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Introduction Of paediatric admissions to hospital, up to 1.8% are a consequence of Adverse Drug Reactions (ADR); a proportion are allergic reactions. Misdiagnosis of drug allergy is important not only for the patient, but also because unevaluated reactions can lead to less effective and more expensive drugs being prescribed. Aim To describe the suspected causative drugs, clinical features, investigations, diagnosis and advice given to patients presenting to the Paediatric Adverse Drug Event Clinic. Methods A retrospective clinic note review was undertaken of all patients presenting to the Adverse Drug Event Clinic with a suspected drug allergy between 2005 and 2010. Children were identified though the electronic letter copies of one consultant. Results Table 1: 66 children (mean age 9.7 years) attended. The suspected drugs were: Antimicrobials (26), Local anaesthetics (17),General anaesthetics (16), Other (7). Rash (31), swelling (28) and urticaria (13) were the most common clinical presentations (table 1). Abstract G47(P) Table 1 Investigations Investigation Number of cases Number of negative results Skin prick testing 60 49 Specific serum IgE 10 10 Intradermal testing 6 5 Direct provocation test 5 5 Table 2: A diagnosis of drug allergy was given in 14 children (21%); all were advised to avoid the drug. Abstract G47(P) Table 2 Advice Advice Total Reassurance 38 Avoid 14 Pragmatically avoid 11 Other 3 Conclusions Medication and Anaesthetic charts are vital in the assessment of potential drug allergy. Investigation to multiple drugs is generally possible in one clinic visit. Around a quarter had a “confirmed” drug allergy. A Drug Challenge (Direct provocation test) was infrequently required to manage the children. These results are in concordance with the British Society for Allergy and Clinical Immunology guidelines, which recommends a drug challenge should only be considered after other investigations have been exhausted and the diagnosis is still unclear.

We report measurements of ten custom-made high-homogeneity LYSO crystals. The investigation is motivated by the need for a compact, high-resolution, and fast electromagnetic calorimeter for a new rare pion decay experiment. Each \\(2.5\\times 2.5 \\times 18\\) cm\\(^3\\) crystal was first characterized for general light yield properties and then its longitudinal response uniformity and energy resolution were measured using low-energy gamma sources. The ten crystals were assembled as an array and subjected to a 30 - 100 MeV positron beam with excellent momentum definition. The energy and timing resolutions were measured as a function of energy, and the spatial resolution was determined at 70 MeV. An additional measurement using monoenergetic 17.6 MeV gammas produced through a p-Li resonance was later made after the photosensors used in positron testing were improved. As an example of the results, the energy resolution at 70 MeV of 1.52 \\(\\pm\\) 0.03% is more than two times better than reported results using previous generation LYSO crystals.

We report measurements of ten custom-made high-homogeneity LYSO crystals. The investigation is motivated by the need for a compact, high-resolution, and fast electromagnetic calorimeter for a new rare pion decay experiment. Each \\(2.5\\times 2.5 \\times 18\\) cm\\(^3\\) crystal was first characterized for general light yield properties and then its longitudinal response uniformity and energy resolution were measured using low-energy gamma sources. The ten crystals were assembled as an array and subjected to a 30 - 100 MeV positron beam with excellent momentum definition. The energy and timing resolutions were measured as a function of energy, and the spatial resolution was determined at 70 MeV. An additional measurement using monoenergetic 17.6 MeV gammas produced through a p-Li resonance was later made after the photosensors used in positron testing were improved. As an example of the results, the energy resolution at 70 MeV of 1.52 \\(\\pm\\) 0.03% is more than two times better than reported results using previous generation LYSO crystals.

PIONEER is a rapidly developing effort aimed to perform a pristine test of lepton flavour universality (LFU) and of the unitarity of the first row of the CKM matrix by significantly improving the measurements of rare decays of the charged pion. In Phase I, PIONEER aims to measure the charged-pion branching ratio to electrons vs.\\ muons \\(R_{e/\\mu}\\) to 1 part in \\(10^4\\), improving the current experimental result \\(R_{e/\\mu}\\,\\text{(exp)} =1.2327(23)\\times10^{-4}\\) by a factor of 15. This precision on \\(R_{e/\\mu}\\) will match the theoretical accuracy of the SM prediction allowing for a test of LFU at an unprecedented level, probing non-SM explanations of LFU violation through sensitivity to quantum effects of new particles up to the PeV mass scale. Phase II and III will aim to improve the experimental precision of the branching ratio of pion beta decay, \\(\\pi^+\\to \\pi^0 e^+ \\nu (\\gamma)\\), currently at \\(1.036(6)\\times10^{-8}\\), by a factor of three and six, respectively. The improved measurements will be used to extract \\(V_{ud}\\) in a theoretically pristine manner. The ultimate precision of \\(V_{ud}\\) is expected to reach the 0.05\\,\\% level, allowing for a stringent test of CKM unitarity. The PIONEER experiment will also improve the experimental limits by an order of magnitude or more on a host of exotic decays that probe the effects of heavy neutrinos and dark sector physics. This input to the 2026 update of the European Strategy for Particle Physics Strategy describes the physics motivation and the conceptual design of the PIONEER experiment, and is prepared based on the PIONEER proposal submitted to and approved with high priority by the PSI program advisory committee (PAC). Using intense pion beams, and state-of-the-art instrumentation and computational resources, the PIONEER experiment is aiming to begin data taking by the end of this decade.

Critical illness can be lethal and devastating to survivors. Improvements in acute care have increased the number of intensive care unit (ICU) survivors. These survivors confront a range of new or worsened health states that collectively are commonly denominated post–intensive care syndrome (PICS). These problems include physical, cognitive, psychological, and existential aspects, among others. Burgeoning interest in improving long-term outcomes for ICU survivors has driven an array of potential interventions to improve outcomes associated with PICS. To date, the most promising interventions appear to relate to very early physical rehabilitation. Late interventions within aftercare and recovery clinics have yielded mixed results, although experience in heart failure programs suggests the possibility that very early case management interventions may help improve intermediate-term outcomes, including mortality and hospital readmission. Predictive models have tended to underperform, complicating study design and clinical referral. The complexity of the health states associated with PICS suggests that careful and rigorous evaluation of multidisciplinary, multimodality interventions—tied to the specific conditions of interest—will be required to address these important problems.

Objective To identify the key mechanisms that clinicians perceive improve care in the intensive care unit (ICU), as a result of their involvement in post-ICU programs. Methods Qualitative inquiry via focus groups and interviews with members of the Society of Critical Care Medicine’s THRIVE collaborative sites (follow-up clinics and peer support). Framework analysis was used to synthesize and interpret the data. Results Five key mechanisms were identified as drivers of improvement back into the ICU: (1) identifying otherwise unseen targets for ICU quality improvement or education programs—new ideas for quality improvement were generated and greater attention paid to detail in clinical care. (2) Creating a new role for survivors in the ICU—former patients and family members adopted an advocacy or peer volunteer role. (3) Inviting critical care providers to the post-ICU program to educate, sensitize, and motivate them—clinician peers and trainees were invited to attend as a helpful learning strategy to gain insights into post-ICU care requirements. (4) Changing clinician’s own understanding of patient experience—there appeared to be a direct individual benefit from working in post-ICU programs. (5) Improving morale and meaningfulness of ICU work—this was achieved by closing the feedback loop to ICU clinicians regarding patient and family outcomes. Conclusions The follow-up of patients and families in post-ICU care settings is perceived to improve care within the ICU via five key mechanisms. Further research is required in this novel area.

Polygenic risk scores (PRS) are designed to serve as single summary measures that are easy to construct, condensing information from a large number of genetic variants associated with a disease. They have been used for stratification and prediction of disease risk. The primary focus of this paper is to demonstrate how we can combine PRS and electronic health records data to better understand the shared and unique genetic architecture and etiology of disease subtypes that may be both related and heterogeneous. PRS construction strategies often depend on the purpose of the study, the available data/summary estimates, and the underlying genetic architecture of a disease. We consider several choices for constructing a PRS using data obtained from various publicly-available sources including the UK Biobank and evaluate their abilities to predict not just the primary phenotype but also secondary phenotypes derived from electronic health records (EHR). This study was conducted using data from 30,702 unrelated, genotyped patients of recent European descent from the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort within Michigan Medicine. We examine the three most common skin cancer subtypes in the USA: basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma. Using these PRS for various skin cancer subtypes, we conduct a phenome-wide association study (PheWAS) within the MGI data to evaluate PRS associations with secondary traits. PheWAS results are then replicated using population-based UK Biobank data and compared across various PRS construction methods. We develop an accompanying visual catalog called PRSweb that provides detailed PheWAS results and allows users to directly compare different PRS construction methods.

This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes. Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals 1 , partly because of a shared genetic origin 2 , 3 , 4 . To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants ( P < 3 × 10 −8 ), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE. Temporal lobe epilepsy (TLE) can be unresponsive to treatment. Here, the authors show that treatment with D-Serine mitigates TLE and acts on neurons and glia, attenuating neuronal loss and reducing astro- and microgliosis in rodents.