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Rationale: HIV-infected adults are at an increased risk of lower respiratory tract infections. HIV infection impairs systemic acquired immunity, but there is limited information in humans on HIV-related cell-mediated immune defects in the lung.Objective: To investigate antigen-specific CD4(+) T cell responses to influenza virus, Streptococcus pneumoniae and Mycobacterium tuberculosis antigens in bronchoalveolar lavage (BAL) and peripheral blood between HIV-infected individuals and HIV-uninfected Malawian adults.Methods: We obtained BAL fluid and blood from HIV-infected individuals (n=21) and HIV-uninfected adults (n=24). We determined the proportion of T cell subsets including naive, memory and regulatory T cells using flow cytometry, and used intracellular cytokine staining to identify CD4(+) T cells recognising influenza virus-, S pneumoniae- and M tuberculosis-antigens.Main Results: CD4(+) T cells in BAL were predominantly of effector memory phenotype compared to blood, irrespective of HIV status (p<0.001). There was immune compartmentalisation with a higher frequency of antigen-specific CD4(+) T cells against influenza virus, S pneumoniae and M tuberculosis retained in BAL compared to blood in HIV-uninfected adults (p<0.001 in each case). Influenza virus- and M tuberculosis-specific CD4(+) T cell responses in BAL were impaired in HIV-infected individuals: proportions of total antigen-specific CD4(+) T cells and of polyfunctional IFN-γ and TNF-α-secreting cells were lower in HIV-infected individuals than in HIV-uninfected adults (p<0.05 in each case).Conclusions: BAL antigen-specific CD4(+) T cell responses against important viral and bacterial respiratory pathogens are impaired in HIV-infected adults. This might contribute to the susceptibility of HIV-infected adults to lower respiratory tract infections such as pneumonia and tuberculosis. [ABSTRACT FROM AUTHOR]

Hernia repairs are among the most common surgical procedures performed by general surgeons annually in the United States, defined as the abnormal protrusion of tissue and/or organs through an anatomical defect in the surrounding wall at various locations in the human body. While some hernias can remain asymptomatic and seemingly harmless, some may lead to intestinal obstruction, ischemic bowel from strangulation of blood supply, or septic shock if not diagnosed and addressed within a short period of time. This case report is about an elderly woman who presented with a Richter's. A Richter's hernia is an atypical type of strangulation where only a portion of the bowel, the antimesenteric border, is trapped within the anatomical defect. Given the limited extent of entrapped bowel, numerous different presentations can be seen, including but not limited to signs of obstruction without signs of ischemia or, in some instances, lack of either sign of obstruction or ischemia. Within this report, we will discuss the need for high clinical suspicion for Richter's hernias when evaluating strangulated hernias without systemic signs of sepsis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Yumen et al.)

Aims: Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors., Findings: Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors., Implications: Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation., Competing Interests: HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer and Kowa & received research grants and donations from Akcea, Pfizer, MSD, AMGEN, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. DA: reports research grants from Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, and the LEO Foundation. JS: received grants and research support from Astra Zeneca, Daiichi-Sankyo, Eli Lilly and Company and Novo Nordisk; speaker fees from Novartis, Astra Zeneca, Daiichi-Sankyo and Sanofi; and consultancy fees from Amgen, Boehringer Ingelheim, Eli Lilly and Company and Sanofi. PD: Received honoraria from Sobi, Novartis, Amgen, Daiichi Sankyo, Sanofi and Amarin. SR: Received honoraria from NOVARTIS, AMGEN, Astra Zeneca, Ultragenyx, Sanofi, Foresite Labs, and research grants from Astra Zeneca. IG-B: received personal honoraria for consulting from Amgen, Regeneron, Aegereon, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Ultragenyx, Sanofi and Amarin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Bashir, Schofield, Downie, France, Ashcroft, Wright, Romeo, Gouni-Berthold, Maan, Durrington and Soran.)

Background: Psoriasis significantly burdens patients' lives, but there is limited data on this in Brazil., Methods: Between May 2022 and January 2023, we conducted a cross-sectional online survey of 563 Brazilian residents aged ≥18 years who had been diagnosed with psoriasis. Spearman's correlation (r) was used to test the correlation between self-assessed disease severity (Simplified Psoriasis Index [saSPI] extent score; range 0 [clear/minor] to 40 [widespread/severe]) and health-related quality of life (QoL, score of 1 means perfect health) and capability (ICECAP-A: score of 1 means full capability) measures. Multivariable linear regression was used to identify predictors of QoL and capability. A thematic analysis examined the free-text responses and identified common themes., Results: The mean age of participants was 42.1 ± 12.4 years, and over half had at least one other long-term condition. The mean QoL score was 0.59 ± 0.25, and the mean capability score was 0.71 ± 0.21. At the time of survey completion, over 80% of respondents reported some level of pain and/or discomfort, and 86% reported feeling anxious and/or depressed. The mean self-assessed saSPI was 7.8 ± 8.6, which negatively correlated with health-related QoL (r = -0.49, P < 0.05) and capability (r = -0.44, P < 0.05). Significant predictors of poorer QoL and reduced capability included high saSPI, number of psoriasis flares and comorbidities, female gender, Black ethnicity, and employment status (unemployed, long-term sick). Frequently reported areas that impacted patients were social stigma/prejudice, powerlessness, lack of education and public awareness, and difficulty obtaining appropriate care/treatment., Conclusions: We found that the clinical manifestations, severity, and associated comorbidities of psoriasis negatively impacted health-related QoL and capability, along with feelings of stigmatization and barriers to specialist treatment. This highlights the need for better access to care and awareness of the disease to improve the lives of people living with psoriasis in Brazil., (© 2024 The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be 'objective' measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics., (© 2024. The Author(s).)

The COVID-19 pandemic has caused major disruptions in clinical services for people with chronic long-term conditions. In this narrative review, we assess the indirect impacts of the COVID-19 pandemic on diabetes services globally and the resulting adverse effects on rates of diagnosing, monitoring, and prescribing in people with type 2 diabetes. We summarise potential practical approaches that could address these issues and improve clinical services and outcomes for people living with diabetes during the recovery phase of the pandemic., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.M. has received speaker fees from Boehringer Ingelheim, AstraZeneca, Abbot, Lupin, Sanofi, Abbott and Jannsen. C.H. has received funding from the following companies for speaker fees, providing education or attendance at conferences: Boehringer Ingelheim, Astra Zeneca, Lilly, MSD, Takeda, Novo Nordisk, Sanofi, Napp, Abbott and Dexcom. J.V. was the National Clinical Director for Diabetes and Obesity at NHS England. K.K. has acted as a consultant, speaker or received grants for investigator-initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche and Applied Therapeutics. K.K. is chair of the ethnicity subgroup of the UK Scientific Advisory Group for Emergencies (SAGE) and is a member of SAGE.KKs research group developed the Diabetes Risk Score recommended by NICE for screening for diabetes. DMA reports research grants from AbbVie, Almirall, Celgene, Eli Lilly, Janssen, Novartis, UCB, and the LEO Foundation. M.R has received consulting fees from Eli Lilly and Company. N.K. has received honoraria from Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim and Abbott for speaker meetings and advisory boards. N.M. has received funding from the following companies for providing educational sessions, attendance at conferences and for attending advisory boards: Boehringer Ingelheim, Astra Zeneca, Lilly, MSD, Takeda, Novo Nordisk, Sanofi, Napp, Abbott, MyLan, Roche, Ascensia and Dexcom. N.S. has received grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and consulting fees from Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA + CD39 + T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA + CD39 + T cells in non-responders and activated cytotoxic CLA + CD39 + T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials., Competing Interests: Declaration of interests E.W.N. is a co-founder, advisor, and shareholder of ImmunoScape and is an advisor for Neogene Therapuetics and NanoString Technologies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is limited understanding of the epidemiology of generalized pustular psoriasis (GPP) internationally, with no population-based estimates of GPP in South East Asia., Objectives: To determine the incidence and prevalence of GPP in the Malaysian population and characterize its flares and trigger factors., Methods: We conducted a population-based cohort study using the Teleprimary Care database between January 2010 and December 2020. We identified 230 dermatologist-confirmed GPP cases using International Classification of Diseases, 10th revision, diagnostic codes. Annual prevalence and incidence rates were stratified by age, sex and ethnicity. We compared data regarding flares and trigger factors for patients with GPP who had associated psoriasis vulgaris (PV) with those who did not have associated PV., Results: The prevalence of GPP was 198 per million (267 women, 127 men) and incidence was 27.2 per million person-years [95% confidence interval (CI) 22.8-31.6]; 35.3 (28.4-42.2) per million person-years for women and 18.3 (13.1-23.5) per million person-years for men. Rates were higher in Chinese individuals [prevalence 271 per million; incidence 41.6 per million person-years (28.9-54.3)] than in the Malay population [prevalence 186; incidence 24.6 (19.4-29.7)] or the Indian ethnic group [prevalence 179; incidence 25.0 (13.8-36.3)]. Annual prevalence was consistently higher in women than in men and highest among the Chinese population, followed by the Indian and Malay populations. Overall, 67% of patients with GPP had associated PV. The prevalence and incidence of GPP without PV were lower than GPP with PV at 66 vs. 132 per million and 19.3 (95% CI 15.6-23.0) vs. 8.0 (95% CI 5.6-10.3) per million person-years, respectively. The mean age at GPP onset was 42.7 years (SD 18.4). A bimodal trend in the age of GPP onset was observed, with first and second peaks at age 20-29 years and age 50-59 years, respectively. Disease onset was significantly earlier in patients with GPP without PV than in those with PV [mean age 37.5 years (SD 20.7) vs. 44.9 years (SD 17.0), P = 0.026]. Flares occurred more frequently in patients without PV than in those with PV [mean number of flares per patient per year was 1.35 (SD 0.77) vs. 1.25 (SD 0.58), P = 0.039]. Common triggers of flares in patients with GPP who did not have PV were infections, pregnancy, menstruation and stress, whereas withdrawal of therapy, particularly systemic corticosteroids, was a more frequent trigger in patients with GPP who also had PV., Conclusions: Our findings contribute to the global mapping of GPP, which will help inform the management of this rare condition., Competing Interests: Conflicts of interest: S.E.C. declares paid activities as advisor, speaker or consultant for AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Sanofi and UCB. C.E.M.G. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Evelo Bioscience, Galderma, GSK, Inmagene, LEO Pharma, Janssen, ONO Pharmaceuticals, Novartis, Pfizer, Sandoz and UCB Pharma. D.M.A. reports research grants from AbbVie, Almirall, Eli Lilly, Janssen, Novartis, UCB, and the LEO Foundation., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Natural proteinaceous pore-forming agents can bind and permeabilize cell membranes, leading to ion dyshomeostasis and cell death. In the search for antidotes that can protect cells from peptide toxins, we discovered that the polyphenol epigallocatechin gallate (EGCG) interacts directly with melittin from honeybee venom, resulting in the elimination of its binding to the cell membrane and toxicity by markedly lowering the extent of its solvent-exposed hydrophobicity and promoting its oligomerization into larger species. These physicochemical parameters have also been shown to play a key role in the binding to cells of misfolded protein oligomers in a host of neurodegenerative diseases, where oligomer-membrane binding and associated toxicity have been shown to correlate negatively with oligomer size and positively with solvent-exposed hydrophobicity. For melittin, which is not an amyloid-forming protein and has a very distinct mechanism of toxicity compared to misfolded oligomers, we find that the size-hydrophobicity-toxicity relationship also rationalizes the pharmacological attenuation of melittin toxicity by EGCG. These results highlight the importance of the physicochemical properties of pore forming agents in mediating their interactions with cell membranes and suggest a possible therapeutic approach based on compounds with a similar mechanism of action as EGCG., (Published by Elsevier B.V.)

Background: There are no population-based epidemiological data on psoriasis in Southeast Asia, including Malaysia., Objectives: To determine the incidence and prevalence of psoriasis over 11 years in multiethnic Johor Bahru, Malaysia., Methods: A population-based cohort study was made using the Teleprimary Care database between January 2010 and December 2020. Cases of psoriasis, identified by ICD-10 diagnostic codes, were validated by dermatologists. Annual prevalence and incidence were estimated and stratified by age, sex and ethnicity., Results: We identified 3932 people with dermatologist-confirmed psoriasis, including 1830 incident cases, among 1 164 724 Malaysians, yielding an 11-year prevalence of 0·34% [95% confidence interval (CI) 0·33-0·35] and incidence of 34·2 per 100 000 person-years (95% CI 32·6-35·8). Rates were higher in Indian patients; the prevalences were 0·54% (0·50-0·58) in Indian, 0·38% (0·36-0·40) in Chinese and 0·29% (0·28-0·30) in Malay patients, and the respective incidences per 100 000 person-years were 52·5 (47·3-57·7), 38·0 (34·1-41·8) and 30·0 (28·2-31·8). Rates were higher in males; the prevalence was 0·39% (0·37-0·41) in males and 0·29% (0·27-0·30) in females, and the respective incidences per 100 000 person-years were 40·7 (38·2-43·2) and 28·3 (26·4-30·3). Between 2010 and 2020, annual psoriasis prevalence and incidence increased steadily from 0·27% to 0·51% and from 27·8 to 60·9 per 100 000 person-years, respectively. Annual rates were consistently higher in male and Indian patients. Overall, psoriasis was significantly more common in males than females [odds ratio (OR) 1·37, 95% CI 1·29-1·46] and in Indian and Chinese patients vs. Malay (OR 1·85, 1·71-2·01 and OR 1·30, 1·20-1·41, respectively). Prevalence increased with age, with the highest rates in the groups aged 50-59 and 60-69 years at 0·67% and 0·66%, respectively. A modest bimodal trend in age of psoriasis onset was observed, with first and second peaks at 20-29 and 50-59 years. Disease onset was significantly earlier in females than males [mean (SD) 36·8 (17·3) vs. 42·0 (17·2) years, P < 0·001] and in Malay vs. Indian and Chinese patients [mean (SD): Malay 36·4 (17·5), Indian 40·8 (15·2), Chinese 47·4 (16·9) years, P < 0·001]., Conclusions: We found that psoriasis incidence and prevalence are increasing and varied by age, sex and ethnicity. Our findings should help inform healthcare planning and management for patients with psoriasis in Malaysia. What is already known about this topic? The incidence and prevalence of psoriasis are generally lower in Asian populations and children. There is a lack of agreement on sex-specific differences in psoriasis incidence and prevalence. There has been no population-based study on the incidence and prevalence of psoriasis in Southeast Asia, including Malaysia. There is no information on differences in psoriasis prevalence and incidence by sex, age and ethnicity in Malaysia. What does this study add? Psoriasis incidence and prevalence are increasing in the multiethnic population of Johor Bahru, Malaysia. Incidence and prevalence rates were higher in male than female patients and were consistently highest among Indian patients, followed by Chinese and Malay. A modest bimodality in the age of psoriasis onset was observed among the groups aged 20-29 and 50-59 years. Psoriasis onset was significantly later in male than female patients and in Chinese vs. Indian and Malay patients., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objective: To compare rates of performing National Institute for Health and Care Excellence-recommended health checks and prescribing in people with type 2 diabetes (T2D), before and after the first COVID-19 peak in March 2020, and to assess whether trends varied by age, sex, ethnicity and deprivation., Methods: We studied 618 161 people with T2D followed between March and December 2020 from 1744 UK general practices registered with the Clinical Practice Research Datalink. We focused on six health checks: haemoglobin A1c, serum creatinine, cholesterol, urinary albumin excretion, blood pressure and body mass index assessment. Regression models compared observed rates in April 2020 and between March and December 2020 with trend-adjusted expected rates derived from 10-year historical data., Results: In April 2020, in English practices, rates of performing health checks were reduced by 76%-88% when compared with 10-year historical trends, with older people from deprived areas experiencing the greatest reductions. Between May and December 2020, the reduced rates recovered gradually but overall remained 28%-47% lower, with similar findings in other UK nations. Extrapolated to the UK population, there were ~7.4 million fewer care processes undertaken March-December 2020. In England, rates for new medication fell during April with reductions varying from 10% (95% CI: 4% to 16%) for antiplatelet agents to 60% (95% CI: 58% to 62%) for antidiabetic medications. Overall, between March and December 2020, the rate of prescribing new diabetes medications fell by 19% (95% CI: 15% to 22%) and new antihypertensive medication prescribing fell by 22% (95% CI: 18% to 26%), but prescribing of new lipid-lowering or antiplatelet therapy was unchanged. Similar trends were observed across the UK, except for a reduction in new lipid-lowering therapy prescribing in the other UK nations (reduction: 16% (95% CI: 10% to 21%)). Extrapolated to the UK population, between March and December 2020, there were ~31 800 fewer people with T2D prescribed a new type of diabetes medication and ~14 600 fewer prescribed a new type of antihypertensive medication., Conclusions: Over the coming months, healthcare services will need to manage this backlog of testing and prescribing. We recommend effective communications to ensure patient engagement with diabetes services, monitoring and opportunities for prescribing, and when appropriate use of home monitoring, remote consultations and other innovations in care., Competing Interests: Competing interests: DMA reports research funding from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, Janssen, UCB and the Leo Foundation outside the submitted work. MKR has received consulting fees and non-promotional lecture fees from Novo Nordisk in relation to cardiovascular disease and diabetes. The company has had no role in influencing the proposed study and is not expected to benefit from this work. Outside the submitted work, MKR reports receiving research funding from Novo Nordisk, consultancy fees from Novo Nordisk and Roche Diabetes Care, and modest owning of shares in GlaxoSmithKline. NM reports honorarium for presentations from Napp Pharmaceuticals, Novo Nordisk, Sanofi, MyLan, Boehringer Ingelheim, Lilly Diabetes, Abbott, Omnia-Med, Takeda UK and AstraZeneca. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Most patients with mental illness are managed in primary care, yet there is a lack of data exploring potential prescribing safety issues in this setting for this population., Objectives: Examine the prevalence of, between-practice variation in, and patient and practice-level risk factors for, 18 mental health-related potentially hazardous prescribing indicators and four inadequate medication monitoring indicators in UK primary care., Method: Cross-sectional analyses of routinely collected electronic health records from 361 practices contributing to Clinical Practice Research Datalink GOLD database. The proportion of patients 'at risk' (based on an existing diagnosis, medication, age and/or sex) triggering each indicator and composite indicator was calculated. To examine between-practice variation, intraclass correlation coefficient (ICC) and median OR (MOR) were estimated using two-level logistic regression models. The relationship between patient and practice characteristics and risk of triggering composites including 16 of the 18 prescribing indicators and four monitoring indicators were assessed using multilevel logistic regression., Results: 9.4% of patients 'at risk' (151 469 of 1 611 129) triggered at least one potentially hazardous prescribing indicator; between practices this ranged from 3.2% to 24.1% (ICC 0.03, MOR 1.22). For inadequate monitoring, 90.2% of patients 'at risk' (38 671 of 42 879) triggered at least one indicator; between practices this ranged from 33.3% to 100% (ICC 0.26, MOR 2.86). Patients aged 35-44, females and those receiving more than 10 repeat prescriptions were at greatest risk of triggering a prescribing indicator. Patients aged less than 25, females and those with one or no repeat prescription were at greatest risk of triggering a monitoring indicator., Conclusion: Potentially hazardous prescribing and inadequate medication monitoring commonly affect patients with mental illness in primary care, with marked between-practice variation for some indicators. These findings support health providers to identify improvement targets and inform development of improvement efforts to reduce medication-related harm., 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.)

The molecular composition of the plasma membrane plays a key role in mediating the susceptibility of cells to perturbations induced by toxic molecules. The pharmacological regulation of the properties of the cell membrane has therefore the potential to enhance cellular resilience to a wide variety of chemical and biological compounds. In this study, we investigate the ability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acute biological threat agents, including melittin from honeybee venom and α-hemolysin from Staphylococcus aureus . Our results show that claramine neutralizes the toxicity of these pore-forming agents by preventing their interactions with cell membranes without perturbing their structures in a detectable manner. We thus demonstrate that the exogenous administration of an aminosterol can tune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers as previously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of the physicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set of cytotoxic effects associated with cell membrane disruption.

Objective: To assess associations between current use of sodium-glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and their combination and risk for major adverse cardiac and cerebrovascular events (MACCE) and heart failure (HF) in people with type 2 diabetes., Research Design and Methods: In three nested case-control studies involving patients with type 2 diabetes in England and Wales (primary care data from the Clinical Practice Research Datalink and Secure Anonymised Information Linkage Databank with linkage to hospital and mortality records), we matched each patient experiencing an event with up to 20 control subjects. Adjusted odds ratios (ORs) for MACCE and HF among patients receiving SGLT2i or GLP-1RA regimens versus other combinations were estimated using conditional logistic regression and pooled using random-effects meta-analysis., Results: Among 336,334 people with type 2 diabetes and without cardiovascular disease, 18,531 (5.5%) experienced a MACCE. In a cohort of 411,206 with type 2 diabetes and without HF, 17,451 (4.2%) experienced an HF event. Compared with other combination regimens, the adjusted pooled OR and 95% CI for MACCE associated with SGLT2i regimens was 0.82 (0.73, 0.92), with GLP-1RA regimens 0.93 (0.81, 1.06), and with the SGLT2i/GLP-1RA combination 0.70 (0.50, 0.98). Corresponding data for HF were SGLT2i 0.49 (0.42, 0.58), GLP-1RA 0.82 (0.71, 0.95), and SGLT2i/GLP-1RA combination 0.43 (0.28, 0.64)., Conclusions: SGLT2i and SGLT2i/GLP-1RA combination regimens may be beneficial in primary prevention of MACCE and HF and GLP-1RA for HF. These data call for primary prevention trials using these agents and their combination., (© 2022 by the American Diabetes Association.)

Aims: We evaluated the relationship between body mass index (BMI) and cancer mortality in incident type 2 diabetes., Methods: We used the Clinical Practice Research Datalink GOLD (1998-2015), linked with the Office of National Statistics mortalities, and derived an incident type 2 diabetes cohort (N = 176 886; aged 30-85 years). We determined BMI ±12 months diabetes diagnosis. The primary outcome was cancer mortality, categorized into deaths from obesity-related cancers (ORCs) and non-ORCs. Secondary outcomes were site-specific cancer mortality and main causes of deaths [cancer, cardiovascular disease (CVD), non-cancer non-CVD]. We developed gender-specific Cox models and expressed risk as hazard ratios and 95% confidence intervals, stratified by smoking status., Results: With 886 850 person-years follow-up, 7593 cancer deaths occurred. Among women who never smoked, there were positive associations between BMI and deaths from endometrial (hazard ratios per 5 kg/m 2 : 1.43; 95% confidence interval 1.26-1.61). Among men, associations between BMI and ORC mortality were inverse but attenuated towards null among never smokers and excluding deaths in the first 2 years. In men, the proportion of CVD deaths increased from 36.8% in BMI category 22.5 to 24.9 kg/m 2 to 43.6% in BMI category ≥40 kg/m 2 (p < .001)., Conclusions: We found some relationships between BMI and cancer mortality in patients with type 2 diabetes, but interpretations need to account for smoking status, reverse causality and deaths from CVD., (© 2022 John Wiley & Sons Ltd.)

Objective: To examine the effects of sleep traits on glycated hemoglobin (HbA1c)., Research Design and Methods: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female)., Results: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect., Conclusions: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes., (© 2022 by the American Diabetes Association.)

This report investigates the homotetrameric membrane protein structure of the S31N M2 protein from Influenza A virus in the presence of a high molar ratio of lipid. The structured regions of this protein include a single transmembrane helix and an amphipathic helix. Two structures of the S31N M2 conductance domain from Influenza A virus have been deposited in the Protein Data Bank (PDB). These structures present different symmetries about the channel main axis. We present new magic angle spinning and oriented sample solid-state NMR spectroscopic data for S31N M2 in liquid crystalline lipid bilayers using protein tetramer:lipid molar ratios ranging from 1:120 to 1:240. The data is consistent with an essentially 4-fold-symmetric structure very similar to the M2 WT structure that also has a single conformation for the four monomers, except at the His37 and Trp41 functional sites when characterized in samples with a high molar ratio of lipid. While detergent solubilization is well recognized today as a nonideal environment for small membrane proteins, here we discuss the influence of a high lipid to protein ratio for samples of the S31N M2 protein to stabilize an essentially 4-fold-symmetric conformation of the M2 membrane protein. While it is generally accepted that the chemical and physical properties of the native environment of membrane proteins needs to be reproduced judiciously to achieve the native protein structure, here we show that not only the character of the emulated membrane environment is important but also the abundance of the environment is important for achieving the native structure. This is a critical finding as a membrane protein spectroscopist's goal is always to generate a sample with the highest possible protein sensitivity while obtaining spectra of the native-like structure.

Purpose: Symptomatic adult spinal deformity (ASD) with an extremely variable presentation with pain, with and without neurogenic leg pain, and/or disturbed sagittal and coronal balance, causes a significant societal burden of disease. It is an important consequence of the aging adult population, generating a plethora of spine-related interventions with variable treatment efficacy and consistently high costs. Recent years have witnessed more than a threefold increase in the prevalence and treatment of ASD, and further increases over the coming decades are expected with the growing elderly population worldwide. The ability to monitor and assess clinical outcomes has not kept pace with these developments. This paper addresses the pressing need to provide a set of common outcome metrics for this growing group of patients with back pain and other disabilities due to an adult spinal deformity., Methods: The standard outcome set was created by a panel with global representation, using a thorough modified Delphi procedure. The three-tiered outcome hierarchy (Porter) was used as a framework to capture full cycle of care. The standardized language of the International Classification of Functioning, Disability and Health (WHO-ICF) was used., Results: Consensus was reached on a core set of 25 WHO-ICF outcome domains ('What to measure'); on the accompanying globally available clinician and patient reported measurement instruments and definitions ('How to measure'), and on the timing of the measurements ('When to measure'). The current work has brought to light domains not routinely reported in the spinal literature (such as pulmonary function, return to work, social participation), and domains for which no adequate instruments have yet been identified (such as how to clinically quantify in routine practice lumbar spinal stenosis, neurogenic claudication, radicular pain, and loss of lower extremity motor function)., Conclusion: A standard outcome set was developed for patients undergoing treatment for adult spinal deformity using globally available outcome metrics. The current framework can be considered a reference for further work, and may provide a starting point for routine methodical and systematic monitoring of outcomes. Post-COVID e-health may accelerate the routine capture of these types of data., (© 2021. The Author(s).)

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer's and Parkinson's diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer's and Parkinson's diseases., Competing Interests: DB and MZ are inventors in a patent for the use of aminosterols in the treatment of Parkinson’s disease. DB and MZ are co-founders of Enterin Inc. and serve as the President and CSO, respectively, of the company. MV, TPJK, and JH are co-founders, and BM and MP are employees of Wren Therapeutics Ltd., which is independently pursuing inhibitors of protein misfolding and aggregation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Limbocker, Staats, Chia, Ruggeri, Mannini, Xu, Perni, Cascella, Bigi, Sasser, Block, Wright, Kreiser, Custy, Meisl, Errico, Habchi, Flagmeier, Kartanas, Hollows, Nguyen, LeForte, Barbut, Kumita, Cecchi, Zasloff, Knowles, Dobson, Chiti and Vendruscolo.)

Using an app, this exploratory study generated information on HRQL in a large cohort of dogs deemed healthy according to the owner. It forms the basis for further studies investigating the natural history of HRQL of dogs to inform the interpretation of interventional studies, but highlights the risks of relying on owner impression of health status. A previously published health-related quality of life (HRQL) instrument (VetMetrica™) that generates scores in four domains of quality of life in dogs - Energetic and Enthusiastic (E/E), Happy and Content (H/C), Active and Comfortable (A/C), and Calm and Relaxed (C/R), generated information on HRQL in 4,217 dogs (3 months-21 years). Dogs were categorized by age; young, 3-47 months, middle-aged, 48-95 months, and old, 96 months and older. Owners considered 2,959 dogs (3-95 months) to be "in perfect health" and these were used to explore the relationship between age, sex, breed and HRQL in apparently healthy dogs. Mean score was significantly greater (better) in young compared to middle-aged dogs in E/E, H/C and A/C and declined with advancing age. In H/C there was a small but significant difference in mean score between female and male dogs (mean greater in females), with a similar rate of decline in each gender with advancing age. In E/E there were very small but statistically significant differences in mean scores between certain breeds. In A/C there was a statistically significant interaction between breed and age and the rate of decline with advancing age differed with breed. Overall, age, breed, and sex predicted very little of the variation seen in HRQL scores. Data from a subset of 152 dogs, for whom clinical information was available, were used to examine the agreement between clinical evidence and owner opinion. According to the clinical records, 89 dogs were healthy and 63 had evidence of chronic disease. There was an approximately 40% disagreement between owner opinion on health status and clinical evidence of chronic disease (35% disagreement in all dogs and 43% in old dogs). HRQL scores were generally higher in dogs for whom there was no evidence of disease in the clinical record., Competing Interests: JR was employed by the company NewMetrica Ltd and AW by Zoetis Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rodger, Scott, Nolan, Wright and Reid.)

Many institutions have developed shared decision-making conferences as a mechanism for reducing treatment costs and improving patient outcomes. Little is known about the process of shared decision-making that takes place in these conferences, and there is the possibility of bias among surgeons and nonsurgeons for treatment within their respective specialties. This study was conducted to determine who is contributing to the decision-making process in a multidisciplinary spine conference and to what extent treatment biases exist among the surgical and nonsurgical members of this conference. Voting data were collected during weekly multidisciplinary spine conferences. Descriptive statistics were calculated on the cases presented and the number and type of physicians voting for each case. The likelihood of a particular vote in the surgeon and nonsurgeon cohorts was evaluated using relative risk calculation and multinomial logistic regression. A total of 262 consecutive cases were analyzed. No significant differences in treatment recommendation were observed between surgery and nonsurgical management (relative risk, 1.1; 95% CI, 0.97-1.25) when comparing votes from the surgeon and nonsurgeon cohorts. Multinomial logistic regression showed the odds of nonsurgeons recommending nonsurgical management over surgery was 20% greater than receiving that recommendation from their surgeon colleagues. Individual surgeon and nonsurgeon voters were evenly distributed above and below the mean for treatment recommendation. Individual and group biases exist among surgeons and nonsurgeons treating degenerative spine diseases. Multidisciplinary conferences may or may not level these biases, depending on how they are conducted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships., Methods: A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control., Results: In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease., Conclusions: Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.

The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size-hydrophobicity-toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation.

Preventive measures in human healthcare are recognized as a means of providing early detection of disease, however, the veterinary profession has not been as effective in communicating the benefits of preventive measures to pet owners. Readily available pet healthcare information on the internet, owners not understanding that regular health evaluations can ensure the well-being of their pets and owners confusing the signs of chronic disease with normal aging have contributed to declining numbers of veterinary visits. The use of web-based generic health-related quality of life (HRQL) measures to evaluate health status (wellness) remotely could facilitate veterinary preventive medicine. This publication describes the development and practical application of an integrated alert system for an online generic HRQL measurement instrument (VetMetrica™) which generates scores in four domains of HRQL-Energetic/Enthusiastic (E/E), Happy/Content (H/C), Active/Comfortable (A/C), and Calm/Relaxed (C/R)-for 2 age groups (young/middle-aged, ≤7 years and old, ≥8 years). The alert provides an early warning, via email to owners, that a potentially significant deterioration in health status has occurred. The model accurately predicted the health status of 93 and 83% of sick young/middle aged and old dogs respectively, with healthy dogs predicted with 83% accuracy. HRQL data, collected via a white-labeled veterinary clinic branded app designed to facilitate connected care between owner and veterinarian, were analyzed for 6,108 dogs, aged between 6 weeks and 16 years. Of these 5,002 were deemed to be in perfect health by their owners, yet the alert was triggered for 1,343 (27%) of these, 75% of which were young/middle-aged and 25% were old, indicating that acute injuries notwithstanding, many middle aged dogs may have been suffering from undetected chronic disease such as osteoarthritis. This work has demonstrated that the use of VetMetrica™ delivered via the PetDialog™ app, which supports 24/7 remote health monitoring is an efficient way for vets to provide all their owners with the opportunity to monitor their animal's wellness throughout their lifetime, providing the vet with a mechanism to identify health problems early while stimulating owners to be more proactive in seeking veterinary attention., (Copyright © 2020 Davies, Scott, Wright and Reid.)

Objectives: Systemic glucocorticoids are widely used in companion animals. This study aimed to estimate the frequency, describe the characteristics and to evaluate risk factors for common side effects to systemic glucocorticoid therapy in dogs under primary veterinary care in the UK. Methods: A cohort study using VetCompass™ data from 455,557 dogs under primary veterinary care during 2013 estimated the frequency of side effects to systemic glucocorticoid therapy occurring within 31 days of therapy. Risk factors for the most common side effects, polyuria and polydipsia (PUPD), were evaluated using multivariable logistic regression modeling ( P < 0.05). Results: During 2013, 28,472 study dogs received systemic glucocorticoids (6.2%, 95% CI 6.2-6.3). Review of the records of 3,000 randomly selected treated dogs identified 148 (4.9%, 95% CI 4.2-5.7%) dogs with at least one side effect recorded within 31 days of therapy. The most frequent side effects were polydipsia (39.2% of total presenting signs), polyuria (28.4%), vomiting (16.2%) and diarrhea (14.9%), dogs receiving only oral systemic glucocorticoids (odds ratio, OR: 3.72) and dogs receiving both oral and injectable systemic glucocorticoid (OR: 10.71) had increased odds of PUPD compared with dogs receiving only injectable systemic glucocorticoid. Focusing on the active substance used, treatment with prednisolone tablets only (OR: 3.53) and treatment with both prednisolone tablets and injectable dexamethasone sodium phosphate (OR: 7.62) showed increased odds of PUPD compared to treatment with injectable dexamethasone sodium phosphate only. Brief: These results can assist veterinarians to optimize therapeutic selection for reduced side effect, to inform owners on common side effects, and help protect the welfare of pets and their owners., (Copyright © 2020 Elkholly, Brodbelt, Church, Pelligand, Mwacalimba, Wright and O'Neill.)

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.

Aims/hypothesis: The aim of this work was to determine how weight patterns together with blood glucose, BP and lipids vary at diagnosis of diabetes by age, sex and ethnicity., Methods: Using the UK Clinical Practice Research Datalink, we identified people with type 2 diabetes (n = 187,601) diagnosed in 1998-2015 and compared their weights, HbA 1c , BP and lipid levels at diagnosis with age-matched people without diabetes (n = 906,182), by sex and ethnic group., Results: Younger age at diagnosis was associated with greater adjusted mean difference (95% CI) in weight between those with vs without type 2 diabetes: 18.7 (18.3, 19.1) kg at age 20-39 years and 5.3 (5.0, 5.5) kg at age ≥ 80 years. Weight differentials were maximal in white women, and were around double in white people compared with South Asian and black people. Despite lower absolute values, BP differences were also greater at younger age of diabetes onset: 7 (6, 7) mmHg at age 20-39 years vs -0.5 (-0.9, -0.2) at age ≥ 80 years. BP differences were greatest in white people, and especially in women. Triacylglycerol level differences were greatest in younger men. Finally, HbA 1c levels were also higher with younger onset diabetes, particularly in black people., Conclusions/interpretation: At diagnosis of type 2 diabetes, when compared with people without diabetes, weight and BP differentials were greater in younger vs older people, in women vs men and in white vs South Asian and black people. These differences were observed even though South Asian and black people tend to develop diabetes a decade earlier with either similar or greater dysglycaemia. These striking patterns may have implications for management and prevention. Graphical abstract.

Alzheimer's disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure-toxicity relationship of Aβ oligomers. For this purpose, we use Zn 2+ -stabilized oligomers of the 40-residue form of Aβ (Aβ 40 ) as models of brain Aβ oligomers and two single-domain antibodies (DesAb 18-24 and DesAb 34-40 ), designed to bind to epitopes at residues 18-24 and 34-40 of Aβ 40 , respectively. We found that the DesAbs induce a change in structure of the Zn 2+ -stabilized Aβ 40 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure-toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of Aβ oligomers.

Relative brain sizes in birds can rival those of primates, but large-scale patterns and drivers of avian brain evolution remain elusive. Here, we explore the evolution of the fundamental brain-body scaling relationship across the origin and evolution of birds. Using a comprehensive dataset sampling> 2,000 modern birds, fossil birds, and theropod dinosaurs, we infer patterns of brain-body co-variation in deep time. Our study confirms that no significant increase in relative brain size accompanied the trend toward miniaturization or evolution of flight during the theropod-bird transition. Critically, however, theropods and basal birds show weaker integration between brain size and body size, allowing for rapid changes in the brain-body relationship that set the stage for dramatic shifts in early crown birds. We infer that major shifts occurred rapidly in the aftermath of the Cretaceous-Paleogene mass extinction within Neoaves, in which multiple clades achieved higher relative brain sizes because of a reduction in body size. Parrots and corvids achieved the largest brains observed in birds via markedly different patterns. Parrots primarily reduced their body size, whereas corvids increased body and brain size simultaneously (with rates of brain size evolution outpacing rates of body size evolution). Collectively, these patterns suggest that an early adaptive radiation in brain size laid the foundation for subsequent selection and stabilization., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Surgical management of complex adult spinal deformities is of high risk, with a substantial risk of operative mortality. Current evidence shows that potential risk and morbidity resulting from surgery for complex spinal deformity may be minimized through risk-factor optimization. The multidisciplinary team care model includes neurosurgeons, orthopaedic surgeons, physiatrists, anesthesiologists, hospitalists, psychologists, physical therapists, specialized physician assistants, and nurses. The multidisciplinary care model mimics previously described integrated care pathways designed to offer a structured means of providing a comprehensive preoperative medical evaluation and evidence-based multimodal perioperative care. The role of each team member is illustrated in the case of a 66-year-old male patient with previous incomplete spinal cord injury, now presenting with Charcot spinal arthropathy and progressive vertebral-body destruction resulting in lumbar kyphosis.

Study Design: Quality improvement with before and after evaluation of the intervention., Objective: To evaluate postoperative opioid utilization at a high-volume tertiary referral center following implementation of an opioid reduction protocol for simple outpatient neurosurgical procedures., Summary of Background Data: The opioid epidemic has been well-publicized both in the scientific and lay press over the last few years. As a response to this crisis many state-wide and national medical groups have sought to develop opioid prescribing guidelines for both acute and chronic pain states. Some guidelines have studied opioid prescribing in orthopedic procedures but have primarily limited their recommendations to simple outpatient orthopedic joint procedures. Although, it is not clear that these opioid prescribing reductions are directly translatable to neurosurgical procedures., Methods: We implemented an opioid reduction protocol geared towards the postoperative management for simple outpatient neurosurgical procedures and measured the effect on number of pills and total morphine equivalent dose (MED) prescribed, postoperative readmissions, refill requests, and conversion to long-term opiate use., Results: Our study population was 246 patients, with 109 patients in the pre-intervention (PRE) group and 137 patients in the post-intervention (POST) group. The vast majority of patients in both groups were discharged with an opioid prescription (93% PRE, 91% POST, P = 0.87). The POST group had significantly lower total discharge opioid medication quantity (52 tabs PRE, 27 tabs POST, P < 0.001), discharge day MED (51.3 PRE, 45.3 POST, P = 0.01), and total discharge MED (287 PRE, 149 POST, P < 0.001)., Conclusion: A standardized discharge protocol for postoperative neurosurgery can lead to significant reductions in opioid discharge quantity without compromising patient safety or increasing the utilization of hospital resources through readmissions, refill requests, or clinic phone calls. This study provides an example of a feasible and effective discharge prescription regimen that may be generalizable to some of the most common outpatient neurosurgical procedures., Level of Evidence: 3.

Study Design: Single-institution retrospective cohort study., Objective: To determine whether prescribing practices at discharge are associated with opioid dependence (OD) in patients undergoing discectomy or laminectomy procedures for degenerative indications., Summary of Background Data: Long-term opioid use in spine surgery is associated with higher healthcare utilization and worse postoperative outcomes. The impact of prescribing practices at discharge within this surgical population is poorly understood., Methods: A query of an administrative database was conducted to identify all patients undergoing discectomy or laminectomy procedures at our high-volume tertiary referral center between 2007 and 2016. For patients included in the analysis, opioid prescription data on admission and discharge were manually abstracted from the electronic health record, including opioid type, frequency, route, and dose, and then converted to daily morphine equivalent dose (MED) values. We defined OD as a consecutive narcotic prescription lasting for at least 90 days within the first 12 months after the index surgical procedure., Results: Of the 819 total patients, 499 (60.9%) patients had an active opioid prescription before surgery. Postoperatively, 813 (99.3%) received at least one narcotic prescription within 30 days of index surgery, and 162 (19.8%) continued with sustained opioid use in the 12 months after surgery. In adjusted analysis, patients with OD had a higher incidence of preoperative depression (P = 0.012) and preoperative opioid use (P < 0.001), as well as a higher frequency of preoperative benzodiazepine prescriptions (P = 0.009), and discharge MED value exceeding 120 mg/day (P = 0.013). Postoperative OD was observed in 7.5% of previously opioid-naïve patients., Conclusion: This is the first study to test for an association between MED values prescribed at discharge and sustained opioid use after lumbar spine surgery. In addition to previously reported risk factors, discharge prescription dose exceeding 120 mg/day is independently associated with OD after spine surgery., Level of Evidence: 3.