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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Toxic epidermal necrolysis (TEN) is a rare, acute life-threatening mucocutaneous disorder that is characterised by epidermal loss/exfoliation exceeding 30% total body surface area (TBSA) and is on a spectrum that includes erythema multiforme and Stevens–Johnson syndrome (SJS). It is estimated that 80% of TEN cases are related to medication reactions; the association based on the recognition that TEN usually develops 1–3 weeks following administration of the suspect drug. It is agreed that primary treatment consists of prompt withdrawal of causative drugs and transfer to a regional burn unit. Transfer to a burn unit, no more than 7 days after onset of symptoms, has been acknowledged as reducing the risk of infections, hospital length of stay and infection-related mortality. Due to the uncertainty surrounding TEN pathogenesis, several different modalities have been proposed for the treatment of TEN, including high-dose intravenous immunoglobulins, plasmapheresis, cyclophosphamide, cyclosporine and systemic steroids; however, these therapies are relatively ineffective. The use of systemic corticosteroids for treatment of TEN has in particular been deemed controversial due to associations with increased infections leading to greater length of hospital stay and increased mortality. Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare relapsing-remitting disorder of unknown aetiology, characterised by granulomatosis inflammation and necrotising vasculitis predominantly affecting small- to medium-sized vessels. While a 5-year survival rate of 75–83% is now realised, relapse and associated morbidity is of concern. The established treatment for GPA follows the recommendations of the French National Authority for Health (HAS) for systematic necrotising vasculitis. With induction treatment, it is recommended that GPA be treated with a combination of systemic corticosteroids and immunosuppressants. A review of the literature failed to identify any previous case where both of these conditions coincide. Our search was conducted through databases which included MEDLINE, PubMed, Scopus, AMED, CINAHL and EMBASE, using keywords: toxic epidermal necrolysis, Wegener’s granulomatosis, granulomatosis with polyangiitis. We submit the rare case of a 22-year-old woman who presented to our regional burn unit with both GPA and TEN, and we discuss the presentation, investigation and multidisciplinary management of the patient, as well as reviewing the literature regarding these two conditions.

Early increase in the level of endothelial progenitor cells (EPCs) in the systemic circulation occurs in patients with septic infection/sepsis. The significance and underlying mechanisms of this response remain unclear. This study investigated the bone marrow EPC response in adult mice with septic infection induced by intravenous injection (i.v.) of Escherichia coli. For in vitro experiments, sorted marrow stem/progenitor cells (SPCs) including lineage(lin)-stem cell factor receptor (c-kit)+stem cell antigen-1 (Sca-1)−, lin−c-kit+, and lin− cells were cultured with or without lipopolysaccharides (LPSs) and recombinant murine vascular endothelial growth factor (VEGF) in the absence and presence of anti-Sca-1 crosslinking antibodies. In a separate set of experiments, marrow lin−c-kit+ cells from green fluorescence protein (GFP)+ mice, i.v. challenged with heat-inactivated E. coli or saline for 24 h, were subcutaneously implanted in Matrigel plugs for 5 weeks. Marrow lin−c-kit+ cells from Sca-1 knockout (KO) mice challenged with heat-inactivated E. coli for 24 h were cultured in the Matrigel medium for 8 weeks. The marrow pool of EPCs bearing the lin−c-kit+Sca-1+VEGF receptor 2 (VEGFR2)+ (LKS VEGFR2+) and LKS CD133+VEGFR2+ surface markers expanded rapidly following septic infection, which was supported by both proliferative activation and phenotypic conversion of marrow stem/progenitor cells. Increase in marrow EPCs and their reprogramming for enhancing angiogenic activity correlated with cell-marked upregulation of Sca-1 expression. Sca-1 was coupled with Ras-related C3 botulinum toxin substrate 2 (Rac2) in signaling the marrow EPC response. Septic infection caused a substantial increase in plasma levels of IFN-γ, VEGF, G-CSF, and SDF-1. The early increase in circulating EPCs was accompanied by their active homing and incorporation into pulmonary microvasculature. These results demonstrate that the marrow EPC response is a critical component of the host defense system. Sca-1 signaling plays a pivotal role in the regulation of EPC response in mice with septic infection.

Introduction Relationships in various forms are an important source of meaning in people’s lives that can benefit their health, wellbeing and happiness. Relationship distress is associated with public health problems such as alcohol misuse, obesity, poor mental health, and child poverty, whilst safe, stable, and nurturing relationships are potential protective factors. Despite increased emphasis on relationship education (RE) in schools, little is known about the views of relationship professionals on relationship education specifically, and how this contrasts with the views of young people (YP). Objectives This Wellcome Centre for the Cultures and Environments of Health funded Beacon project seeks to fill this gap by exploring their perspectives and inform the future development of relationship education. Methods We conducted focus groups with YP (n=4) and interviews with relationship professionals (n=10). The data was then thematically analysed. Results Themes from YP focus groups included: ‘Good and bad relationships’; ‘Learning about relationships’; ‘the role of schools’ and ‘Beyond Relationship Education’. Themes from interviews with relationship professionals included: ‘essential qualities of healthy relationships’; ‘how YP learn to relate’ and ‘the role of RE in schools’. Conclusions YP and relationship professionals recognised the importance of building YP’s relational capability in schools with a healthy relationship with oneself at its foundation. Relationship professionals emphasised the need for a developmental approach, stressing the need for flexibility, adaptability, commitment and resilience to maintain relationships over the life course. YP often presented dichotomous views, such as relationships being either good or bad relationships, and perceived a link between relationships and mental health. Although not the focus of current curriculum guidance, managing relationship breakdowns and relationship transitions through the life course were viewed as important with an emphasis on building relational skills. This research suggests that schools need improved RE support, including specialist expertise and resources, and guidance on signposting YP to external sources of help. There is also potential for positive relationship behaviours being modelled and integrated throughout curriculums and reflected in a school’s ethos. Future research should explore co-development, evaluation and implementation of RE programmes with a range of stakeholders. Disclosure of Interest None Declared

The electrical performances of III-nitride blue micro-light-emitting diodes (µLEDs) with different tunnel junction (TJ) epitaxial architectures grown by metalorganic chemical vapor deposition are investigated. A new TJ structure that employs AlGaN is introduced. The current density–voltage characteristic is improved by incorporating AlGaN layer above the n-side of the TJ layer, and the effects of the AlGaN/GaN superlattices is examined. Based upon the data from band diagram simulation, net positive polarization charge is formed at the AlGaN/GaN interface, which results in a reduction in tunneling distance and increase in tunneling probability. Moreover, similar electrical improvement is observed in various device dimensions and is independent of operating current density, suggesting that AlGaN/GaN biaxial tensile strain or current spreading is not the main contribution for the improvement. Finally, the effects on the efficiency performances are determined. While the maximum external quantum efficiency of the TJ devices remains identical, the wall-plug efficiency of µLEDs is enhanced significantly by the proposed AlGaN-enhanced TJ design. This work reveals the possibility of energy efficient TJ contact with high transparency in the visible wavelength range.

Abstract Background There is an urgent need for evidence on how interventions can prevent or mitigate cancer-related financial hardship. Our objectives are to compare self-reported financial hardship, quality of life, and health services use between patients receiving a financial navigation intervention versus a comparison group at 12 months follow-up, and to assess patient-level factors associated with dose received of a financial navigation intervention. Methods The Cancer Financial Experience (CAFÉ) study is a multi-site randomized controlled trial (RCT) with individual-level randomization. Participants will be offered either brief (one financial navigation cycle, Arm 2) or extended (three financial navigation cycles, Arm 3) financial navigation. The intervention period for both Arms 2 and 3 is 6 months. The comparison group (Arm 1) will receive enhanced usual care. The setting for the CAFÉ study is the medical oncology and radiation oncology clinics at two integrated health systems in the Pacific Northwest. Inclusion criteria includes age 18 or older with a recent cancer diagnosis and visit to a study clinic as identified through administrative data. Outcomes will be assessed at 12-month follow-up. Primary outcomes are self-reported financial distress and health-related quality of life. Secondary outcomes are delayed or foregone care; receipt of medical financial assistance; and account delinquency. A mixed methods exploratory analysis will investigate factors associated with total intervention dose received. Discussion The CAFÉ study will provide much-needed early trial evidence on the impact of financial navigation in reducing cancer-related financial hardship. It is theory-informed, clinic-based, aligned with patient preferences, and has been developed following preliminary qualitative studies and stakeholder input. By design, it will provide prospective evidence on the potential benefits of financial navigation on patient-relevant cancer outcomes. The CAFÉ trial’s strengths include its broad inclusion criteria, its equity-focused sampling plan, its novel intervention developed in partnership with clinical and operations stakeholders, and mixed methods secondary analyses related to intervention dose offered and dose received. The resulting analytic dataset will allow for rich mixed methods analysis and provide critical information related to implementation of the intervention should it prove effective. Trial registration ClinicalTrials.gov NCT05018000 . August 23, 2021.

Beech leaf disease (BLD) is a recently discovered disease that is causing severe damage to American beech (Fagus grandifolia) in northeastern North America. The recently described nematode Litylenchus crenatae subsp. mccannii was detected in BLD-affected foliage and may be associated with the disease. However, speculation on the direct role of the nematode in infection still remains. In this study, we profiled the microbial communities associated with asymptomatic, symptomatic, and naïve (control) American beech foliage by using a high-throughput sequence-based metabarcoding analysis of fungi, bacteria, phytoplasmas, and nematodes. We then used both a differential abundance analysis and indicator species analysis as well as several diversity metrics to try and discover microbes associated only with symptomatic foliage. To do so, we amplified the organism-specific phylogenetic informative regions of the 16S, 18S, and internal transcribed spacer (ITS)1 regions using Illumina MiSeq. Our results detected the amplicon sequence variant (ASV) associated with the nematode L. crenatae subsp. mccannii but in all symptom types. However, four ASVs associated with the bacterial genera Wolbachia, Erwinia, Paenibacillus, and Pseudomonas and one ASV associated with the fungal genus Paraphaeosphaeria were detected only in symptomatic samples. In addition, we identified significant differences based on symptom type in both the α- and β-diversity indices for the bacterial and fungal communities. These results suggest that L. crenatae subsp. mccannii may not be fully responsible for BLD but, rather, that other microbes may be contributing to the syndrome, including the putative nematode endosymbiont Wolbachia sp.

Abstract Background Quantitative polymerase chain reaction (qPCR) is the technique of choice for quantifying gene expression. While the technique itself is well established, approaches for the analysis of qPCR data continue to improve. Results Here we expand on the common base method to develop procedures for testing linear relationships between gene expression and either a measured dependent variable, independent variable, or expression of another gene. We further develop functions relating variables to a relative expression value and develop calculations for determination of associated confidence intervals. Conclusions Traditional qPCR analysis methods typically rely on paired designs. The common base method does not require such pairing of samples. It is therefore applicable to other designs within the general linear model such as linear regression and analysis of covariance. The methodology presented here is also simple enough to be performed using basic spreadsheet software.

The use of flexible bronchoscopy (FB) with bronchoalveolar lavage (BAL) to diagnose and manage pulmonary complications has been shown to be safe in adult cancer patients, but whether its use is safe in pediatric cancer patients remains unclear. Thus, to describe the landscape of FB outcomes in pediatric cancer patients and to help define the populations most likely to benefit from the procedure, we undertook a retrospective review of FBs performed in patients younger than 21 years treated at our institution from 2002 to 2017. We found that a greater volume of total fluid instilled during BAL was significantly associated with increased probabilities of positive BAL culture (p=0.042), positive bacterial BAL culture (p=0.037), and positive viral BAL culture (p=0.0496). In more than half of the FB cases, findings resulted in alterations in antimicrobial treatment. Our study suggests that for pediatric cancer patients, FB is safe, likely provides diagnostic and/or therapeutic benefits, and has implications for treatment decisions.

Standardized rounding checklists during multidisciplinary rounds (MDR) can reduce medical errors and decrease length of pediatric intensive care unit (PICU) and hospital stay. We added a standardized process for MDR in our oncologic PICU. Our study was a quality improvement initiative, utilizing a four-stage Plan–Do–Study–Act (PDSA) model to standardize MDR in our PICU over 3 months, from January 2020 to March 2020. We distributed surveys to PICU RNs to assess their understanding regarding communication during MDR. We created a standardized rounding checklist that addressed key elements during MDR. Safety event reports before and after implementation of our initiative were retrospectively reviewed to assess our initiative’s impact on safety events. Our intervention increased standardization of PICU MDR from 0% to 70% over three months, from January 2020 to March 2020. We sustained a rate of zero for CLABSI, CAUTI, and VAP during the 12-month period prior to, during, and post-intervention. Implementation of a standardized rounding checklist may improve closed-loop communication amongst the healthcare team, facilitate dialogue between patients’ families and the healthcare team, and reduce safety events. Additional staffing for resource RNs, who assist with high acuity patients, has also facilitated bedside RN participation in MDR, without interruptions in clinical care.

Abstract Background qPCR has established itself as the technique of choice for the quantification of gene expression. Procedures for conducting qPCR have received significant attention; however, more rigorous approaches to the statistical analysis of qPCR data are needed. Results Here we develop a mathematical model, termed the Common Base Method, for analysis of qPCR data based on threshold cycle values (C q ) and efficiencies of reactions (E). The Common Base Method keeps all calculations in the logscale as long as possible by working with log10(E) ∙ C q , which we call the efficiency-weighted C q value; subsequent statistical analyses are then applied in the logscale. We show how efficiency-weighted C q values may be analyzed using a simple paired or unpaired experimental design and develop blocking methods to help reduce unexplained variation. Conclusions The Common Base Method has several advantages. It allows for the incorporation of well-specific efficiencies and multiple reference genes. The method does not necessitate the pairing of samples that must be performed using traditional analysis methods in order to calculate relative expression ratios. Our method is also simple enough to be implemented in any spreadsheet or statistical software without additional scripts or proprietary components.

Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 × 107 CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia. By contrast, the amount of soluble SHH ligand in marrow elutes was significantly reduced. These contrasting alterations suggested that SHH ligand release from BMCs was reduced and/or binding of soluble SHH ligand to BMCs was enhanced. At both 12 and 24 h of bacteremia, SHH mRNA expression by BMCs was significantly upregulated. This upregulation of SHH mRNA expression was followed by a marked increase in SHH protein expression in BMCs. Activation of the ERK1/2–SP1 pathway was involved in mediating the upregulation of SHH gene expression. The major cell type showing the enhancement of SHH expression in the bone marrow was lineage positive cells. Gli1 positioned downstream of the SHH receptor activation serves as a key component of the hedgehog (HH) pathway. Primitive hematopoietic precursor cells exhibited the highest level of baseline Gli1 expression, suggesting that they were active cells responding to SHH ligand stimulation. Along with the increased expression of SHH in the bone marrow, expression of Gli1 by marrow cells was significantly upregulated at both mRNA and protein levels following bacteremia. This enhancement of Gli1 expression was correlated with activation of hematopoietic stem/progenitor cell proliferation. Mice with Gli1 gene deletion showed attenuation in activation of marrow hematopoietic stem/progenitor cell proliferation and inhibition of increase in blood granulocytes following bacteremia. Our results indicate that SHH signaling is critically important in the regulation of hematopoietic stem/progenitor cell activation and reprogramming during the granulopoietic response to serious bacterial infection.