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Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [ 11 C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority ( P  = 0.00055 and P  = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA. Comparison of non-invasive [ 11 C]metomidate PET-CT with adrenal vein sampling for predicting biochemical remission of primary aldosteronism showed non-superiority, suggesting that the non-invasive method is suitable for the diagnosis of unilateral primary aldosteronism.

Targeted Induced Local Lesions in Genomes (TILLING) is a reverse genetics approach to identify novel sequence variation in genomes, with the aims of investigating gene function and/or developing useful alleles for breeding. Despite recent advances in wheat genomics, most current TILLING methods are low to medium in throughput, being based on PCR amplification of the target genes. We performed a pilot-scale evaluation of TILLING in wheat by next-generation sequencing through exon capture. An oligonucleotide-based enrichment array covering ~2 Mbp of wheat coding sequence was used to carry out exon capture and sequencing on three mutagenised lines of wheat containing previously-identified mutations in the TaGA20ox1 homoeologous genes. After testing different mapping algorithms and settings, candidate SNPs were identified by mapping to the IWGSC wheat Chromosome Survey Sequences. Where sequence data for all three homoeologues were found in the reference, mutant calls were unambiguous; however, where the reference lacked one or two of the homoeologues, captured reads from these genes were mis-mapped to other homoeologues, resulting either in dilution of the variant allele frequency or assignment of mutations to the wrong homoeologue. Competitive PCR assays were used to validate the putative SNPs and estimate cut-off levels for SNP filtering. At least 464 high-confidence SNPs were detected across the three mutagenized lines, including the three known alleles in TaGA20ox1, indicating a mutation rate of ~35 SNPs per Mb, similar to that estimated by PCR-based TILLING. This demonstrates the feasibility of using exon capture for genome re-sequencing as a method of mutation detection in polyploid wheat, but accurate mutation calling will require an improved genomic reference with more comprehensive coverage of homoeologues.

Realising the potentially substantial benefits of chimeric antigen receptor (CAR) T-cell therapy for children with cancer is hindered by non-scientific barriers that are also relevant for other rare diseases. A solely commercial development model will not deliver optimally due to insufficient return on investment for pharmaceutical companies. Access to therapies is restricted for patients who might benefit and advancing innovation in the academic research setting is difficult. Challenges relating to CAR T-cell therapies in paediatric malignancies and how they might be addressed were discussed in a meeting convened by ACCELERATE—an international multistakeholder organisation aiming to advance the timely investigation of new anticancer drugs. New academic and biopharma hybrid development models could benefit rare populations and coordination of early development can promote synergy and avoid duplicative efforts. Following promising first-in-child trials, new models are needed to support pivotal trials, decentralised manufacturing, registration, and reduced costs. The European Medicines Agency and the US Food and Drug Administration encourage academic development and early discussions. A biotech company funded via a pooled investment vehicle could provide access to safe and effective products for children and adolescents with cancer through registration and reimbursement.

PurposeThe indications for pre-hospital resuscitative thoracotomy (PHRT) remain undefined. The aim of this paper is to explore the variation in practice for PHRT in the UK, and review the published literature.MethodsMEDLINE and PUBMED search engines were used to identify all relevant articles and 22 UK Air Ambulance Services were sent an electronic questionnaire to assess their PHRT practice.ResultsFour European publications report PHRT survival rates of 9.7, 18.3, 10.3 and 3.0% in 31, 71, 39 and 33 patients, respectively. All patients sustained penetrating chest injury. Six case reports also detail survivors of PHRT, again all had sustained penetrating thoracic injury. One Japanese paper presents 34 cases of PHRT following blunt trauma, of which 26.4% survived to the intensive therapy unit but none survived to discharge. A UK population reports a single survivor of PHRT following blunt trauma but the case details remain unpublished. Ten (45%) air ambulance services responded, each service reported different indications for PHRT. All perform PHRT for penetrating chest trauma, however, length of allowed pre-procedure down time varied, ranging from 10 to 20 min. Seventy percent perform PHRT for blunt traumatic cardiac arrest, a procedure which is likely to require aggressive concurrent circulatory support, despite this only 5/10 services carry pre-hospital blood products.ConclusionsCurrent indications for PHRT vary amongst different geographical locations, across the UK, and worldwide. Survivors are likely to have sustained penetrating chest injury with short down time. There is only one published survivor of PHRT following blunt trauma, despite this, PHRT is still being performed in the UK for this indication.

Background Patient and public involvement (PPI) in research is widely acknowledged as essential to achieving successful and impactful research. Despite this acknowledgement, there are limited reports on how to approach and apply meaningful PPI throughout the research cycle and how to address challenges for researchers such as doctoral students, particularly when undertaking research on sensitive topics. This paper provides insights and examples for researchers new to PPI, on the impact of active PPI and recommendations for building and developing a PPI group in a paediatric focused doctoral research study with bereaved parents and carers. Methods PPI was informed by the research cycle. The GRIPP2 short-form checklist was used to report PPI. The research was funded by the National Institute for Health and Care Research. Results PPI enhanced the research through input into the study design, recruitment, co-design of the study website and branding; and ethics amendments to increase participation in response to the COVID-19 pandemic. The literature review was extended to incorporate a PPI consultation phase and members contributed to data analysis. A flexible approach enabled involvement to develop iteratively throughout the research study, resulting in changes being made to enhance the study design and outcomes. Conclusion This paper contributes to the limited knowledge base on embedding PPI into a doctoral research study and within the paediatric setting specifically working in partnership with bereaved parents and carers. Employing an adaptive approach to meet individual PPI needs, building a trusting and respectful partnership, creating shared ownership and investment in the research, are essential components to successful PPI. Plain English summary Involving patients and the public in research provides the opportunity to develop meaningful outcomes that are relevant to the population being studied. Despite the benefits of patient and public involvement in research, guidelines that support researchers in doing so, lack detail on how to do this effectively. This is particularly important for those new to research such as doctoral students, who have so much to learn in developing a research study. Different approaches and applications to involvement are also likely to be needed depending on the population being studied. There are limited published papers on examples of how doctoral students have engaged and involved patients and the public in the context of their studies, and specifically within the children’s setting, working in partnership with bereaved parents and carers, or those with seriously ill children. This paper offers examples and insights for those new to research in how to involve patients and the public throughout the research cycle. Specifically undertaking research in a sensitive subject of a particular childhood cancer which has poor outcomes and how to incorporate and evaluate successful patient and public involvement in their research activities such as study design and analysis of the results. Parent and carer reflections on their experiences of being involved are also reported and researcher recommendations for approaching and working with a patient and public group are described.

Better prognostic information for resected extrahepatic cholangiocarcinoma could guide treatment strategies and potentially improve outcome. This study performed a systematic review and meta-analysis to identify prognostic biomarkers for further investigation. Relevant literature was identified using Medline, EMBASE and Web of Science. Primary end point was overall survival assessed on univariate analysis. Log hazard ratio and variance were calculated and pooled using a random effects inverse variance approach. Hazard ratio and 95% confidence intervals were calculated. Thirty-seven studies, including 2371 patients, met the inclusion criteria. Subsequently nine biomarkers predictive of OS were identified (HR, 95% CI): VEGF (2.32, 1.57-3.44), COX-2 (1.94, 1.01-3.71), GLUT-1 (2.09, 1.52-2.89), Cyclin D1 (1.96, 1.02-3.76), p16 (0.68, 0.47-0.98), p27 (0.48, 0.3-0.78), E-Cadherin (0.47, 0.35-0.63), Fascin (2.19, 1.35-3.55), and Ki-67 (1.69, 1.02-2.79). Meta-analysis has identified a number of prognostic biomarkers for resected extrahepatic cholangiocarcinoma. These markers warrant further investigation as potential therapeutic targets and validation in a prospective setting.

Lemierre’s disease is characterized by sepsis, often with an oropharyngeal source, secondary septic emboli and internal jugular vein thrombosis (Lancet 1:701–3, 1936. Clin Microbiol Rev 20(4):622–59, 2007). Septic emboli affecting many bodily sites have been reported, including the lungs, joints, bones, and brain. The case report describes an unusual case of Lemierre’s disease in a 64 year old gentleman causing profound sepsis, acute kidney injury, bilateral iliopsoas abscesses and a right hand abscess. To our knowledge, this is the first reported case of Lemierre’s disease in the context of bilateral psoas abscesses, and highlights the ambiguity surrounding the definition of Lemierre’s disease. The clinical literature review highlights the difficulty in definitively diagnosing the condition and offers some suggestions for recognising and refining the diagnostic criterion of Lemierre’s.

Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

In order to be able to compare individuals of differing size, glomerular filtration rate (GFR) is conventionally indexed to body surface area (BSA). This does not, however, suit children because they naturally have a relatively high BSA simply because of their small size. The aim of the study was to identify an appropriate simple whole-body variable based on height and weight suitable for indexing GFR that would be simultaneously appropriate for both children and adults. A database of 532 routine clinical GFR measurements, each based on 3 venous blood samples obtained between 2 and 4 h after injection of (51)Cr-ethylenediaminetetraacetic acid, was analyzed to give GFR and, using only the half-time of the slope of the clearance curve, the quotient GFR to extracellular fluid volume (ECV). BSA was obtained from the Haycock formula, which is based on height and weight raised to indices to give units of area. Both GFR and GFR/ECV were corrected for the 1-compartment assumption using previously published empiric correction formulas. ECV was obtained by dividing GFR by GFR/ECV. An equation analogous to Haycock's was derived in which the indices of height and weight were varied to give an iterative best fit to ECV instead of BSA. GFR, ECV, and BSA increase as functions of age until about age 13 y, corresponding to a BSA of about 1.35 m(2), which was taken as the cutoff point between children and adults. As humans grow, their ratio of height to effective radius changes as a nonlinear function of surface area. Humans must therefore change shape as they grow. Moreover, the ECV-to-weight ratio decreases as a function of body size, suggesting that humans also change body composition as they grow. The new equation, giving an iterative best fit to ECV, was ECV = weight(0.6469) x height(0.7236) x 0.02154. ECV, either measured or estimated from the new equation, corresponding to a BSA of 1.73 m(2), was 12.9 L. Expressed as values normalized to the corresponding average adult values, the new equation and the second-order polynomial fit to ECV were superimposed as they increased as functions of BSA or weight. In contrast, normalized BSA and normalized weight were respectively larger and smaller than normalized ECV in children. GFR indexed to the new equation correlated more closely with GFR indexed to ECV than did GFR indexed to BSA and, along with GFR/ECV, showed a greater fall as a function of age than did GFR/BSA. When required in absolute units rather than as a rate of turnover of ECV, GFR is appropriately indexed to indices of height and weight as defined by this new equation, which avoids disadvantages to children from indexing to BSA. This unmasks higher values of filtration function in children than have hitherto been recognized.

Background/Aims: To compare body surface area (BSA) with lean body mass (LBM) for scaling extracellular fluid volume (ECV) and glomerular filtration rate (GFR). Methods:Phase 1: Total body water (TBW), bromide space and LBM were measured with 3H-water, 77Br and dual X-ray absorptiometry, respectively, in 6 healthy adults. Phase 2: ECV and GFR were measured with 51Cr-EDTA in 95 healthy adults and 56 children (0.5-13 years). ECV was calculated as GFR divided by GFR/ECV, both corrected for the one-compartment assumption. LBM was estimated (eLBM) in adults from height and weight and in children using a height/weight formula for estimating ECV and a constant derived from a separate adult population relating ECV to eLBM. Results:Phase 1: LBM and BSA correlated closely with TBW and bromide space. With LBM, the regressions passed through the origin, but with BSA, the intercepts were significantly below zero. Phase 2: GFR/BSA and ECV/BSA were higher in men than women but no difference was recorded in GFR/eLBM, GFR/ECV or ECV/eLBM. ECV showed a linear relation with eLBM and a non-linear relation with BSA. GFR/BSA and ECV/BSA correlated significantly with BSA but neither GFR/eLBM nor ECV/eLBM correlated with eLBM. Conclusion: eLBM is preferable to BSA for scaling GFR and ECV. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]