores for major depressive disorder (MDD), bipolar disorder and schizophrenia. Replication was performed among 655 self-reported non-White participants, across sexes, and among 7190 individuals with an ICD-10 code for MDD from linked inpatient or primary care records., Results: Four broad symptom dimensions were identified, encompassing negative cognition, functional impairment, insomnia and atypical symptoms. These dimensions replicated across ancestries, sexes and individuals with inpatient or primary care MDD diagnoses, and were also consistent among 43 090 self-reported White participants with undiagnosed self-reported depression. Every dimension was associated with increased risk of nearly every psychiatric diagnosis and polygenic risk score. However, while certain psychiatric diagnoses were disproportionately associated with specific symptom dimensions, the three polygenic risk scores did not show the same specificity of associations., Conclusions: An analysis of questionnaire data from a large community-based cohort reveals four replicable symptom dimensions of depression with distinct clinical, but not genetic, correlates.

Context: Acute toxicity caused by illicit substance use is a common reason for emergency department (ED) presentation. Knowledge of the substances involved is helpful for predicting and managing potential toxicity, but limited information is available about the accuracy of patient-reported substance exposure. This study assessed the accuracy of the history of exposure in those reporting use of a single substance by comparison with those identified by detailed toxicological analysis, focusing on synthetic cannabinoid receptor agonists (SCRA)., Methods: Adults (≥16 years) presenting between March 2015 and July 2021 to participating UK hospitals with toxicity after reporting use of a single illicit substance were included. Exposure details were documented from medical records and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry (HRAM LCMS). Sensitivity, specificity, and positive and negative predictive values of the exposure history were calculated by comparison with biological sample analysis ("gold standard")., Results: Single substance exposure was reported for 474 (median age 33 years, IQR: 18 range 16-75, 80% males) patients. Analysis commonly identified multiple substances (Median 3, IQR 2-5). A history of exposure was documented for 121 of 151 patients where a SCRA or metabolite was detected on analysis (sensitivity 80.1%, 95% CI 72.9, 86.2%). Corresponding proportions were lower for 3,4-methylenedioxymethamphetamine (MDMA, 44/70, 62.9%., 95% CI 50.5%, 74.1%), heroin 41/108 (38.0% 95% CI 28.8-47.8%) and cocaine (22/56, 31.3%, 95% CI 20.9, 43.6%)., Conclusions: Multiple undeclared substances were detected analytically in most patients reporting single substance use. Clinicians should be alert to the potential presence and toxicity of unreported substances when managing patients presenting after substance misuse.

Background and Aims: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26 th  May 2016, made the production, supply and sale of all non-exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA., Design: Observational study., Setting: Thirty-four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study., Participants: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure., Measurements: Toxicological analyses of patient samples were conducted using liquid-chromatography tandem mass-spectrometry. Time-series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression., Findings: SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99-1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94-1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non-SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98-1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98-1.04; P = 0.478) implementation of the PSA., Conclusions: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: Synthetic cannabinoid receptor agonists (SCRA) are commonly encountered new psychoactive substances. Here we report the recent detection of ADB-BUTINACA in samples from patients attending United Kingdom emergency departments with toxicity after suspected drug misuse and describe the associated clinical features., Methods: Consenting adults (≥16 y) presenting to participating hospitals with toxicity after suspected drug misuse have been included in the Identification Of Novel psychoActive substances (IONA) study since March 2015. Demographic and clinical features are recorded and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry., Results: By December 2021, analytical data were available for 1279 IONA participants and ADB-BUTINACA was detected in at least one sample from 10 (9 males, age range 16-51 median 45 years), all presenting since February 2021. Smoking 'spice' was reported by four patients, two had ingested edible "cannabis" gums and four reported heroin use (2 intravenous, 1 smoked, 1 route not known). Co-use of pregabalin (oral) and crack cocaine (smoked) were also reported. In 3 cases ADB-BUTINACA was the only substance detected, while in seven other substances of misuse were also detected including other SCRA, opioids, benzodiazepines cocaine and pregabalin. Clinical features reported in these 2 groups respectively included reduced level of consciousness (3/3, 6/7), agitation (0/3, 4/7), tachycardia (0/3, 3/7), seizures (1/3, 1/7), hallucinations (1/3, 1/7), hypotension (1/3, 1/7). Metabolic acidosis (1/3, 0/7) and respiratory acidosis (1/3, 0/7), All 10 patients recovered with supportive care, including intubation and ventilation for one case. The median length of hospital stay was 19 h (range 2.6-131 h)., Conclusions: ADB-BUTINACA has recently emerged as a drug of misuse in England. Clinical features of toxicity are consistent with those of other SCRA and include reduced level of consciousness, respiratory and/or metabolic acidosis, seizures, confusion and hallucinations.

Investigating effects of aging on neurophysiological mechanisms underlying working memory provides a better understanding of potential targets for brain intervention to prevent cognitive decline. Theta-gamma coupling (TGC) indexes the ability to order information processed during working memory tasks. Frontal theta event-related synchronization (ERS) and parietal alpha event-related desynchronization (ERD) index cognitive control and interference inhibition, respectively. Relative contributions of TGC, theta ERS, and alpha ERD in relation to stimulus presentation are not characterized. Further, differential effect of normal aging on pre- or post-stimulus processes is unknown. Electroencephalography was recorded in 66 younger and 41 older healthy participants while performing 3-back working memory task. We assessed relationships between 3-back task performance and each of post-stimulus TGC, pre-stimulus parietal alpha ERD, and pre-stimulus frontal theta ERS in each age group. While older adults performed worse on 3-back task than younger adults, TGC, alpha ERD, or theta ERS did not differ between the two groups. TGC was positively associated with 3-back performance in both age groups; pre-stimulus alpha ERD was associated with performance among younger adults; and pre-stimulus theta ERS was not associated with performance in either group. Our findings suggest that both pre-stimulus interference inhibition and post-stimulus ordering of information are important for working memory in younger adults. In contrast, performance in older adults appears to depend only on post-stimulus ordering of information. These specific contributions of neurophysiological resources may explain the poorer performance of older adults and suggest different targets to enhance working memory in age groups., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

The challenge of defining and cataloging the building blocks of the brain requires a standardized approach to naming neurons and organizing knowledge about their properties. The US Brain Initiative Cell Census Network, Human Cell Atlas, Blue Brain Project, and others are generating vast amounts of data and characterizing large numbers of neurons throughout the nervous system. The neuroscientific literature contains many neuron names (e.g. parvalbumin-positive interneuron or layer 5 pyramidal cell) that are commonly used and generally accepted. However, it is often unclear how such common usage types relate to many evidence-based types that are proposed based on the results of new techniques. Further, comparing different types across labs remains a significant challenge. Here, we propose an interoperable knowledge representation, the Neuron Phenotype Ontology (NPO), that provides a standardized and automatable approach for naming cell types and normalizing their constituent phenotypes using identifiers from community ontologies as a common language. The NPO provides a framework for systematically organizing knowledge about cellular properties and enables interoperability with existing neuron naming schemes. We evaluate the NPO by populating a knowledge base with three independent cortical neuron classifications derived from published data sets that describe neurons according to molecular, morphological, electrophysiological, and synaptic properties. Competency queries to this knowledge base demonstrate that the NPO knowledge model enables interoperability between the three test cases and neuron names commonly used in the literature., (© 2022. The Author(s).)

Objectives: Previous studies have identified various bacterial taxa that are altered in cats with chronic enteropathies (CE) vs healthy cats. Therefore, the aim of this study was to develop a targeted quantitative molecular method to evaluate the fecal microbiota of cats., Methods: Fecal samples from 80 client-owned healthy cats and 68 cats with CE were retrospectively evaluated. A panel of quantitative PCR (qPCR) assays was used to measure the fecal abundance of total bacteria and seven bacterial taxa: Bacteroides , Bifidobacterium , Clostridium hiranonis , Escherichia coli , Faecalibacterium , Streptococcus and Turicibacter. The nearest centroid classifier algorithm was used to calculate a dysbiosis index (DI) based on these qPCR abundances., Results: The abundances of total bacteria, Bacteroides , Bifidobacterium , C hiranonis , Faecalibacterium and Turicibacter were significantly decreased, while those of E coli and Streptococcus were significantly increased in cats with CE ( P <0.027 for all). The DI in cats with CE was significantly higher compared with healthy cats ( P <0.001). When the cut-off value of the DI was set at 0, it provided 77% (95% confidence interval [CI] 66-85) sensitivity and 96% (95% CI 89-99) specificity to differentiate the microbiota of cats with CE from those of healthy cats. Fifty-two of 68 cats with CE had a DI >0., Conclusions and Relevance: A qPCR-based DI for assessing the fecal microbiota of cats was established. The results showed that a large proportion of cats with CE had an altered fecal microbiota as evidenced by an increased DI. Prospective studies are warranted to evaluate the utility of this assay for clinical assessment of feline CE.

Previous studies have described reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swab and saliva samples. This multisite clinical evaluation describes the validation of an improved sample preparation method for extraction-free RT-LAMP and reports clinical performance of four RT-LAMP assay formats for SARS-CoV-2 detection. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva samples from asymptomatic and symptomatic individuals across health care and community settings. For direct RT-LAMP, overall diagnostic sensitivity (DSe) was 70.35% (95% CI, 63.48%-76.60%) on swabs and 84.62% (95% CI, 79.50%-88.88%) on saliva, with diagnostic specificity of 100% (95% CI, 98.98%-100.00%) on swabs and 100% (95% CI, 99.72%-100.00%) on saliva, compared with quantitative RT-PCR (RT-qPCR); analyzing samples with RT-qPCR ORF1ab C T values of ≤25 and ≤33, DSe values were 100% (95% CI, 96.34%-100%) and 77.78% (95% CI, 70.99%-83.62%) for swabs, and 99.01% (95% CI, 94.61%-99.97%) and 87.61% (95% CI, 82.69%-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and diagnostic specificity were 96.06% (95% CI, 92.88%-98.12%) and 99.99% (95% CI, 99.95%-100%) for swabs, and 80.65% (95% CI, 73.54%-86.54%) and 99.99% (95% CI, 99.95%-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use cases, including frequent, interval-based direct RT-LAMP of saliva from asymptomatic individuals who may otherwise be missed using symptomatic testing alone., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Whole-animal, in vivo protein metabolism rates have been reported in temperate and tropical, but not Antarctic fish. Growth in Antarctic species is generally slower than lower latitude species. Protein metabolism data for Antarctic invertebrates show low rates of protein synthesis and unusually high rates of protein degradation. Additionally, in Antarctic fish, increasing evidence suggests a lower frequency of successful folding of nascent proteins and reduced protein stability. This study reports the first whole-animal protein metabolism data for an Antarctic fish. Groups of Antarctic, Harpagifer antarcticus , and temperate, Lipophrys pholis , fish were acclimatized to a range of overlapping water temperatures and food consumption, whole-animal growth and protein metabolism measured. The rates of protein synthesis and growth in Antarctic, but not temperate fish, were relatively insensitive to temperature and were significantly lower in H. antarcticus at 3°C than in L. pholis . Protein degradation was independent of temperature in H. antarcticus and not significantly different to L. pholis at 3°C, while protein synthesis retention efficiency was significantly higher in L. pholis than H. antarcticus at 3°C. These results suggest Antarctic fish degrade a significantly larger proportion of synthesized protein than temperate fish, with fundamental energetic implications for growth at low temperatures., Competing Interests: We declare we have no competing interests., (© 2022 The Authors.)

As neuroscience projects increase in scale and cross international borders, different ethical principles, national and international laws, regulations, and policies for data sharing must be considered. These concerns are part of what is collectively called data governance. Whereas neuroscience data transcend borders, data governance is typically constrained within geopolitical boundaries. An international data governance framework and accompanying infrastructure can assist investigators, institutions, data repositories, and funders with navigating disparate policies. Here, we propose principles and operational considerations for how data governance in neuroscience can be navigated at an international scale and highlight gaps, challenges, and opportunities in a global brain data ecosystem. We consider how to approach data governance in a way that balances data protection requirements and the need for open science, so as to promote international collaboration through federated constructs such as the International Brain Initiative (IBI)., Competing Interests: Declaration of interests M.E.M. is a founder and has equity interest in SciCrunch.com, a technology startup providing services in support of Research Resource Identifiers and reproducible science., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Plankton drive a major sink of carbon across the global oceans. Dead plankton, their faeces and the faeces of plankton feeders, form a huge rain of carbon sinking to the seabed and deep ocean, reducing atmospheric CO 2 levels and thus helping to regulate the climate. Any change in plankton communities, ecosystems or habitats will perturb this carbon sink, potentially increasing atmospheric CO 2 . Fishing is a major cause of ocean ecosystem disturbance affecting all trophic levels including plankton, but its potential impact on the carbon sink is unknown. As both fisheries and the carbon sink depend on plankton, there is spatial overlap of these fundamental ecosystem services. Here, we provide the first global maps of this spatial overlap. Using an upper quartile analysis, we show that 21% of the total upper ocean carbon sink (export) and 39% of fishing effort globally are concentrated in zones of intensive overlap, representing 9% of the ocean surface area. This overlap is particularly evident in the Northeast Atlantic suggesting this region should be prioritized in terms of research and conservation measures to preserve the high levels of sinking carbon. Small pelagic fish dominate catches here and globally, and their exploitation could reduce important faecal pellet carbon sinks and cause trophic cascades affecting plankton communities. There is an urgent need to recognize that, alongside climate change, fishing might be a critical influence on the ability of the ocean to sequester atmospheric CO 2 . Improved understanding of this influence, and how it will change with the climate, will be important for realizing a sustainable balance of the twin needs for productive fisheries and strong carbon sinks., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Poleward range shifts are a global-scale response to warming, but these vary greatly among taxa and are hard to predict for individual species, localized regions or over shorter (years to decadal) timescales. Moving poleward might be easier in the Arctic than in the Southern Ocean, where evidence for range shifts is sparse and contradictory. Here, we compiled a database of larval Antarctic krill, Euphausia superba and, together with an adult database, it showed how their range shift is out of step with the pace of warming. During a 70-year period of rapid warming (1920s-1990s), distribution centres of both larvae and adults in the SW Atlantic sector remained fixed, despite warming by 0.5-1.0°C and losing sea ice. This was followed by a hiatus in surface warming and ice loss, yet during this period the distributions of krill life stages shifted greatly, by ~1000 km, to the south-west. Understanding the mechanism of such step changes is essential, since they herald system reorganizations that are hard to predict with current modelling approaches. We propose that the abrupt shift was driven by climatic controls acting on localized recruitment hotspots, superimposed on thermal niche conservatism. During the warming hiatus, the Southern Annular Mode index continued to become increasingly positive and, likely through reduced feeding success for larvae, this led to a precipitous decline in recruitment from the main reproduction hotspot along the southern Scotia Arc. This cut replenishment to the northern portion of the krill stock, as evidenced by declining density and swarm frequency. Concomitantly, a new, southern reproduction area developed after the 1990s, reinforcing the range shift despite the lack of surface warming. New spawning hotspots may provide the stepping stones needed for range shifts into polar regions, so planning of climate-ready marine protected areas should include these key areas of future habitat., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Objectives: Fairness is a core concept meant to grapple with different forms of discrimination and bias that emerge with advances in Artificial Intelligence (eg, machine learning, ML). Yet, claims to fairness in ML discourses are often vague and contradictory. The response to these issues within the scientific community has been technocratic. Studies either measure (mathematically) competing definitions of fairness, and/or recommend a range of governance tools (eg, fairness checklists or guiding principles). To advance efforts to operationalise fairness in medicine, we synthesised a broad range of literature., Methods: We conducted an environmental scan of English language literature on fairness from 1960-July 31, 2021. Electronic databases Medline, PubMed and Google Scholar were searched, supplemented by additional hand searches. Data from 213 selected publications were analysed using rapid framework analysis. Search and analysis were completed in two rounds: to explore previously identified issues (a priori), as well as those emerging from the analysis (de novo)., Results: Our synthesis identified 'Three Pillars for Fairness': transparency, impartiality and inclusion. We draw on these insights to propose a multidimensional conceptual framework to guide empirical research on the operationalisation of fairness in healthcare., Discussion: We apply the conceptual framework generated by our synthesis to risk assessment in psychiatry as a case study. We argue that any claim to fairness must reflect critical assessment and ongoing social and political deliberation around these three pillars with a range of stakeholders, including patients., Conclusion: We conclude by outlining areas for further research that would bolster ongoing commitments to fairness and health equity in healthcare., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Non-medical use of novel benzodiazepines has recently become common. Here, we describe the recent frequent detection of flubromazolam in patients attending United Kingdom emergency departments., Methods: Adults presenting to participating hospitals with toxicity after suspected drug misuse were studied between March 2015 and January 2021. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry., Results: Flubromazolam and/or its mono-hydroxylated metabolite were detected in samples from 14 of 957 patients, all presenting since July 2020. Reported clinical features included reduced level of consciousness (10), confusion/agitation (6) and acidosis (5) but multiple other substances were detected in all patients. All patients survived to discharge (length of hospital stay 3.0 to 213 h, median 24.1 h). There was no correlation between admission blood/serum flubromazolam concentrations (range 1.7-480.5 ng/ml, median 7.4 ng/ml) and Glasgow Coma Scale or length of hospital stay. In one patient who needed intubation and ventilation for five days, there was an exponential decline in flubromazolam concentrations with time (calculated half-life 39.8 h). Hydroxyl-flubromazolam was also identified at all time points., Conclusions: Flubromazolam has been detected frequently in drug users presenting to UK emergency departments since July 2020. Prolonged toxicity may occur as a result of the long half-life of flubromazolam and the production of metabolites likely to be active.