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Transesophageal echocardiography (TEE) is the gold standard for the detection of valvular vegetations (VV). Differentiating small VV from degenerative changes is challenging and prone to inter-observer variability. We evaluated inter-observer agreement regarding aortic (AV) and mitral valve (MV) findings on TEEs ordered for suspected infective endocarditis (IE).A total of 349 consecutive TEEs were evaluated. Studies were classified as "definite, possible, or no" IE with valve masses classified further by morphology. Nine faculty echocardiographers scored randomly selected TEEs of the AV (N = 38) and MV (N = 35). Inter-reader variability was calculated using the Fleiss/Scott Kappa (Kf).Positive blood cultures were present in 81% and 45% had definite IE by the modified Duke criteria. There was moderate reader agreement regarding the presence of a valvular mass for both the AV (Kf = .41, 95% CI [.30-.53]) and MV (Kf = .49, 95% CI [.34-.65]). For diagnosis of IE, there was fair agreement for the AV (Kf = .29, 95% CI [.18-.42]) and moderate agreement for the MV (Kf = .53, 95% CI [.36-.70]). Masses described as large, multi-lobulated, or pedunculated were more frequently categorized as clinical IE, (p .006, both valves), however those with filamentous lesions were not (p .001, both valves).In a large academic center, the inter-observer agreement for the presence of a left sided valvular mass was moderate and agreement regarding the final diagnosis of IE was fair to moderate, with better agreement among readers evaluating the MV. Lesion morphology is associated with the clinical diagnosis of IE.

Aim To evaluate a web-based tool for estimating and explaining three scenarios for expected survival time to people with advanced cancer (patients), their family members (FMs), and other healthcare professionals (HCPs). Methods Thirty-three oncologists estimated the “median survival of a group of similar patients” for patients seeking quantitative prognostic information. The web-based tool generated worst-case, most likely, and best-case scenarios for survival based on the oncologist’s estimate. Oncologists presented the scenarios to each patient and provided a printed summary to patients, FMs, and HCPs. Attitudes to the information were assessed by questionnaires. Observed survival for each patient was compared with the oncologist’s estimated survival and the three scenarios. Results Prognosis was discussed with 222 patients: median age 67 years; 61% male; most common primary sites pancreas 15%, non-small-cell lung 15%, and colorectal 12%. The median (range) for observed survival times was 9 months (0.5–43) and for oncologist’s estimated survival times was 12 months (2–96). Ninety-one percent of patients, 91% of FMs, and 84% of HCPs agreed that it was helpful having life expectancy explained as three scenarios. The majority (77%) of patients judged the information presented about their life expectancy to be the same or better than they had expected before the consultation. The survival estimates met a priori criteria for calibration, precision, and accuracy. Conclusions Patients, FMs, and HCPs found it helpful to receive personalized prognostic information formatted as three scenarios for survival. It was feasible, acceptable, and safe to use a web-based resource to do this.

Background Asthma and atherosclerotic cardiovascular disease share an underlying inflammatory pathophysiology. We hypothesized that persistent asthma is associated with carotid plaque burden, a strong predictor of atherosclerotic cardiovascular disease events. Methods and Results The MESA (Multi‐Ethnic Study of Atherosclerosis) enrolled adults free of known atherosclerotic cardiovascular disease at baseline. Subtype of asthma was determined at examination 1. Persistent asthma was defined as asthma requiring use of controller medications, and intermittent asthma was defined as asthma without controller medications. B‐mode carotid ultrasound was performed to detect carotid plaques (total plaque score [TPS], range 0–12). Multivariable regression modeling with robust variances evaluated the association of asthma subtype and carotid plaque burden. The 5029 participants were a mean (SD) age of 61.6 (10.0) years (53% were women, 26% were Black individuals, 23% were Hispanic individuals, and 12% were Chinese individuals). Carotid plaque was present in 50.5% of participants without asthma (TPS, 1.29 [1.80]), 49.5% of participants with intermittent asthma (TPS, 1.25 [1.76]), and 67% of participants with persistent asthma (TPS, 2.08 [2.35]) ( P ≤0.003). Participants with persistent asthma had higher interleukin‐6 (1.89 [1.61] pg/mL) than participants without asthma (1.52 [1.21] pg/mL; P =0.02). In fully adjusted models, persistent asthma was associated with carotid plaque presence (odds ratio, 1.83 [95% confidence interval, 1.21–2.76]; P P P =0.02) or CRP (C‐reactive protein) ( P =0.01). Conclusions Participants with persistent asthma had higher carotid plaque burden and higher levels of inflammatory biomarkers, compared with participants without asthma. Adjustment for baseline inflammatory biomarkers did not attenuate the association between carotid plaque and asthma subtype, highlighting the increased atherosclerotic cardiovascular disease risk among those with persistent asthma may be multifactorial.

Key points Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Survivors may develop a severe myasthenic syndrome or paralysis, associated with increased plasma levels of cyclohexanol, an insecticide solvent metabolite. Analysis of synaptic transmission at neuromuscular junctions in isolated mouse skeletal muscle, using isometric tension recording and microelectrode recording of endplate voltages and currents, showed that cyclohexanol reduced postsynaptic sensitivity to acetylcholine neurotransmitter (reduced quantal size) while simultaneously enhancing evoked transmitter release (increased quantal content). Patch recording from transfected cell lines, together with molecular modelling, indicated that cyclohexanol causes selective, allosteric antagonism of postsynaptic nicotinic acetylcholine receptor and block of presynaptic K+ -channel function. The data provide insight into the cellular and molecular mechanisms of neuromuscular weakness following intentional ingestion of agricultural organophosphorus insecticides. Our findings also extend understanding of the effects of alcohols on synaptic transmission and homeostatic synaptic function. Abstract Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Some survivors develop a severe, acute or delayed myasthenic syndrome. In animal models, similar myasthenia has been associated with increasing plasma concentration of one insecticide solvent metabolite, cyclohexanol. We investigated possible mechanisms using voltage and current recordings from mouse neuromuscular junctions (NMJs) and transfected human cell lines. Cyclohexanol (10-25 mM) reduced EPP amplitudes by 10-40% and enhanced depression during repetitive (2-20 Hz) stimulation by up to 60%. EPP decay was prolonged more than two fold. MEPPs were attenuated by more than 50%. Cyclohexanol inhibited whole-cell currents recorded from CN21 cells expressing human postjunctional acetylcholine receptors (hnAChR) with an IC50 of 3.74 mM. Cyclohexanol (10-20 mM) also caused prolonged episodes of reduced-current, multi-channel bursting in outside-out patch recordings from hnAChR expressed in transfected HEK293T cells, reducing charge transfer by more than 50%. Molecular modelling indicated cyclohexanol binding (-6kcal.mol-1 ) to a previously-identified alcohol binding site on nicotinic AChR α-subunits. Cyclohexanol also increased quantal content of evoked transmitter release by ∼50%. In perineurial recordings, cyclohexanol selectively inhibited pre-synaptic K+ -currents. Modelling indicated cyclohexanol binding (-3.8 kcal.mole-1 ) to voltage-sensitive K+ -channels at the same site as tetraethylammonium (TEA). TEA (10 mM) blocked K+ -channels more effectively than cyclohexanol but EPPs were more prolonged in 20 mM cyclohexanol. The results explain the pattern of neuromuscular dysfunction following ingestion of organophosphorus insecticides containing cyclohexanol precursors and suggest that cyclohexanol may facilitate investigation of mechanisms regulating synaptic strength at NMJs. Graphical Abstract: Cyclohexanol, the principal metabolite of a common agricultural insecticide solvent cyclohexanone, acts both presynaptically and postsynaptically to impair neuromuscular transmission. [1] Cyclohexanol binds to sites in the pore of voltage-sensitive K-channels that also bind the K+ -channel blocker tetraethylammonium (TEA), with the effect of reducing presynaptic motor nerve terminal K+ -currents and increasing quantal content of evoked transmitter release. [2] Simultaneously, cyclohexanol binds allosterically to an alcohol binding site on postsynaptic nicotinic acetylcholine receptors, altering ligand-gating characteristics and reducing charge transfer. The combined, overall effects of [1] and [2] result in reduced amplitude, prolonged depolarization and enhanced synaptic depression of endplate potentials (EPPs), weakening tetanic tension responses and causing fade in twitch responses to low frequency nerve stimulation. These effects mimic myasthenia or paralysis that occur in self-harming individuals who have swallowed significant quantities of organophosphorus insecticide, a significant public health issue in rural Asia. The present findings therefore provide an explanation for these clinical signs; and indicate potential utility of cyclohexanol in further study of mechanisms of neuromuscular synaptic homeostasis. This article is protected by copyright. All rights reserved.

Background\ud \ud Although non-invasive central and peripheral stimulations are accruing support as promising treatments in different neurological conditions, their effects on dysarthria have not been systematically investigated.\ud \ud \ud \ud Objective\ud \ud The purpose of this review was to examine the evidence base of non-invasive stimulation for treating dysarthria, identify which stimulation parameters have the most potential for treatment and determine safety risks.\ud \ud \ud \ud Methods\ud \ud A systematic review with meta-analysis, when possible, involving publications indexed in MEDLINE, PsychINFO, EMBASE CINHAL the Linguistics and Language Behavioral Abstracts, Web of Science, Cochrane Register of Control Trials and 2 trial registries was completed. Articles were searched in December 2018 and updated in June 2021 using keywords related to brain and electrical stimulation, dysarthria and research design. We included trials with randomised, cross-over or quasi-experimental designs; involving a control group; and investigating treatment of neurogenic dysarthria with non-invasive stimulation. Methodological quality was determined with the Cochrane's Risk of Bias-2 tool.\ud \ud \ud \ud Results\ud \ud In total, 6186 studies were identified; 10 studies (6 randomised controlled trials and 4 cross-over studies) fulfilled the inclusion criteria. All 10 trials (268 adults with Parkinson's disease, stroke and neurodegenerative cerebellar ataxia) focused on brain stimulation (6 repetitive transcranial magnetic stimulation; 3 transcranial direct current stimulation; and 1 repetitive transorbital alternating current stimulation). Adjunct speech-language therapy was delivered in 2 trials. Most trials reported one or more positive effects of stimulation on dysarthria-related features; however, given the overall high risk of bias and heterogeneity in participant, trial and outcome measurement characteristics, no conclusions can be drawn. Post-treatment size effects for 2 stroke trials demonstrated no statistically significant differences between active and sham stimulation across 3 dysarthria outcomes.\ud \ud \ud \ud Conclusions\ud \ud Evidence for use of non-invasive brain stimulation in treating dysarthria remains inconclusive. Research trials that provide reliable and replicable findings are required.

We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.

BackgroundThe importance of developmentally appropriate transitional care in young people with juvenile-onset rheumatic and musculoskeletal disease is well recognised. The Paediatric Rheumatology European Society (PReS) / European League Against Rheumatism (EULAR) Taskforce has developed international recommendations and standards for transitional care and a growing evidence base supports the positive benefits of such care. However, there is also evidence that universal implementation has yet to be realised. In 2020, against this background the COVID-19 pandemic arrived with significant impact on all our lives, young and old, patient, public and professional alike. The unfortunate reality of the pandemic with potential for unfavourable outcomes on healthcare provision during transition was acknowledged by the PReS working groups in a position statement to support healthcare professionals, young people and their caregivers.AimThe aim of this review is to present the literature which provides the rationale for the recommendations in the PReS Position Statement.SummaryThe following areas are specifically addressed: the prime importance of care coordination; the impact of the pandemic on the various aspects of the transition process; the importance of ensuring continuity of medication supply; the pros and cons of telemedicine with young people; ensuring meaningful involvement of young people in service development and the importance of core adolescent health practices such as routine developmental assessment psychosocial screening and appropriate parental involvement during transitional care.

Forced vital capacity (FVC) is an essential respiratory measurement for assessment and monitoring of patients with Amyotrophic Lateral Sclerosis (ALS). Our clinic rapidly implemented remote assessment of FVC after COVID-19 related restrictions on respiratory testing were imposed, using mini-spirometers and video consultation. We sought to evaluate the patient's experiences of performing remote respiratory assessments to guide future development and optimisation of the service. Twenty-five patients completed surveys. The mean age was 65.2 years and average time from diagnosis was 17.04 (2-99) months. Seventy-two percent (n = 18) required help from a caregiver to perform the tests. Ninety-two percent (n = 23) of patients reported that overall, they were satisfied and were happy to continue with remote respiratory assessment. Reducing the number of clinic visits for review and assessment was valued by 92% (n = 23) and reducing the risk associated with COVID-19 was valued by 96% (n = 24). The highest frequency reported as acceptable for performing the remote breathing assessments was monthly (60%, n = 15), followed by every second month (28%, n = 7). Remote respiratory testing is viewed positively by patients. These technologies used in combination with video-consultations and other novel forms of remote monitoring implemented in response to the COVID-19 crisis will continue to be valuable tools for clinical care in future. However, further evaluation of the validity of remote respiratory assessment is required.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Standard high-flux hemodialysis (HD) clears urea very efficiently but is less efficient at clearing uremic toxins with larger molecule size, which diffuse more slowly. Hemodiafiltration (HDF) provides much higher convection rates, thereby reliably increasing the clearance of these larger toxins. However, the high ultrafiltration volumes employed by HDF significantly increase the concentration of proteins and lipids in the dialyzer blood compartment. This has the effect of increasing plasma viscosity, which opposes solute diffusion, and increasing plasma oncotic pressure, which opposes convection. The negatively charged plasma proteins also influence the equilibration of ions between dialysate and blood compartments. These effects result in varying conditions for solute transport along the length of the dialyzer and along the radial distance from the membrane within the dialyzer fibers. High-flux dialyzers can be designed to augment solute diffusion and internal filtration, so that their performance approaches that of HDF. This avoids some of the mechanical complexity of HDF, but such enhanced dialyzers may be more difficult to manufacture, control and monitor. Here, we present and discuss the most important physical phenomena associated with HDF therapy, providing an overview of its main concepts and principles. In particular, we discuss the physics of solute diffusion and convection and the factors affecting them, and we compare predilution or postdilution HDF with enhanced HD.

Current risk stratification strategies do not fully explain cardiovascular disease (CVD) risk. We aimed to evaluate the association of low-density lipoprotein (LDL-P) and high-density lipoprotein (HDL-P) particles with progression of coronary artery calcium and carotid wall injury. All participants in the Multi-Ethnic Study Atherosclerosis (MESA) with LDL-P and HDL-P measured by ion mobility, coronary artery calcium score (CAC), carotid intima-media thickness (IMT), and carotid plaque data available at Exam 1 and 5 were included in the study. CAC progression was annualized and treated as a categorical or continuous variable. Carotid IMT and plaque progression were treated as continuous variables. Fully adjusted regression models included established CVD risk factors, as well as traditional lipids. Mean (±SD) follow-up duration was 9.6 ± 0.6 years. All LDL-P subclasses as well as large HDL-P at baseline were positively and significantly associated with annualized CAC progression, however, after adjustment for established risk factors and traditional lipids, only the association with medium and very small LDL-P remained significant (β -0.02, p = 0.019 and β 0.01, p = 0.003, per 1 nmol/l increase, respectively). Carotid plaque score progression was positively associated with small and very small LDL-P (p

Introduction In 2010, the Canadian province of British Columbia (BC) initiated the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) program to improve HIV testing, linkage to care, and treatment uptake, thereby operationalizing the HIV Treatment as Prevention (TasP) framework at the population-level. In this analysis, we evaluated self-reported HIV care experiences and therapeutic outcomes among people diagnosed with HIV prior to and after implementation of this provincial program. Methods A cross-sectional analysis was performed on the baseline data of a cohort of people living with HIV (PLWH) (19 years and older) in the province of BC sampled from July 2016 to September 2018. All participants consented to linking their survey data to the provincial HIV treatment registry. Individuals diagnosed with HIV from January 1 2000—December 31 2009 were classified as pre-intervention and those diagnosed January 1 2010—December 31 2018 as post-intervention cohorts. Bivariate analyses were run using Chi-square and Wilcoxon Rank Sum tests. Cox proportional hazards regression model demonstrates time to antiretroviral therapy (ART) initiation (from HIV baseline) and virological suppression (2 consecutive plasma viral load measurements Results Of the 325 participants included in this analysis, 198 (61%) were diagnosed with HIV in the pre-intervention era and 127 (39%) in the post-intervention era. A higher proportion of participants in post-intervention era were diagnosed at walk-in clinics (45% vs. 39%) and hospitals (21% vs. 11%) (vs pre-intervention) (p = 0.042). Post-intervention participants had initiated ART with less advanced HIV disease (CD4 count 410 vs. 270 cells/ul; p = 0.001) and were less likely to experience treatment interruptions at any point in the 5 years after HIV diagnosis (17% vs. 48%; p Conclusions We found favourable treatment experiences and more timely ART initiation and virologic suppression after a targeted TasP provincial program. Our results illustrate the importance of accessible low-barrier HIV testing and treatment in tackling the HIV epidemic.

Background A regional Australian Primary Health Network (PHN) has been subsidising administrative staff from local general practices to undertake the Medical Practice Assisting (MPA) course as part of its MPA Program. The MPA Program aimed to upskill administrative staff to undertake clinical tasks and fill in for busy or absent Practice Nurses (PNs), freeing up PNs to increase revenue-generating activity, avoiding casual replacement staff wages, and increasing patient throughput. An impact assessment was undertaken to evaluate the impact and estimate the economic costs of the MPA program to the PHN, general practices, and students to inform future uptake of the intervention. Methods The Framework to Assess the Impact of Translational Health Research (FAIT) was utilised. Originally designed to assess the impact of health research, this was its first application to a health services project. FAIT combines three validated methods of impact assessment—Payback, economic analysis and narratives underpinned by a program logic model. Quantified metrics describe the impacts of the program within various “domains of benefit”, the economic model costs the intervention and monetises potential consequences, and the narrative tells the story of the MPA Program and the difference it has made. Data were collected via online surveys from general practitioners (GPs), PNs, practice managers; MPA graduates and PHN staff were interviewed by phone and on Zoom. Results FAIT was effective in evidencing the impacts and economic viability of the MPA Program. GPs and PNs reported greater work satisfaction, PNs reported less stress and reduced workloads and MPA graduates reported higher job satisfaction and greater confidence performing a range of clinical skills. MPA Program economic costs for general practices during candidature, and 12 month post-graduation was estimated at $69,756. With effective re-integration planning, this investment was recoverable within 12 months through increased revenue for practices. Graduates paid appropriately for their new skills also recouped their investment within 24 months. Conclusion Utilisation of MPA graduates varied substantially between practices and COVID-19 impacted on their utilisation. More strategic reintegration of the MPA graduate back into the practice to most effectively utilise their new skillset could optimise potential benefits realised by participating practices.

Infection with SARS-CoV-2 may trigger a delayed hyper-inflammatory illness in children called paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS). A similar syndrome is increasingly recognised in adults termed multisystem inflammatory syndrome in adults (MIS-A) and may present acutely to medical or surgical specialties with severe symptoms, such as acute abdominal pain or cardiogenic shock. No national guidelines exist in the UK for the management of MIS-A and there is limited evidence to guide treatment plans. We undertook a national Delphi process to elicit opinions from experts in hyperinflammation about the diagnosis and management of MIS-A with the dual aim of improving recognition and producing a management guideline. Colleagues in paediatrics successfully initiated a national consensus management document that facilitated regional multidisciplinary referral and follow-up pathways for children with PIMS-TS, and we propose a similar system be developed for adult patients across the UK. This would facilitate better recognition and treatment of MIS-A across the multiple specialties to which it may present as well as enable follow-up with specialty services post-discharge.

The aim of this study is to investigate the relationships between psychological/social factors and transfer readiness from paediatric to adult rheumatology services in pre- and post-transfer young people (YP) with juvenile idiopathic arthritis (JIA). Participants completed questionnaires measuring a broad range of psychological/social factors (generalised anxiety, pain-specific anxiety, pain-related thoughts, depression, prosocial behaviours, problem behaviours, arthritis-related quality of life (QoL), social support, family functioning) and transfer readiness (transfer-related knowledge and skills, health-related self-efficacy). JIA disease activity was measured on the same day as the questionnaires. This study received all relevant ethical and regulatory approvals, and informed consent was received from or on behalf of all participants. In total, 40 pre-transfer YP with JIA aged 10-16 years (M = 13.54 years, 26 females) and their parents/guardians participated at Sheffield Children's NHS Foundation Trust, and 40 post-transfer YP with JIA aged 16-24 years (M = 20.16 years, 26 females) participated at Sheffield Teaching Hospitals NHS Foundation Trust. For both pre- and post-transfer YP, greater transfer readiness was associated with lower generalised anxiety levels, lower pain-specific anxiety levels, fewer pain-related thoughts, lower depression levels, fewer problem behaviours, better arthritis-related QoL, better social support, and better family functioning. Greater transfer readiness was also associated with less JIA disease activity for post-transfer YP only. A broad range of psychological/social factors were associated with transfer readiness in pre- and post-transfer YP with JIA. This highlights the importance of assessing and addressing YP's psychological/social well-being during their transition to adult services. Key Points • A wide range of psychological and social factors may be associated with how ready young people with juvenile idiopathic arthritis feel to move from paediatric to adult rheumatology services. • Transition outcomes may be improved by comprehensively assessing and addressing young people's psychological and social well-being.

The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions-often providing critical recommendations regarding ongoing cancer treatment. Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient's comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.

Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.

Objectives:\ud Health technology assessment aims to inform and support healthcare decision making, and trials are part of that process. The purpose of this study was to measure the impact of a sample of trials in a meaningful but robust fashion.\ud \ud Methods:\ud All randomized controlled trials funded and published by the UK National Institute of Health Research in the Health Technology Assessment journal series and other peer-reviewed journals were identified for 2006 to 2015. Citation analysis was performed for all trials, and quantitative content analysis was undertaken on a purposive sample to determine whether impact could be categorized as “instrumental” (ie, having a clear influence on key research and policy publications).\ud \ud Results:\ud The search identified 133 relevant trials. The citation rate per trial was 102.97. Of the 133 trials, 129 (98%) were cited in 1 or more systematic reviews or meta-analyses (mean per trial = 7.18, range = 0-44). Where they were cited, the trials were used in some form of synthesis 63% of the time. Ninety-one of the 133 (68%) trials were found to be cited in 1 or more guidance or policy document (mean per trial = 2.75, range = 0-26) and had an instrumental influence 41% of the time. The publication of these trials’ results in journals other than the Health Technology Assessment journal appears to enhance the discoverability of the trial data. Altmetric.com proved to be very useful in identifying unique policy and guidance documents.\ud \ud Conclusion:\ud These trials have impressive citation rates, and a sizeable proportion are certainly being used in key publications in a genuinely instrumental manner.

The advent of immune checkpoint inhibition represents a paradigm shift in the treatment of an increasing number of cancers. However, the incredible therapeutic promise of immunotherapy brings with it the need to understand and manage its diverse array of potential adverse events. The skin is the most common site of immune-related adverse vents (irAEs), which can present with a wide variety of disparate morphologies and severities. These toxicities can endanger patient health and the ability to continue on therapy. This review summarizes our current understanding of the presentation and management of the most common and clinically significant cutaneous irAEs associated with immune checkpoint inhibitor (ICI) therapy. Effective management of these cutaneous irAEs requires an understanding of their morphology, their appropriate clinical characterization, and their potential prognostic significance. Their treatment is additionally complicated by the desire to minimize compromise of the patient's anti-neoplastic regimen and emphasizes the use of non-immunosuppressive interventions whenever possible. However, though cutaneous irAEs represent a challenge to both oncologist and dermatologist alike, they offer a unique glimpse into the mechanisms that underlie not only carcinogenesis, but many primary dermatoses, and may provide clues to the treatment of disease even beyond cancer.

Primary abdominal wall sarcomas are rare, heterogeneous tumours. The mainstay of management is surgery, although local recurrences (LR) and distant metastases (DM) are common.Overall survival (OS) and disease-free survival (DFS) were primary outcomes; factors associated with prognosis secondary outcomes.Patients undergoing surgery of primary abdominal wall sarcomas between April 2008 and May 2018 were identified at two referrals centres for sarcoma surgery. Patient demographics, tumour and treatment-related characteristics were recorded and analysed.A cohort of 65 patients underwent surgical resection with a median follow-up of 56 months, 5-year OS and DFS were 69% and 71%, respectively. Eleven patients (16.9%) experienced a recurrence event: 6 LR (9.2%), 10 DM (15.4%) and 5 both (7.7%). At univariate analysis, size (p = 0.03), grade (p = 0.001) and depth (p = 0.04) were associated with OS while size (p = 0.02) was associated with DFS. No significant relationship with tumour depth, type of surgery, surgical margin status or neo-/adjuvant treatment was demonstrated.Recurrence events are less common following treatment of abdominal wall sarcomas if compared to extremities STSs, but size (≥5 cm), high malignancy grade (FNCLCC 3) and depth are associated with worse OS.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. Objectives: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. Methods: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan–Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. Results: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15–44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%–86%) in those

Little is known about T-cell responses during acute coronavirus disease-2019 (COVID-19). We measured T-cell interferon gamma (IFN-{gamma}) responses to spike 1 (S1), spike 2 (S2), nucleocapsid (N) and membrane (M) SARS-CoV-2 antigens using the T-SPOT(R) Discovery SARS-CoV-2 assay, a proven EliSPOT technology, in 114 hospitalised adult COVID-19 patients and assessed their association with clinical disease phenotype. T-SPOT(R) Discovery SARS-CoV-2 responses were detectable within 2 days of a positive PCR and did not correlate with vaccination status or symptom duration. Higher responses to S1 protein associated with a higher symptom burden, and serum IL-6 levels. Despite treatment with dexamethasone this subgroup was also at greater risk of requiring continuous positive airway pressure (CPAP) in the days following sampling. Higher T-cell responses measured using T-SPOT(R) Discovery SARS-CoV-2 associate with progressive disease in acute COVID-19 disease and may have utility as a prognostic biomarker that should be evaluated in larger cohorts.

The IEEE and ICNIRP had specified a maximum permissible exposure for instantaneous peak electric field of 100 kV/m. However, no rationale was given for this limit. A novel exposure system was designed through a detailed process of analytical analysis, numerical modelling and prototype testing. The system consists of a cylindrical re-entrant resonant cavity that can achieve an electric field strength of more than 100 kV/m with an input power of 200 W. The working of the system was evaluated in simulation and experiment in terms of scattering parameters, electric field distributions and specific absorption rate. The system was then used to carry out in-vitro exposures of a human lymphoid cell line (GG0257) to a 1195 MHz signal at 53 dBm peak power and a pulse width of 550 ns at a range of interpulse intervals to identify heating-induced changes in cell viability. The proposed system offers high Q value of 5920 in unloaded condition which was reduced to 57 when loaded with 12 ml of cell culture but still offering 67 kV/m of the field intensity. Using the system for the exposure of GG0257 cells lasting 18 min, interpulse intervals of 11 μs or less caused a reduction in the number of viable cells and a corresponding increase in necrotic cells. For a shorter exposure duration of 6 min, the reduction in cell viability was seen at interpulse intervals of 5.5 μs or less. The designed exposure system is well capable of handling high intensity electric fields. Temperature measurements with a fibre optic probe and temperature sensitive labels showed that changes in viability were associated with temperature increases above 46 °C. This novel exposure system is an efficient means to investigate the possible relationship between peak field intensity and biological effects to provide a rationale behind the maximum exposure limit of 100 kV/m.

ImportanceWhether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.ObjectiveTo determine whether SDD reduces in-hospital mortality in critically ill adults.Design, Setting, and ParticipantsA cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.InterventionsICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.Main Outcomes and MeasuresThe primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.ResultsOf 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, −1.7% [95% CI, −4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, −11.0%; 95% CI, −14.7% to −7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, −1.95%; 95% CI, −3.5% to −0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, −0.24%; 95% CI, −0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (−3.3% vs −1.59%; mean difference, −1.71% [1-sided 97.5% CI, −∞ to 4.31%] and 0.88% vs 0.55%; mean difference, −0.32% [1-sided 97.5% CI, −∞ to 5.47%]) in the first and second periods, respectively.Conclusions and RelevanceAmong critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit.Trial RegistrationClinicalTrials.gov Identifier: NCT02389036

Background Studies in 1983 and 1993 identified and ranked symptoms experienced by cancer patients receiving chemotherapy. We repeated the studies to obtain updated information on patient perceptions of chemotherapy-associated symptoms. Patients and methods A cross-sectional interview and patient-reported outcome questionnaires were administered to out-patients receiving chemotherapy. Patients selected from 124 cards to identify and rank the severity of physical and non-physical symptoms they had experienced and attributed to chemotherapy (primary endpoint). The patient’s medical oncologist and primary chemotherapy nurse were invited to rank the five symptoms they believed the patient would rank as their most severe. We analysed the association of symptoms and their severity with patient demographics, chemotherapy regimen, and patient-reported outcomes. Results were compared to the earlier studies. Results Overall, 302 patients completed the interview: median age 58 years (range 17–85); 56% female; main tumour types colorectal 81 (27%), breast 67 (22%), lung 49 (16%); 45% treated with curative intent. Most common symptoms (reported by >50%) were: alopecia, general weakness, effects on family/partner, loss of taste, nausea, fatigue, difficulty sleeping, effects on work/home duties, and having to put life on hold. The most severe symptoms (ranked by >15% in top five) were: concern about effects on family/partner, nausea, fear of the future, fatigue, not knowing what will happen, putting my life on hold, and general weakness. Perceptions of doctors and nurses of patients’ symptom severity closely matched patients’ rankings. Conclusions Compared to earlier studies, there was an increase in non-physical concerns such as effects on family and future, and a decrease in physical symptoms, particularly vomiting, but nausea, fatigue and general weakness remained bothersome. Highlights • Symptoms related to chemotherapy have changed over time, likely due to less toxic regimens and improvements in supportive care. • Effects on family/partner, fear of the future, not knowing what will happen, and “life on hold” were major issues for patients. • Vomiting has decreased but nausea, fatigue and general weakness remain common symptoms for chemotherapy patients.

Background and Aims The incidence of inflammatory bowel disease [IBD] diagnosed before adulthood is increasing worldwide. Transition from paediatric to adult health care requires certain skills. The aim of this study was to identify factors affecting these skills. Methods This review was registered on the PROSPERO database [CRD42019152272]. Inclusion criteria were: 1] studies of factors affecting transition readiness skills in patients with IBD; 2] written in English; 3] published since 1999. MEDLINE, CINAHL, and PsychINFO databases were searched between 1999 and 2019. Quality was assessed using the Joanna Briggs Institute critical appraisal tools. Results Searches identified 822 papers. Sixteen papers were included. Age was positively associated with skills including disease knowledge and performing self-management behaviours [14 studies]. Improvement often occurs at 18; however, skill deficiency may still remain. Increased self-efficacy [confidence] was associated with greater disease knowledge and performing self-management behaviours [three studies]. Self-efficacy was positively correlated with transition duration [two studies] and health-related quality of life [r = 0.57, p Conclusions Potentially modifiable factors have been identified that could be supported in the transitioning IBD population, to improve transition readiness. Identification of those with non-modifiable characteristics associated with poor readiness may aid targeted support.