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Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged. We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0–2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed. Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59–71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2–10) and median follow-up was 28 months (IQR 16–34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients. Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors. Bristol Myers Squibb.

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Measures to facilitate this goal include: the establishment of a framework to monitor and assess the burden of stroke (and its risk factors) and stroke services at a national level; the implementation of integrated population-level and individual-level prevention strategies for people at any increased risk of cerebrovascular disease, with emphasis on early detection and control of hypertension; planning and delivery of acute stroke care services, including the establishment of stroke units with access to reperfusion therapies for ischaemic stroke and workforce training and capacity building (and monitoring of quality indicators for these services nationally, regionally, and globally); the promotion of interdisciplinary stroke care services, training for caregivers, and capacity building for community health workers and other health-care providers working in stroke rehabilitation; and the creation of a stroke advocacy and implementation ecosystem that includes all relevant communities, organisations, and stakeholders. Introduction The global burden of stroke is huge: in 2020, stroke was the second leading cause of death (6·6 million deaths) and the third leading cause of disability (responsible for 143 million disability-adjusted life-years [DALYs]) after neonatal disorders (in children) and ischaemic heart disease (in adults).1,2 Alarmingly, evidence suggests that the incidence of stroke in younger individuals (ie, people younger than 55 years) is increasing worldwide.3 The absolute number of people affected by stroke, which includes those who die or remain disabled, has almost doubled in the past 30 years.1 Most of the contemporary stroke burden—86% of global deaths and 89% of global DALYs lost because of stroke in 2020—is in low-income and middle-income countries (LMICs),1 and the burden of stroke is increasing faster in LMICs than in high-income countries (HICs).1 Stroke is also a leading cause of depression and dementia, which are other common non-communicable diseases (NCDs).4,5 Little progress has been made by most countries towards Sustainable Development Goal (SDG) 3.4—reducing premature mortality from NCDs by a third between 2015 and 2030.6 Achieving SDG 3.4 worldwide, which would in turn facilitate the achievement of nine other SDGs,7 would require an additional US$140 billion of spending on NCD interventions from 2023–30, but could help to avert 39 million deaths and generate $2·7 trillion in net economic benefits (with benefits outweighing costs by a factor of 19:1).6 Given that the incidence of stroke rises with age, the combination of growing populations and ageing demographics is likely to result in large increases in global deaths and disability in the future unless major improvements occur in population prevention programmes that reduce the risk of stroke.8 Thus, pragmatic solutions to reduce the burden of stroke and related NCDs are urgently needed to save lives and improve brain health, quality of life, and socioeconomic productivity globally.8–11 Key messages Multiple factors contribute to the high burden of stroke in low-income and middle-income countries, including undetected and uncontrolled hypertension, lack of easily accessible, high-quality health services, insufficient attention to and investment in prevention, air pollution, population growth, unhealthy lifestyles (eg, poor diet, smoking, sedentary lifestyle, obesity), an earlier age of stroke onset and greater proportion of haemorrhagic strokes than in high-income countries, and the burden of infectious diseases resulting in competition for limited healthcare resources. Major facilitators include professional stroke organisations and networks that could advocate and build capacity for stroke care and research, and universal health coverage that can facilitate population-wide access to evidence-based care (pre-hospital care, acute care, rehabilitation, and prevention).

The Proteus syndrome affects some tissues and not others and is thought to be caused by a somatic mutation. Investigators found that the mutation is caused by activation of AKT1, an enzyme that mediates glucose metabolism, cell proliferation, and apoptosis. The Proteus syndrome is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to the development of tumors 1 , 2 (Figure 1). It is thought that Joseph Merrick, an Englishman who lived in the late 19th century and became the subject of the play and film The Elephant Man, had the Proteus syndrome. This uncommon syndrome (with an incidence of <1 case per 1 million population) has not been reported to recur in a family but has been reported in discordant monozygotic twins. 3 These observations support the hypothesis that the Proteus syndrome is caused . . .

Background Awareness of prescribing practices helps identify opportunities to improve antibiotic use (AU). Objectives To estimate AU prevalence in dogs and cats in U.S. veterinary teaching hospitals (VTHs) and identify antibiotic drugs commonly prescribed, indications for use, and evidence of bacterial infection. Animals Medical record data were collected from dogs and cats examined at 14 VTHs. Methods Data were collected from VTH medical records of dogs and cats examined by primary care, urgent care, emergency and critical care, internal medicine, and surgery services on a single day during August 13‐September 3, 2020. Data included signalment; clinical service; inpatient or outpatient status; clinical conditions; diagnostic tests; evidence of bacterial infection; intended reason for AU; name and route of antibiotics prescribed. Results Of 883 dogs and cats, 322 (36.5%) were prescribed at least 1 antibiotic. Among 285 antibiotics administered systemically intended for treatment of infection, 10.9% were prescribed without evidence of infection. The most common class of antibiotics presribed for systemic administration was potentiated penicillin for dogs (115/346, 33.3%) and cats (27/80, 33.8%). For dogs and cats, first‐generation cephalosporins (93/346, 26.9% and 11/80, 13.8%, respectively) and fluoroquinolones (51/346, 14.7% and 19/80, 23.8%, respectively) was second or third most‐prescribed. Common AU indications included skin, respiratory, and urinary conditions, and perioperative use. Conclusions and Clinical Importance Collaborative data collection provides a sustainable methodology to generate national AU prevalence estimates and bring attention to areas requiring additional research and detailed data collection. These efforts can also identify practice improvement opportunities in settings where future veterinarians are trained.

ABSTRACTBackgroundObesity is a complex, chronic, stigmatized disease whereby abnormal or excess body fat may impair health or increase the risk of medical complications, and can reduce quality of life and shorten lifespan in children and families. We developed this guideline to provide evidence-based recommendations on options for managing pediatric obesity that support shared decision-making among children living with obesity, their families, and their health care providers. MethodsWe followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We used the Guidelines International Network principles to manage competing interests. Caregivers, health care providers, and people living with obesity participated throughout the guideline development process, which optimized relevance. We surveyed end users (caregivers, health care providers) to prioritize health outcomes, completed 3 scoping reviews (2 on minimal important difference estimates; 1 on clinical assessment), performed 1 systematic review to characterize families’ values and preferences, and conducted 3 systematic reviews and meta-analyses to examine the benefits and harms of behavioural and psychological, pharmacologic, and surgical interventions for managing obesity in children. Guideline panellists developed recommendations focused on an individualized approach to care by using the GRADE evidence-to-decision framework, incorporating values and preferences of children living with obesity and their caregivers. RecommendationsOur guideline includes 10 recommendations and 9 good practice statements for managing obesity in children. Managing pediatric obesity should be guided by a comprehensive child and family assessment based on our good practice statements. Behavioural and psychological interventions, particularly multicomponent interventions (strong recommendation, very low to moderate certainty), should form the foundation of care, with tailored therapy and support using shared decision-making based on the potential benefits, harms, certainty of evidence, and values and preferences of children and families. Pharmacologic and surgical interventions should be considered (conditional recommendation, low to moderate certainty) as therapeutic options based on availability, feasibility, and acceptability, and guided by shared decision-making between health care providers and families. InterpretationThis guideline will support children, families, and health care providers to have informed discussions about the balance of benefits and harms for available obesity management interventions to support value- and preference-sensitive decision-making.

BackgroundA single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.MethodsThree families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.ResultsGenetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.ConclusionThese data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.