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To better understand utilization of HIV prevention, care, and treatment services by young men who have sex with men (YMSM) and young transgender persons (YTG), of Black race or Hispanic/Latino/Latina ethnicity in the U.S. South, we conducted semi-structured interviews with 127 clients at one of four community based organizations (CBOs) in Miami, Atlanta, New Orleans/Baton Rouge, or Columbia, South Carolina. Across sites, the service that most commonly drew respondents into the CBO was HIV and STD testing. Other services commonly used included HIV/STI treatment, counseling services/support groups, and PrEP services. Social/organizational/structural facilitators of service utilization include the welcoming climate/culture of the CBOs, ease of access to the services, and transportation services to reach the CBOs. Suggested service enhancements include broader range of comprehensive, navigational-type services beyond HIV testing and service co-location. Research on how to reduce stigma in the surrounding communities may help reduce health disparities experienced by these populations.

This study evaluated messages and communication approaches for maternal immunization uptake in Kenya. We identified persuasive communication aspects that would inform maternal immunization attitudes, intent, and vaccine uptake.We conducted a two-phased mixed methods study with pregnant women and their male partners in three regions of Kenya. Discussions were conducted in English and Swahili languages by trained focus group moderators. Baseline measures included a survey and discussions about potential messages and accompanying visuals. Follow-up focus groups with the same participants included a survey about previously discussed messages, visuals, and communication impressions. The second round of focus groups focused on message preferences developed from the first round, along with rank order discussion for final message selection. Following transcription of focus group discussions, we conducted analyses using NVivo software. Quantitative data analyses included frequencies, factor analyses, reliability assessment, regression modeling, and comparative assessment of rank order.The sample (N = 118) included pregnant women (n = 91) and their partners (n = 27) from diverse Kenyan regions (Bondo/Lwak/Siaya, Mombasa, and Nairobi). A four-factor solution resulted from factor analyses that included subscales "positive ad attitudes" (n = 5 items, α = 0.82), "negative ad attitudes" (n = 4 items, α = 0.75), "ad indifference" (n = 2 items, α = 0.52), and "ad motivation" (n = 4 items, α = 0.71). Overall, the positive ad attitudes factor (β = 0.61, p = 0.03) was the only significant component in the overall model examining message selections (χThe results indicated that positive attitudes were shaped by incorporating highly relatable factors in messages. Implications for subsequent campaigns and research directions are discussed.

The registration of the tumour necrosis factor-α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti- interleukin (IL)-17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL-1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL-36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better-defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required.

Since the advent of direct-acting antiviral therapy, the elimination of hepatitis c virus (HCV) as a public health concern is now possible. However, identification of those who remain undiagnosed, and re-engagement of those who are diagnosed but remain untreated, will be essential to achieve this. We examined the extent of HCV infection among individuals undergoing liver function tests (LFT) in primary care. Residual biochemistry samples for 6007 patients, who had venous blood collected in primary care for LFT between July 2016 and January 2017, were tested for HCV antibody. Through data linkage to national and sentinel HCV surveillance databases, we also examined the extent of diagnosed infection, attendance at specialist service and HCV treatment for those found to be HCV positive. Overall HCV antibody prevalence was 4.0% and highest for males (5.0%), those aged 37–50 years (6.2%), and with an ALT result of 70 or greater (7.1%). Of those testing positive, 68.9% had been diagnosed with HCV in the past, 84.9% before the study period. Most (92.5%) of those diagnosed with chronic infection had attended specialist liver services and while 67.7% had ever been treated only 38% had successfully cleared infection. More than half of HCV-positive people required assessment, and potentially treatment, for their HCV infection but were not engaged with services during the study period. LFT in primary care are a key opportunity to diagnose, re-diagnose and re-engage patients with HCV infection and highlight the importance of GPs in efforts to eliminate HCV as a public health concern.

Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT.PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258.We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe.In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited.Accuray.

STUDY QUESTIONWhat effects did treatment using hyaluronic acid (HA) binding/selection prior to ICSI have on clinical outcomes in the Hyaluronic Acid Binding sperm Selection (HABSelect) clinical trial?SUMMARY ANSWEROlder women randomized to the trial’s experimental arm (selection of sperm bound to immobilized (solid-state) HA) had the same live birth rates as younger women, most likely a result of better avoidance of sperm with damaged DNA.WHAT IS KNOWN ALREADYRecent randomized controlled trials (RCTs) investigating the efficacy of HA-based sperm selection prior to ICSI, including HABSelect, have consistently reported reductions in the numbers of miscarriages among couples randomized to the intervention, suggesting a pathological sperm-mediated factor mitigated by prior HA-binding/selection. The mechanism of that protection is unknown.STUDY DESIGN, SIZE, DURATIONThe original HABSelect Phase 3 RCT ran from 2014 to 2017 and included 2752 couples from whom sperm samples used in control (ICSI) and intervention (Physiological IntraCytoplasmic Sperm Injection; PICSI) arms of the trial were stored frozen for later assessment of DNA quality (DNAq). The trial overlapped with its mechanistic arm, running from 2016 to 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSAs miscarriage reduction was a significant secondary outcome of the trial, samples (n = 1247) selected for the mechanistic analysis were deliberately enriched for miscarriage outcomes (n = 92 or 7.4%) from a total of 154 miscarriages (5.6%) among all (n = 2752) couples randomized by stratified random sampling. Values from fresh semen samples for sperm concentration (mml), percentage forward progressive motility and percentage HA-binding score (HBS) were obtained before being processed by differential density gradient centrifugation or (rarely) by swim-up on the day of treatment. Surplus sperm pellets were recovered, aliquoted and cryopreserved for later analysis of DNAq using slide-based Comet, TUNEL, acridine orange (AO) and the sperm chromatin dispersion (SCD) assays. Following their classification into normal and abnormal sample subcategories based on reference values for sperm concentration and motility, relationships with HBS and DNAq were examined by Spearman correlation, Student’s t-tests, Mann Whitney U tests, and logistic regression (univariable and multivariable). Parsimonious selection enabled the development of models for exploring and explaining data trends. Potential differences in future cumulative pregnancy rates relating to embryo quality were also explored.MAIN RESULTS AND THE ROLE OF CHANCEResults from the 1247 sperm samples assayed for HBS and/or DNAq, generated data that were considered in relation to standard physiological measures of (sperm) vitality and to treatment outcomes. All measures of HBS and DNAq discriminated normal from abnormal sperm samples (P LIMITATIONS, REASONS FOR CAUTIONHABSelect was a prospective RCT and the mechanistic study group was drawn from its recruitment cohort for retrospective analysis, without the full benefit of randomization. The clinical and mechanistic aspects of the study were mutually exclusive in that measures of DNAq were obtained from residual samples and not from HA-selected versus unselected sperm. Models for fitting mechanistic with baseline and other clinical data were developed to compensate for variable DNAq data quality. HABSelect used a solid-state version of PICSI and we did not assess the efficacy of any liquid-state alternatives. PICSI reduced fertilization rates and did not improve the outlook for cumulative pregnancy rates.WIDER IMPLICATIONS OF THE FINDINGSNotwithstanding the interventional effect on fertilization rates and possibly blastocyst formation (neither of which influenced pregnancy rates), poor sperm DNAq, reflected by lower HBS, probably contributed to the depression of all gestational outcomes including live births, in the HABSelect trial. The interventional avoidance of defective sperm is the best explanation for the equalization in live birth rates among older couples randomized to the trial’s PICSI arm. As patients going forward for assisted conception cycles globally in future are likely to be dominated by an older demographic, HA-based selection of sperm for ICSI could be considered as part of their treatment plan.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by the National Institute for Health Research (NIHR) EME (Efficacy and Mechanism Evaluation)-11-14-34. National Research Ethics Service approval 11/06/2013: 13/YH/0162. S.L. is CEO of ExamenLab Ltd (company number NI605309).TRIAL REGISTRATION NUMBERISRCTN99214271.

BACKGROUND Clinical response in hidradenitis suppurativa (HS) is most commonly assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR) measure. Dermal tunnels, increased body mass index, smoking and antibiotic use significantly decrease the odds of achieving HiSCR. However, there are few data exploring if clinical features are also associated with length of time to achieve clinical response and/or time to lose clinical response. AIM To explore whether variables associated with achievement of HiSCR are associated with time to achieve HiSCR and time to loss of HiSCR in patients with HS treated with adalimumab 40 mg weekly in the PIONEER open-label extension study. METHODS Time-to-event analyses were performed to estimate time to achieve HiSCR and time to loss of HiSCR. The log rank test was used to compare cumulative incidence curves for a priori patient- and disease-associated factors. Cox regression analysis was performed to compare time-to-event outcomes in the presence of a priori variables. All statistical analyses were completed with R software (V3.5.3). RESULTS Presence of dermal tunnels significantly increased the time to achieve HiSCR (median 32.6 vs. 14.3 weeks, P = 0.02) and the hazard ratio (HR) was significant after controlling for patient and disease factors (HR = 0.70, 95% CI 0.51-0.96, P = 0.03). A positive family history of HS significantly decreased the time to loss of HiSCR (median 11.4 vs. 18 weeks, P

Aims Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment. Materials and methods Patients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed. Results In total, 228 patients were included; median age 72 years (51–87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naive patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06–2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63–1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51–1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival. Conclusions Ra-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naive patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.

An evaluation of the patient experience, from referral to first assessment, at an outpatient emergency burns assessment service in a UK burn unit. All patients attending their first appointment were invited to complete a questionnaire, covering patient expectations following referral, their journey to the hospital and an evaluation of the appointment. Process mapping was used to map the patient journey within the department and identify functional bottlenecks and waits. 35 new patients completed the questionnaire over a four-week period in February 2019. 70% of respondents had received no printed information about their condition or the hospital prior to the appointment and 28% of patients did not know what to expect from attending the clinic. Patients incurred high direct and indirect costs in order to attend their appointments. 86% patients felt more confident about looking after their injury following their appointment. The patient journey through the clinic was observed for 19 patients; four functional bottlenecks were identified. The longest waits were for clinical photography and completion of nursing paperwork. A multimodal approach to this quality improvement project has enabled the service to identify process bottlenecks and through consultation with stakeholders, develop staff training and patient information to improve the service.

Background The association of adalimumab therapy with malignancy and infection is established in other inflammatory diseases; however, rates of hidradenitis suppurativa (HS) are based on case reports or retrospective healthcare data and the effect of adalimumab therapy on these rates is unknown. Previously reported rates in the PIONEER OLE Phase 3 study reported on rates only in a subpopulation of 88 participants rather than the entire cohort. Aim To quantify rates of malignancy and serious infection in all patients with HS treated with adalimumab 40 mg weekly. Methods Reanalysis was undertaken of individual patient data from the PIONEER 1, PIONEER 2 and PIONEER open-label extension Phase 3 trial data encompassing 591 unique patients with HS administered adalimumab 40 mg weekly without concurrent antibiotic exposure. Incidence rates of serious infection and malignancy were calculated. Results Incidence rates of serious infection and malignancy were 2.14 and 0.46 per 100 patient-years, respectively. Rates of infection and malignancy were comparable to those in other inflammatory conditions examined. Conclusion Incidence of serious infection in patients with HS on adalimumab is comparable to those with psoriasis and inflammatory arthropathies, but the incidence of malignancy is increased. This may reflect disease-specific malignancy risk rather than an effect of adalimumab.

BACKGROUND: The Hidradenitis Suppurativa Clinical Response (HiSCR) is the gold standard primary outcome measure for Hidradenitis Suppurativa (HS) clinical trials, however it does not assess the presence of draining tunnels, a common finding in advanced disease. It is unclear what the effect of the presence or absence of draining tunnels has upon the efficacy of adalimumab therapy in moderate and advanced disease. OBJECTIVES: We evaluated the efficacy of adalimumab versus placebo using the International Hidradenitis Suppurativa Severity Score System (IHS4). Additionally, we assessed the impact of draining tunnels upon therapeutic response as measured by both the HiSCR and change in nodule counts. METHODS: Re-analysis was conducted using the IHS4 and PIONEER 1 and 2 Individual Patient Data. Both binary outcomes (achieving HISCR and achieving change in IHS4 severity category) and continuous outcomes (nodule counts and IHS4 score) were calculated using R version 3.5.3. Regression modeling was undertaken to assess the impact of draining tunnels and other variables. P

Abstract. Background: People who have mental illness are at increased risk of suicide. Therefore, identifying "typical" trajectories to suicide in this population has the potential to improve the effectiveness of suicide prevention strategies. Aim: The aim of this study was to explore the pathways to suicide among a sample of Victorians with a diagnosed mental illness. Method: Victorian Suicide Register (VSR) data were used to generate life charts and identify typical life trajectories to suicide among 50 Victorians. Results: Two distinct pathways to suicide were identified: (1) where diagnosis of mental illness appeared to follow life events/stressors; and (2) where diagnosis appeared to precede exposure to life events/stressors. Some events acted as distal factors related to suicide, other events were more common as proximal factors, and still others appeared to act as both distal and proximal factors. Limitations: The data source might be biased because of the potential for incomplete information, or alternatively, the importance of some factors in a person's life may have been overstated. Conclusion: Strategies to reduce suicide need to consider the chronology of exposure to stressors in people's lives and clearly need to be different depending on whether proximal or distal risk factors are the target of a given strategy or intervention.

BackgroundMore men than women in the UK are living with overweight or obesity, but men are less likely to engage with weight loss programmes. Healthy Dads, Healthy Kids is an effective Australian weight management programme that targets fathers, who participate with their primary school-aged children. Behavioural interventions do not always transfer between contexts, so an adaptation of the Healthy Dads, Healthy Kids programme to an ethnically diverse UK setting was trialled.ObjectivesTo adapt and test the Australian Healthy Dads, Healthy Kids programme for delivery to men in an ethnically diverse, socioeconomically disadvantaged UK setting.DesignPhase 1a studied the cultural adaptation of the Healthy Dads, Healthy Kids programme and was informed by qualitative data from fathers and other family members, and a theoretical framework. Phase 1b was an uncontrolled feasibility trial. Phase 2 was a randomised controlled feasibility trial.SettingTwo ethnically diverse, socioeconomically disadvantaged UK cities.ParticipantsIn phase 1a, participants were parents and family members from black and minority ethnic groups and/or socioeconomically deprived localities. In phases 1b and 2, participants were fathers with overweight or obesity and their children aged 4–11 years.InterventionsThe adapted Healthy Dads, Healthy Kids intervention comprised nine sessions that targeted diet and physical activity and incorporated joint father–child physical activity. Healthy Dads, Healthy Kids was delivered in two programmes in phase 1b and four programmes in phase 2. Those in the comparator arm in phase 2 received a family voucher to attend a local sports centre.Main outcome measuresThe following outcomes were measured: recruitment to the trial, retention, intervention fidelity, attendance, feasibility of trial processes and collection of outcome data.ResultsForty-three fathers participated (intervention group,n = 29) in phase 2 (48% of recruitment target), despite multiple recruitment locations. Fathers’ mean body mass index was 30.2 kg/m2(standard deviation 5.1 kg/m2); 60.2% were from a minority ethnic group, with a high proportion from disadvantaged localities. Twenty-seven (63%) fathers completed follow-up at 3 months. Identifying sites for delivery at a time that was convenient for the families, with appropriately skilled programme facilitators, proved challenging. Four programmes were delivered in leisure centres and community venues. Of the participants who attended the intervention at least once (n = 20), 75% completed the programme (attended five or more sessions). Feedback from participants rated the sessions as ‘good’ or ‘very good’ and participants reported behavioural change. Researcher observations of intervention delivery showed that the sessions were delivered with high fidelity.ConclusionsThe intervention was well delivered and received, but there were significant challenges in recruiting overweight men, and follow-up rates at 3 and 6 months were low. We do not recommend progression to a definitive trial as it was not feasible to deliver the Healthy Dads, Healthy Kids programme to fathers living with overweight and obesity in ethnically diverse, socioeconomically deprived communities in the UK. More work is needed to explore the optimal ways to engage fathers from ethnically diverse socioeconomically deprived populations in research.Trial registrationCurrent Controlled Trials ISRCTN16724454.FundingThis project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 8, No. 2. See the NIHR Journals Library website for further project information.

Background The Daily Mile is designed to increase physical activity levels with children running or walking around school grounds for 15-min daily. It has been adopted by schools worldwide and endorsed as a solution to tackle obesity, despite no robust evidence of its benefits. We conducted a cluster randomised controlled trial to determine its clinical and cost-effectiveness. Methods Forty schools were randomly assigned (1:1) to either the Daily Mile intervention or control group in which only the usual school health and wellbeing activities were implemented. The primary outcome was BMI z-score (BMIz) at 12 months follow-up from baseline, with planned subgroup analysis to examine differential effects. Primary economic analysis outcome was incremental cost per Quality-Adjusted-Life-Year (QALY) gained. Results Using a constrained randomisation approach, balanced on school size, baseline BMIz and proportion of pupils eligible for free school meals, 20 schools were allocated to intervention (n = 1,153 participants) and 20 to control (n = 1,127); 3 schools withdrew (2 intervention, 1 control). At 12 months, BMIz data were available for 18 intervention schools (n = 850) and 19 control schools (n = 820 participants). Using intention-to-treat analysis the adjusted mean difference (MD) in BMIz (intervention − control) was −0.036 (95% CI: −0.085 to 0.013, p = 0.146). Pre-specified subgroup analysis showed a significant interaction with sex (p = 0.001) suggesting a moderate size benefit of The Daily Mile in girls (MD −0.097, 95% CI −0.156 to −0.037). This was consistent with the exploratory economic results that showed The Daily Mile to be highly cost-effective in girls (£2,492 per QALY), but not in boys, and overall to have a 76% chance of cost-effectiveness for the whole sample, at the commonly applied UK threshold of £20,000 per QALY. Conclusions Overall the Daily Mile had a small but non-significant effect on BMIz, however, it had a greater effect in girls suggesting that it might be considered as a cost-effective component of a system-wide approach to childhood obesity prevention.

Lichen planopilaris (LPP) is a scarring alopecia that is characterized by a lichenoid interface infiltrate with follicular extension. We present a case of LPP composed predominantly of plasma cells in a 52-year-old man. The patient was originally diagnosed with scalp psoriasis 30 years before presentation. Punch biopsies performed at an outside institution 2 years before presentation revealed lymphocyte-predominant LPP. After referral to the senior author's institution due to inadequate response to therapy, biopsies demonstrated a robust, superficial, and deep lichenoid interface dermatitis composed predominantly of plasma cells. Immunohistochemical and special staining for CD138, MUM-1, kappa and lambda light chains, immunoglobulin G4, CD3, CD20, PAX5, CD5, CD7, CD4, CD8, CD43, CD123, Gram, Grocott's methenamine silver stain, treponemal antibody, colloidal iron, and Movat showed a scarring alopecia and were not supportive of a hematolymphoid, infectious, or autoimmune etiology. B-cell clonality studies were below the threshold needed for definitive diagnosis of a clonal process. Doxycycline and hydroxychloroquine were subsequently added to the patient's treatment regimen, leading to an improvement of symptoms. We present this case to bring awareness to this unusual feature and discuss its differential diagnosis.

Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC

Key Points Question In children with relapsing corticosteroid-sensitive nephrotic syndrome, does daily low-dose corticosteroid given at the time of upper respiratory tract infection prevent upper respiratory tract infection–related relapse? Findings In this randomized clinical trial of 365 children, daily low-dose corticosteroid therapy resulted in no difference in the frequency of upper respiratory tract infection–related relapses compared with placebo. Meaning Results of this study suggest that low-dose corticosteroid treatment is not beneficial as a strategy to prevent upper respiratory tract infection–related relapses., Importance In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. Objective To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection–related relapses. Design, Setting, and Participants This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. Interventions At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. Main Outcomes and Measures The primary outcome was the incidence of first upper respiratory tract infection–related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. Results The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection–related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, −0.02; 95% CI, −0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). Conclusions and Relevance The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. Trial Registration isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39, This randomized clinical trial investigates whether a low daily dose of prednisolone in children with relapsing steroid-sensitive nephrotic syndrome prevents upper respiratory tract infection–related relapse.

Background Although there is emerging data regarding the psychometric properties of the Child Health Utility-9D instrument, more evidence is required with respect to its validity for use in different country settings. The aim of this study was to examine the construct validity of the CHU-9D-CHN instrument in Chinese children. Methods Baseline Health-Related Quality of Life (HRQoL) and demographic data were collected from children recruited to the CHIRPY DRAGON obesity prevention intervention randomised controlled trial in China. HRQoL was measured using the Chinese version of the CHU-9D instrument (CHU-9D-CHN) and the PedsQL instrument. CHU-9D-CHN utility scores were generated using two scoring algorithms [UK and Chinese tariffs]. Discriminant validity, known-group validity and convergent validity were evaluated using non-parametric test for trend, Kruskal–Wallis test and Spearman correlation coefficient analysis respectively. Results Data was available for 1,539 children (mean age 6 years). The CHU-9D-CHN was sensitive to known group differences determined by the median PedsQL total score. Furthermore, the mean CHU-9D-CHN utility values decreased linearly with increasing levels of severity on each dimension of the PedsQL for emotional and social functioning domains. They decreased monotonically with increasing levels of severity on each dimension of the PedsQL for physical and school functioning domains (p p p Conclusions Overall, the findings provide some support for the construct validity of the CHU-9D-CHN within a Chinese population aged 6–7 years. However, some uncertainty remains. We recommend future studies continue to test the validity of the CHU-9D in different country settings. Trial registration: ISRCTN Identifier ISRCTN11867516, Registered on 19/08/2015

Workers who kneel or squat frequently are at a high risk of developing knee pathologies. Knee Savers® are wedge-shaped pads, worn on the lower calf by baseball catchers that aim to reduce this risk. This study examined how Knee Savers® change the bilateral quadriceps muscle activity during dorsiflexed kneeling, and heels-up and flat-foot squatting. For twenty participants, integrated and peak electromyography (EMG) during descent and ascent phases, mean EMG during a 10-s static phase, and participants’ subjective perception of muscle fatigue were compared between equipment conditions (with (W) and without (WO) Knee Savers®). Knee Savers® did not significantly reduce integrated or peak EMG during transitions into and out of the postures; however, they significantly reduced (p

Summary Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.

Background Childhood obesity prevalence continues to be at high levels in the United Kingdom (UK). South Asian children (mainly Pakistani and Bangladeshi origin) with excess adiposity are at particular risk from the cardiovascular consequences of obesity. Many community-based children’s weight management programmes have been delivered in the UK, but none have been adapted for diverse cultural communities. The aim of the Child weigHt mANaGement for Ethnically diverse communities (CHANGE) study, was to culturally adapt an existing children’s weight management programme for children aged 4–11 years so that the programme was more able to meet the needs of families from South Asian communities. Methods The adaptation process was applied to First Steps, an evidence informed programme being delivered in Birmingham (a large, ethnically diverse city). A qualitative study was undertaken to obtain the views of South Asian parents of children with excess weight, who had fully or partially attended, or who had initially agreed but then declined to attend the First Steps programme. The resulting data were integrated with current research evidence and local programme information as part of a cultural adaptation process that was guided by two theoretical frameworks. Results Interviews or focus groups with 31 parents in their preferred languages were undertaken. Themes arising from the data included the need for convenient timing of a programme in a close familiar location, support for those who do not speak English, the need to focus on health rather than weight, nutritional content that focuses on traditional and Western diets, more physical activity content, and support with parenting skills. The data were mapped to the Behaviour Change Wheel framework and Typology of Cultural Adaptation to develop an intervention programme outline. The research evidence and local programme information was then used in the detailed planning of the programme sessions. Conclusions The process of cultural adaptation of an existing children’s weight management programme resulted in a theoretically underpinned programme that is culturally adapted at both the surface and deep structural levels. Trial registration ISRCTN81798055, registered: 13/05/2014. Electronic supplementary material The online version of this article (10.1186/s12889-019-7159-5) contains supplementary material, which is available to authorized users.

A prenatal care provider's recommendation for maternal vaccines is one of the strongest predictors of vaccine acceptance during pregnancy. Aside from basic talking points, few resources exist to help obstetric care providers effectively navigate conversations with vaccine hesitant patients. This paper describes the development and acceptability of "VaxChat," an hour-long, evidence-based video tutorial aimed at improving obstetric care providers' ability to promote maternal vaccines. Between June and November 2017, 62 obstetric care providers registered to receive continuing medical education credit for viewing VaxChat. Of the post-tutorial responses received, over 90% said VaxChat increased their knowledge of what to say to vaccine hesitant patients, increased their confidence in addressing vaccinations with their pregnant patients, and will help them improve their practice culture regarding maternal vaccine promotion. Eighty percent intend to change how they approach vaccine conversations. These data suggest VaxChat may be a welcome complement to existing provider-to-patient talking points.

Purpose\udTo establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.\udMethods and Materials\udIn this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.\udResults\udOne hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.\udConclusions\udPIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.

Symplastic hemangiomas are benign vascular lesions that demonstrate atypia in vascular smooth muscle and interstitial cells with sparing of endothelial cells. We present four cases of this rare tumor. The patients (2M;2F) ranged in age from 57-83 years (median 74); lesions were located on the leg (n=3) and back (n=1), and ranged from 6-8 mm. SH were well-circumscribed and dermal-based, often with an epidermal collarette (3/4). They were characterized by the presence of variably atypical, hyperchromatic/pleomorphic epithelioid to spindled cells within vascular walls (3/4) and/or perivascular stroma (4/4). Atypical multinucleated cells were present in 3 of 4 cases. The overall mitotic rate was low (0-2 mitotic figures per 10 HPFs; mean 0.75 per 10 HPFs), but atypical mitotic figures were seen in 2 of 4 cases. Atypical cells were negative for SMA (0/2), desmin (0/2), AE1/3 (0/2), and CAM5.2 (0/1). ERG, CD31, and CD34 stains were positive in endothelial cells but negative in atypical cells (4/4). Lesional cells and vessels were negative for podoplanin (3/3). Symplastic hemangioma is a benign tumor with bizarre atypia that may be mistaken for malignancy. We present four cases of this rare entity to increase awareness of this tumor and discuss the differential diagnosis. This article is protected by copyright. All rights reserved.

Hidradenitis Suppurativa is a chronic inflammatory disease manifesting in painful nodules, abscesses and malodorous draining tunnels with a pre-disposition to flexural regions of skin. Traditional surgical interventions include excision of clinically visible lesions and in severe cases - excision down to fascia of entire anatomical regions (axilla, groin) and repair with split-thickness grafting or skin substitutes. However, such techniques are plagued by long healing times (up to several months), extensive tissue loss and high recurrence rates given that a large proportion of disease is not clinically visible. Deroofing is a tissue-saving surgical technique, ideal for Hurley Stage 2 disease, which when combined with bedside pre-operative sonography can allow for the accurate identification and removal of occult dermal tunnels whilst minimising the risks of pain, infection, minimising healing times and can be safely conducted in the setting of immunomodulatory therapy.

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6–21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6–21 years) are low (18–44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), cross-state (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n = 119). The first component was significantly correlated with the social skills measure (r=-0.26, p = 0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p = 0.001) and with connectome similarity during MovieDM (r=-0.28, p = 0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to the development of social skills. We infer that the maturation of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs—features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome.

Introduction Dynamic contrast-enhanced CT (DCE-CT) and positron emission tomography/CT (PET/CT) have a high reported accuracy for the diagnosis of malignancy in solitary pulmonary nodules (SPNs). The aim of this study was to compare the accuracy and cost-effectiveness of these. Methods In this prospective multicentre trial, 380 participants with an SPN (8–30 mm) and no recent history of malignancy underwent DCE-CT and PET/CT. All patients underwent either biopsy with histological diagnosis or completed CT follow-up. Primary outcome measures were sensitivity, specificity and overall diagnostic accuracy for PET/CT and DCE-CT. Costs and cost-effectiveness were estimated from a healthcare provider perspective using a decision-model. Results 312 participants (47% female, 68.1±9.0 years) completed the study, with 61% rate of malignancy at 2 years. The sensitivity, specificity, positive predictive value and negative predictive values for DCE-CT were 95.3% (95% CI 91.3 to 97.5), 29.8% (95% CI 22.3 to 38.4), 68.2% (95% CI 62.4% to 73.5%) and 80.0% (95% CI 66.2 to 89.1), respectively, and for PET/CT were 79.1% (95% CI 72.7 to 84.2), 81.8% (95% CI 74.0 to 87.7), 87.3% (95% CI 81.5 to 91.5) and 71.2% (95% CI 63.2 to 78.1). The area under the receiver operator characteristic curve (AUROC) for DCE-CT and PET/CT was 0.62 (95% CI 0.58 to 0.67) and 0.80 (95% CI 0.76 to 0.85), respectively (p Conclusions PET/CT has a superior diagnostic accuracy to DCE-CT for the diagnosis of SPNs. Combining both techniques improves the diagnostic accuracy over either test alone and could be cost-effective.

Background Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web‐based data collection system for early‐stage MF with legal data‐sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in‐built intelligence in the database system ensures accurate staging. Objectives To develop a prognostic index for MF. Methods Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies. Results In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early‐stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 1290)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF. Conclusions This confirmed early‐stage MF cohort is being followed‐up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.

Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole

Hidradenitis suppurativa is a chronic inflammatory dermatosis with presentations ranging from painful nodules and abscesses to draining tunnels. Using an unbiased proteomics approach, we assessed cardiovascular-, cardiometabolic-, and inflammation-related biomarkers in the serum of patients with moderate-to-severe hidradenitis suppurativa. The serum of patients with hidradenitis suppurativa clustered separately from that of healthy controls and had an upregulation of neutrophil-related markers (Cathepsin D, IL-17A, CXCL1). Patients with histologically diagnosed dermal tunnels had higher serum lipocalin-2 levels compared with those without tunnels. Consistent with this, patients with tunnels had a more neutrophilic-rich serum signature, marked by Cathepsin D, IL-17A, and IL-17D alterations. There was a significant serum‒skin correlation between proteins in the serum and the corresponding mRNA expression in skin biopsies, with healthy-appearing perilesional skin demonstrating a significant correlation with neutrophil-related proteins in the serum. CSF3 mRNA levels in lesional skin significantly correlated with neutrophil-related proteins in the serum, suggesting that CFS3 in the skin may be a driver of neutrophilic inflammation. Clinical significantly correlated with the levels of lipocalin-2 and IL-17A in the serum. Using an unbiased, large-scale proteomic approach, we demonstrate that hidradenitis suppurativa is a systemic neutrophilic dermatosis, with a specific molecular signature associated with the presence of dermal tunnels.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

Background: A possible association between COVID-19 infection and thrombosis, either as a direct consequence of the virus or as a complication of inflammation, is emerging in the literature. Data on the incidence of venous thromboembolism (VTE) is extremely limited.\ud \ud Methods: We describe 3 cases of thromboembolism refractory to heparin treatment, the incidence of VTE in an inpatient cohort, and a case-control study to identify risk factors associated with VTE.\ud \ud Results: We identified 274 confirmed (208) or probable (66) COVID-19 patients. 21 (7.7%) were diagnosed with VTE. D-dimer was elevated in both cases (confirmed VTE) and controls (no confirmed VTE) but higher levels were seen in confirmed VTE cases (4.1vs 1.2 µg/mL P

Background Hidradenitis suppurativa is an autoinflammatory disorder of keratinization, with dysregulation of T helper type 17 cytokines. Brodalumab is a monoclonal antibody that targets the interleukin (IL) 17 receptor A receptor. Objectives To assess the safety and tolerability and clinical response at weeks 12 and 24 of brodalumab in moderate to severe HS. Ten participants with no history of inflammatory bowel disease were administered brodalumab 210 mg/1.5 mL subcutaneously at weeks 0, 1, and 2 and every 2 weeks thereafter until week 24. Participants were assessed for adverse events (grade 2/3 adverse events) and clinical response (Hidradenitis Suppurativa Clinical Response [HiSCR], Sartorius, International Hidradenitis Suppurativa Severity Scoring System [IHS4]), including ultrasonography and skin biopsies. Results All 10 participants completed the study. No grade 2/3 adverse events associated with the use of brodalumab were reported. All patients (100%) achieved HiSCR, and 80% achieved IHS4 category change at week 12. HiSCR achievement occurred as early as week 2, likely due to the unique blockade of IL-17A, IL-17C, and IL-17F by brodalumab. Significant improvements were seen in pain, itch, quality of life, and depression. Conclusions Brodalumab was well tolerated in this HS cohort, with no serious adverse events and improvement in clinical outcomes. Alterations in dose frequency may be required in those with advanced disease, which requires further exploration.

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

Background Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. Objective We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. Methods Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. Results RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase–positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. Conclusions Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

BACKGROUND: Recent serogroup C meningococcal disease outbreaks led to meningococcal vaccine recommendations for Southern California men who have sex with men (MSM). Assessment of vaccine confidence is critical to improving vaccine coverage in the context of disease outbreaks wherein immunization(s) are recommended. METHODS: We surveyed MSM using venue-based sampling and began development of the vaccine confidence index (VCI) with 30 survey items corresponding to trust- and safety-related perceptions. We performed exploratory factor analyses and computed the Cronbach’s alpha coefficient to assess internal consistency of the VCI. We created a categorical confidence variable (low, medium, and high confidence) and conducted bivariate and multivariate analyses to evaluate associations with reported confidence and immunization uptake. RESULTS: Ten survey items were included in the final VCI and formed the confidence measure. Participants with low confidence had the lowest levels of reported uptake for both meningococcal vaccines. Confidence differed significantly (p ≤ 0.05) between MSM who indicated they received vaccines recommended within the context of the outbreak and those who did not. CONCLUSIONS: Our VCI is sensitive to a number of issues that may influence vaccine confidence. It is useful for assessing MSM trust and acceptance of recommended immunizations and may be used to inform intervention development.

For black MSM living in the Deep South, the intersection of sexuality, race, and geography impacts HIV risk substantially. Between July and September 2016, we conducted a qualitative study among HIV-negative black MSM in five southern cities in the US with elevated HIV prevalence. Analysis included assessment of interrater reliability, cluster analysis, and descriptive statistics. We enrolled 99 black MSM (mean age: 33.6; SD = 12.8; range: 17–68 years). Four overarching themes emerged: harboring fear of HIV and the internalization of HIV stigma; scrutinizing potential partners to assess riskiness and HIV status; embracing distance and isolation from those perceived as a threat to HIV status; and exhibiting self-efficacy toward HIV prevention and utilizing risk reduction strategies. Future HIV prevention efforts may benefit by balancing risk and deficit based strategies with those that emphasize resilience, address disenfranchisement via structural interventions, and assess and treat inherent trauma(s).

Achieving optimal health among people living with HIV (PLWH) requires linkage to clinical care upon diagnosis, followed by ongoing engagement in HIV clinical care. A disproportionate number of black/African American and Hispanic/Latino men who have sex with men (MSM) living with HIV do not, however, achieve ongoing care. We conducted semistructured interviews in 2014 with 84 urban black/African American and Hispanic/Latino MSM living with HIV to understand their barriers and facilitators to engagement. We classified men as care-engaged or not at the time of the interview, and conducted content analysis of the interview transcripts to identify barriers and facilitators to engagement. Respondent mean age was 42.4 years (range, 20-59). Over half (59.5%, n = 50) were black/African American. Slightly more than a third (38.1%, n = 32) reported not being continuously care-engaged since diagnosis, and 17.9% (n = 15) delayed entry, although they have subsequently entered and remained in care. Sustained engagement began with overcoming denial after diagnosis and having treatment plans, as well as having conveniently located care facilities. Engagement also was facilitated by services tailored to meet multiple patient needs, effective patient-provider communication, and providers who show empathy and respect for their patients. Respondents were less likely to be care-engaged when these factors were absent. It can be difficult for racial and ethnic minority MSM living with HIV to begin and sustain care engagement. To optimize care engagement, our findings underscore the value of (1) convenient multipurpose HIV care facilities that meet patient needs; (2) excellent provider-patient communication that reinforces respect, trust, and HIV treatment literacy; and (3) assisting PLWH to create personalized treatment plans and overcome possible challenges such as diagnosis denial.

Background Economic evaluation normally requires information to be collected on outcome improvement using utility values. This is often not collected during the treatment of substance use disorders making cost-effectiveness evaluations of therapy difficult. One potential solution is the use of mapping to generate utility values from clinical measures. This study develops and evaluates mapping algorithms that could be used to predict the EuroQol-5D (EQ-5D-5 L) and the ICEpop CAPability measure for Adults (ICECAP-A) from the three commonly used clinical measures; the CORE-OM, the LDQ and the TOP measures. Methods Models were estimated using pilot trial data of heroin users in opiate substitution treatment. In the trial the EQ-5D-5 L, ICECAP-A, CORE-OM, LDQ and TOP were administered at baseline, three and twelve month time intervals. Mapping was conducted using estimation and validation datasets. The normal estimation dataset, which comprised of baseline sample data, used ordinary least squares (OLS) and tobit regression methods. Data from the baseline and three month time periods were combined to create a pooled estimation dataset. Cluster and mixed regression methods were used to map from this dataset. Predictive accuracy of the models was assessed using the root mean square error (RMSE) and the mean absolute error (MAE). Algorithms were validated using sample data from the follow-up time periods. Results Mapping algorithms can be used to predict the ICECAP-A and the EQ-5D-5 L in the context of opiate dependence. Although both measures can be predicted, the ICECAP-A was better predicted by the clinical measures. There were no advantages of pooling the data. There were 6 chosen mapping algorithms, which had MAE scores ranging from 0.100 to 0.138 and RMSE scores ranging from 0.134 to 0.178. Conclusion It is possible to predict the scores of the ICECAP-A and the EQ-5D-5 L with the use of mapping. In the context of opiate dependence, these algorithms provide the possibility of generating utility values from clinical measures and thus enabling economic evaluation of alternative therapy options. Trial registration ISRCTN22608399. Date of registration: 27/04/2012. Date of first randomisation: 14/08/2012. Electronic supplementary material The online version of this article (10.1186/s12955-018-0926-7) contains supplementary material, which is available to authorized users.

Imidacloprid (IMI) is the largest selling insecticide internationally. Little is known about the toxicokinetics of IMI in fish, however. In vivo time-course studies were conducted to study the distribution and elimination of IMI in rainbow trout. Animals confined to respirometer-metabolism chambers were injected with a low (47.6 μg/kg), medium (117.5 μg/kg) or high (232.7 μg/kg)dose directly into the bloodstream and allowed to depurate. The fish were then sampled to characterize the loss of IMI from plasma and its appearance in expired water (all dose groups) and urine (medium dose group only). In vitro biotransformation of IMI was evaluated using trout liver S9 fractions. The plasma time-course data indicated an early (< 12 h) distributional phase followed by a log-linear terminal elimination phase. Mean total clearance (CLT) values determined by non-compartmental analysis were 21.8, 27.0 and 19.5 mL/h/kg for the low, medium and high dose groups, respectively. Estimated half-lives for the same groups were 67.0, 68.4 and 68.1 h, while mean fitted values for the steady-state volume of distribution (VSS) were 1.72, 2.23 and 1.81 L/kg. Measured branchial elimination rates were much lower than expected, suggesting that IMI is highly bound in blood. Renal clearance rates were greater than measured rates of branchial clearance (60% of CLT in the medium dose group), possibly indicating a role for renal membrane transporters. There was no evidence for hepatic biotransformation of IMI. Collectively, these findings suggest that IMI would accumulate in trout in continuous waterborne exposures.

Background Hypertension is a growing public health problem in many developing countries including Ethiopia. It is a silent killer and most patients are detected to have it incidentally when they are admitted to hospital for unrelated disease or subjected to pre-employment or preoperative medical checkups. Information on the prevalence of hypertension and its associated factors is to be considered vital to focus and improve prevention and control of cardiovascular diseases. The study design was a cross-sectional survey. The study population consisted of adults aged 25–65 years who lived in Jigjiga city of eastern Ethiopia for at least 6 months. Data were collected using a pretested structured questionnaire, and blood pressure was measured using standardized instruments by trained clinical nurses. Hypertension was defined as having Systolic BP ≥ 140 mmHg or Diastolic BP ≥ 90 mmHg or reported use of regular anti-hypertensive medications prescribed by professionals for raised BP. Data were entered into a computer using Epi Info Version 3.5.1 and exported to SPSS version 16.0 for analysis. Multiple logistic regressions were fitted and Odds ratios with 95% confidence intervals were calculated to identify independently associated factors. Results The prevalence of hypertension was 28.3%. Family history of Hypertension [Adjusted OR 5.7; 95% CI (2.9, 10.9)], having high level of income [Adjusted OR 3.1; 95% CI (1.5, 6.3)], being male [Adjusted OR 2.4; 95% CI (1.3, 4.3)], being above grade 12 [Adjusted OR 2.2; 95% CI (1.2, 3.9)], and having BMI ≥ 25 [Adjusted OR 2.0; 95% CI (1.1, 3.5)] were significantly associated with hypertension. Conclusion Consistent with the literatures, the prevalence of hypertension was high and may show a hidden epidemic in this population. If established with more robust and nationally representative studies, the finding calls for efficient health screening and regular checkups as well as interventions promoting healthy lifestyles. Accordingly, health promotion regarding hypertension should be provided in the population as means of primary prevention. Electronic supplementary material The online version of this article (10.1186/s13104-017-2966-1) contains supplementary material, which is available to authorized users.

Purpose Total skin electron beam radiation therapy (TSEB) is a very effective treatment of mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB, a low-dose schedule of TSEB was introduced in the United Kingdom. Methods and Materials A protocol of 12 Gy in 8 fractions over a period of 2 weeks was agreed on by use of the Stanford University technique. Data were collected prospectively, and the results were analyzed according to the European Organisation for Research and Treatment of Cancer–International Society for Cutaneous Lymphomas endpoints (EORTC-ISCL). Toxicity was scored according to CTCAE v4.0 (Common Terminology Criteria for Adverse Events version 4.0). Results One hundred three patients received treatment, with a median follow-up period of 20.6 months (range, 3.3-53 months). Of these patients, 54 had stage IB disease, 33 had stage IIB, 12 had stage III, and 4 had stage IV. The median age was 68 years (range, 26-91 years). The complete response rate was 18%, the partial response rate was 69%, stable disease was present in 8%, and progression on treatment was found in 5%. In the patients who had a complete response, the median time to relapse was 7.3 months. The median response duration was 11.8 months. Median progression-free survival for all patients was 13.2 months. It was significantly longer, at 26.5 months, in patients with stage IB disease compared with 11.3 months in patients with stage IIB (P=.003; hazard ratio, 2.66) and 10.2 months in patients with stage III (P=.002; hazard ratio, 4.62). The treatment was well tolerated with lower toxicity than higher-dose schedules. Conclusions The low-dose TSEB schedule of 12 Gy in 8 fractions over a period of 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides.

Objectives This study assessed influences on vaccination decisions among parents of young children and examined common vaccination information and advice sources. Methods Using panel samples of parents of children under 7 years, web-based surveys were conducted in 2012 (n = 2603) and 2014 (n = 2518). A vaccine decision-making typology (non-hesitant acceptors, hesitant acceptors, delayers, and refusers) was established and weighted population estimates of potential factors influencing parental vaccination decision (e.g., provider influence, source of information and advice) were computed by year and decision type. Results Delayers and refusers were more likely than acceptors to know someone whose child experienced a severe reaction to a vaccine or delayed/refused vaccine(s). High proportions of delayers (2012: 33.4%, 2014: 33.9%) and refusers (2012: 49.6%, 2014: 58.6%) reported selecting their healthcare provider based on whether the provider would allow them to delay/refuse vaccines. Providers were the most frequently reported trusted vaccine information source among all parents, though more often by acceptors than refusers (2012, 2014: p

The Australasian Psoriasis Collaboration has reviewed the evidence for managing moderate to severe psoriasis in those who are pregnant or are breast-feeding, or planning a family. The severity of the psoriasis, associated comorbidities and specific anti-psoriasis treatment, along with other exposures, can have a deleterious effect on pregnancy outcomes. Psoriasis itself increases the risk of preterm and low birthweight babies, along with spontaneous and induced abortions, but no specific birth defects have been otherwise demonstrated. The baseline risk for a live born baby to have a major birth defect is 3%, and significant neuro-developmental problem is 5%. In Australia, pregnant women with psoriasis are more likely to be overweight or obese, depressed, or smoke in their first trimester, and are also less likely to take prenatal vitamins or supplements. Preconception counselling to improve maternal, pregnancy and baby health is therefore strongly encouraged. The topical and systemic therapies commonly used in psoriasis are each discussed separately, with regards to pregnancy exposure, breast-feeding and effects on male fertility and mutagenicity. The systemic therapies included are acitretin, adalimumab, apremilast, certolizumab, ciclosporin, etanercept, infliximab, ixekizumab, methotrexate, NBUVB, prednisone, PUVA, secukinumab and ustekinumab. The topical therapies include dithranol (anthralin), calcipotriol, coal tar, corticosteroids (weak, potent and super-potent), moisturisers, salicylic acid, tacrolimus, and tazarotene. As a general recommendation, effective drugs that have been widely used for years are preferable to newer alternatives with less foetal safety data. It is equally important to evaluate the risks of not treating, as severe untreated disease may negatively impact both mother and the foetus.