Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved].

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.

Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT.

BACKGROUND: Oral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care. DESIGN: Placebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded. SETTING: Nine NHS head and neck cancer sites in England and Wales. PARTICIPANTS: A total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy. INTERVENTION: Random allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20-30 spots per session. Sham low-level laser therapy was delivered in an identical manner. MAIN OUTCOME MEASURE: The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome. RESULTS: A total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm. LIMITATIONS: The trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient's mouth. CONCLUSIONS: This trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services. FUTURE WORK: Further well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research. TRIAL REGISTRATION: This trial is registered as ISRCTN14224600. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information.

Around 9 out of 10 head and neck cancer patients undergoing treatment experience pain, swelling and sores in their mouth (oral mucositis). This can lead to weight loss, painful ulcers, difficulty talking, eating and drinking, and even hospitalisation. Current care includes helping patients to keep their mouth and teeth clean, encouraging them to have a healthy diet and prescribing mouthwashes, painkillers and mouth-coating gels. However, these treatments give limited help in preventing or treating this condition. The LiTEFORM trial looked at whether or not low-level laser therapy could be used to prevent and treat oral mucositis. Patients were allocated to one of two arms at random: active laser or fake (sham) laser. Neither the patients nor the hospital staff knew which laser was being used. Eighty-seven people joined the study during the time allowed (44 received low-level laser therapy and 43 received sham treatment); however, this was a smaller number than the planned target of 380 people. As a result, no meaningful conclusion can be drawn from the results about whether the therapy is beneficial or cost-effective. People receiving the low-level laser therapy reported slightly more soreness in their mouth than those receiving the sham laser, but this could be down to chance. The number of participants is too small to draw conclusions about whether or not the low-level laser is helpful. Some patients found the laser treatment sessions to be difficult. Setting up a new service delivering laser therapy at the same time as cancer treatments was more complicated than originally anticipated. Problems included the scheduling of appointments, finding suitable rooms and having enough trained staff with time to deliver laser therapy. However, this study has provided us with knowledge on how best to set up a laser therapy service in the NHS as part of the cancer treatment pathway and the costs involved. These findings could help future studies looking into low-level laser therapy for those with head and neck cancer.

Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls.

BACKGROUND & AIMS: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Student and School Characteristics Associated With COVID-19-Related Learning Decline Among Middle and High School Students in K-12 Schools.

BACKGROUND: COVID-19-disrupted schools, including shifts to virtual learning which may have impacted academic progress. This study assessed characteristics associated with changes in academic grades (before and during the pandemic) for different learning modalities for US students ages 13-19. METHODS: Students (N = 2152) completed a web survey on school-related experiences during the 2020-2021 school year. County social vulnerability and SARS-CoV-2 transmission data were merged with survey data. Multivariable logistic regression analysis for grade change was conducted with student and school characteristics for each learning modality, controlling for community characteristics. RESULTS: Greater proportions of remote/virtual (34.4%) and hybrid (30.1%) learning students reported grade decline compared to in-person students (19.9%). Among in-person students, odds of reporting same/improved grades were 65% lower among non-Hispanic black students and 66% lower among non-Hispanic students from other races, compared to non-Hispanic white students. Among hybrid students, odds of reporting same/improved grades for students reporting anxiety were 47% lower than students without anxiety, and odds of reporting same/improved grades among students reporting substance use were 40% lower than students not reporting substance use. Among remote/virtual students, odds of reporting same/improved grades among students with depression were 62% lower than odds of students not reporting depression symptoms. Remote/virtual students who received school-provided educational services also had 1.55 times the odds of reporting same/improved grades, compared to remote/virtual students not receiving these services. CONCLUSIONS: Academic grades were negatively impacted during COVID-19 and learning mode may have contributed. Understanding these impacts is critical to student health and academic achievement.

Conceptual Framework for Understanding Incident Management Systems During Public Health Emergencies.

OBJECTIVE: Effective incident management is essential for coordinating efforts of multiple disciplines and stakeholders when responding to emergencies, including public health disasters such as the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS: Existing research frameworks tend to focus on formal structures and doctrine (eg, ICS-NIMS); however, organizational processes that underlie incident management have not been systematically assessed and synthesized into a coherent conceptual framework. RESULTS: The lack of a framework has hindered the development of measures of performance that could be used to further develop the evidence base and facilitate process improvement. To address this gap, we present a conceptual framework of incident management drawn from expert feedback and a review of literature on incident management and related fields. The framework features 23 measurement constructs grouped into 5 domains: (1) situational awareness and information sharing, (2) incident action and implementation planning, (3) resource management and mobilization, (4) coordination and collaboration, and (5) feedback and continuous quality improvement. CONCLUSIONS: As such, the article provides a first step toward the development of robust measures for assessing the performance and effectiveness of incident management systems.

'Persistent throat symptoms' versus 'laryngopharyngeal reflux': a cross-sectional study refining the clinical condition.

OBJECTIVE: Many patients are assessed for chronic symptoms including: dysphonia, 'globus', throat clearing, postnasal secretions and cough; commonly grouped together and attributed to 'laryngopharyngeal reflux'. This study aimed to explore a clinical trial's baseline dataset for patterns of presenting symptoms, which might provide a more rational basis for treatment. DESIGN: Baseline data were analysed for participants entering the Trial Of Proton-Pump Inhibitors in Throat Symptoms: age, body mass index, Reflux Symptom Index, Comprehensive Reflux Symptom Score, Laryngopharyngeal Reflux-Health-related Quality of Life questionnaire and Reflux Finding Score (RFS-endoscopic examination). The relationships between the questionnaires and demographic factors were assessed. Exploratory factor analysis (EFA) was conducted on individual symptom items in the combined questionnaires. The EFA factors were applied to a Cluster Analysis of participants, to explore the presence of identifiable patient. RESULTS: Throat clearing and globus were the highest ranked scores in the 344 participants. Increasing age was inversely associated with symptom severity (p<0.01). There was no relationship between the RFS and any of the three questionnaires. EFA resulted in a seven-factor model with clinically meaningful labels: voice, cough, gastrointestinal symptoms, airway symptoms and dysphagia, throat clearing, lump in throat, and life events. Cluster analysis failed to demonstrate any clinically meaningful clusters of patients. CONCLUSION: This study offers a framework for future research and demonstrates that individual symptoms cannot be used to group patients. The analysis supports the use of a broad 'umbrella' term such as persistent throat symptoms. TRIAL REGISTRATION NUMBER: ISRCTN38578686.

Multidrug-resistant Uro-associated Escherichia coli Populations and Recurrent Urinary Tract Infections in Patients Performing Clean Intermittent Self-catheterisation.

BACKGROUND: The AnTIC trial linked continuous low-dose antibiotic prophylaxis treatments to a lower incidence of symptomatic urinary tract infections (UTIs) among individuals performing clean intermittent self-catheterisation (CISC). OBJECTIVE: To explore potential mechanisms underlying the protective effects of low-dose antibiotic prophylaxis treatments, blood and urine samples and uro-associated Escherichia coli isolates from AnTIC participants were analysed. DESIGN SETTING AND PARTICIPANTS: Blood samples (n = 204) were analysed for TLR gene polymorphisms associated with UTI susceptibility and multiple urine samples (n = 558) were analysed for host urogenital responses. E.coli sequence data for 45 temporal isolates recovered from the urine samples of 16 trial participants in the prophylaxis (n = 9) and no-prophylaxis (n = 7) study arms, and characterised by multidrug resistance (MDR), were used to classify individual strains. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: TLR polymorphism data were analysed using Poisson regression. Concentrations of urine host defence markers were analysed using linear mixed-effects models, which accounted for repeated urine samples. RESULTS AND LIMITATIONS: Urine samples from CISC users, irrespective of antibiotic treatment regimens, were associated with robust urothelial innate responses. No links were identified between TLR genotype and CISC user susceptibility to recurrent UTIs. Microbiological study data were limited to the predominant MDR E. coli population; participants prescribed low-dose prophylactic antibiotics were predominantly colonised by a single uro-associated E. coli strain, while participants given acute antibiotic treatments were each colonised by more than one E. coli strain. CONCLUSIONS: Antibiotic treatments did not impact urogenital responses to infection in CISC users. Host genetics in terms of TLR polymorphisms played no role in determining CISC user susceptibility to or protection from recurrent UTIs. Prophylactic antibiotic treatments associated with MDR E. coli were associated with colonisation by stable uro-associated E. coli genotypes. PATIENT SUMMARY: Our findings show that the natural urogenital defences of clean intermittent self-catheterisation (CISC) users were not impacted by antibiotic treatments. For some CISC users, prophylaxis with low-dose antibiotics selected for a stable, predominantly, Esherichia coli rich uromicrobiota.

Motivators of Continued Participation in Public Health Emergency Response Among Federal Public Health Workers: A Qualitative Study.

The purpose of this study was to identify factors that motivate public health workers to deploy to the field during an emergency event. We conducted 25 semistructured interviews with employees at the US Centers for Disease Control and Prevention, all of whom had deployed to the field for the 2014-2016 Ebola, 2016-2017 Zika, and 2017 hurricane responses. We used a grounded theory approach in our analysis of the data. Themes that emerged from the interviews related to responder autonomy, competence, and relatedness, which are consistent with self-determination theory. Motivating factors included having clarity about the response role, desire to be challenged, ability to apply existing skills in the field (or apply new skills learned during deployment to their home office), desire to be helpful, and feeling rewarded by working with affected populations, communities, and other response staff. These preliminary findings suggest that introjected and identified motivating factors may form the foundation of willingness among public health workers to assist during an emergency event. Understanding what motivates staff at public health agencies to participate in emergency deployment can inform the development of recruitment strategies, strengthen effectiveness of response activities, and improve overall agency preparedness.

Reproducibility of 19 F-MR ventilation imaging in healthy volunteers.

PURPOSE: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine (19 F)-MRI of inhaled perfluoropropane, implemented at two research sites. METHODS: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018-June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath-hold. Four 19 F-MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1 H images to ventilation images before semi-automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient. RESULTS: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoVobserver1 = 0.43%; CoVobserver2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers. CONCLUSION: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19 F-MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies.

CDC's Community-Based Organization Behavioral Outcomes Project: Perspectives for Researchers, Implementers and Funders.

Behavioral interventions have been a crucial tool for the prevention of HIV transmission since early in the epidemic. The Centers for Disease Control and Prevention (CDC) has provided funding for evidence-based behavioral interventions (EBIs) at health departments and community-based organizations (CBOs) since 2004. From 2006 to 2015, CDC funded 25 CBOs to evaluate one or more of seven EBIs designed to prevent HIV through the Community-based Organization Behavioral Outcomes Project (CBOP) as implemented outside of a research setting. For each EBI, CBOP showed that most HIV risk behaviors improved after the intervention, and improvements were similar to those observed in research studies. Our findings show that behavioral interventions can be successfully implemented in real-world settings. Although the focus of HIV prevention has largely shifted toward biomedical interventions in recent years, successful implementation often depends on behavioral components. Lessons from CBOP can inform future efforts to develop and implement behavioral interventions for HIV and other areas of public health.

Applying the Ready, Willing, and Able Framework to Assess Agency Public Health Emergency Preparedness: The CDC Perspective.

Public health emergencies in the United States have been complex, frequent, and increasingly costly in the past decade, at times overwhelming government agencies that are primarily resourced for routine, nonemergency health functions. Emergencies are not always predictable, and adequate resources are not always available to prepare staff in advance for emergency response roles and to mobilize them quickly when a new threat emerges. Additionally, real-world data that connect preparedness levels to response outcomes may be difficult to obtain, further limiting continuous quality improvement efforts by public health officials. In this article, we apply the Ready, Willing, and Able (RWA) framework to identify areas for improvement related to organizational and staff readiness, willingness, and ability to respond during a public health emergency. We share emergency response deployment, training, and personnel data collected as part of emergency response activations (2008 to 2018) at the Centers for Disease Control and Prevention to illustrate how the framework may be applied at government agencies to improve response processes and effectiveness. Additionally, we propose potential metrics aligned with the framework constructs that may help emergency managers consistently assess agency preparedness and, over time, be incorporated into broader standardized measurement methods. We conclude that the RWA framework is a practical tool that can complement other preparedness approaches currently in use at government public health agencies.

Prostate cancer androgen receptor splice variant 7 biomarker study - a multicentre randomised feasibility trial of biomarker-guided personalised treatment in patients with advanced prostate cancer (the VARIANT trial) study protocol.

INTRODUCTION: Prostate cancer is the most common male cancer with one in four developing non-curable metastatic disease. Initial treatment responses to hormonal therapies are transient and further management options lie between (1) further hormone therapy or (2) a non-hormonal approach involving additional chemotherapy or molecular radiotherapy (radium-223). There is no clear rationale for choosing between these mechanistically different treatment approaches. The biology of hormone resistance is driven through abnormal androgen receptor activity and we can assay this through a blood test measuring androgen receptor variant 7 (AR-V7) expression in circulating tumour cells. Despite increasing evidence supporting AR-V7's role as a prognostic marker, the clinical utility of such measures remains unknown in helping personalise treatment decisions. METHODS AND DESIGN: The VARIANT feasibility trial is a pragmatic design, to be run over 18 months with participants randomised into the intervention arm receiving biomarker (AR-V7) guided clinical treatment and participants randomised into the control arm with conventional standard management (no biomarker guidance). AR-V7 positive participants (likely to be insensitive to further hormone treatment) will receive chemotherapy or in other cases radium-223 (where routinely available). Seventy male ≥18 years old participants with metastatic castrate resistant prostate cancer clinically indicated to proceed to further hormone therapy or chemotherapy, will be recruited from three National Health Service Trusts based in England, Scotland and Wales. The feasibility primary outcome is willingness of patients to be randomised and clinicians to recruit to a biomarker-based treatment strategy, with trial data informing the basis of a definitive and appropriately powered randomised control trial. ETHICS AND DISSEMINATION: Formal ethics review was undertaken with a favourable opinion, through Wales NRES Committee 2 18/WA/0419. Findings to be disseminated through patient and professional organisations that have expressed their support, media outlets and peer-reviewed journal publication. TRIAL REGISTRATION NUMBER: ISRCTN10246848; pre-results.

A case-control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE).

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p-value = 6.24 × 10-8 ), rs74477937 (p-value = 8.56 × 10-8 ) and rs78707086 (p-value = 8.55 × 10-8 ) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta-analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.

Pruritus Is Common and Undertreated in Patients With Primary Biliary Cholangitis in the United Kingdom.

BACKGROUND AND AIMS: Little is known about the prevalence or treatment of pruritus associated with primary biliary cholangitis (PBC). We analyzed data from patients with PBC recruited from all clinical centers in the United Kingdom (UK) to characterize the prevalence, severity, progression, and treatment of pruritus. METHODS: We performed cross-sectional and longitudinal studies of patients in the UK-PBC cohort to assess trajectories of pruritus. Data on pruritus frequency, severity, and therapy were collected via paper questionnaires completed by 2194 patients at their initial assessment in 2011 and then again in 2014 and 2017. Self-reported treatment data were validated against the prescription record of PBC cohort in the Clinical Practice Research Datalink, a primary care database. We defined persistent pruritus as itch that occurs frequently or all the time and severe pruritus as PBC-40 pruritus domain scores of 12 or more, throughout their disease course. Latent class mixed models were used to study pruritus trajectories and identify factors associated with high pruritus. RESULTS: At initial assessment, 1613 (73.5%) patients had experienced pruritus at some point since their development of PBC-persistent pruritus was reported by 34.5% of the patients and severe pruritus by 11.7%. Only 37.4% of patients with persistent pruritus and 50% with severe pruritus reported ever receiving cholestyramine. Frequencies of rifampicin use were 11% in patients with persistent pruritus and 23% in patients with severe pruritus. Comparison of 2011 and 2014 surveys (comprising 1423 patients) showed consistent self-reported data on pruritus. Proportions of patients in the UK-PBC cohort treated with cholestyramine or naltrexone (37.4% and 4.4%) did not differ significantly from proportions treated in the Clinical Practice Research Datalink cohort (30.4% and 4.4%) (P = .07 for cholestyramine and P = .32 for naltrexone). Latent class mixed models (n = 1753) identified 3 different groups of pruritus. Multivariable analysis identified younger age at diagnosis and higher level of alkaline phosphatase at 12 months after diagnosis as factors significantly associated with persistent high pruritus. CONCLUSIONS: In a large national cohort study of patients with PBC, we found a high prevalence of pruritus and inadequate guideline-recommended therapy. Patient-reported data used to determine pruritus prevalence and treatment are reliable. Younger age and levels of higher alkaline phosphatase were associated with persistent pruritus. We need to increase awareness and management of pruritus in PBC in the UK.

Continuous low-dose antibiotic prophylaxis for adults with repeated urinary tract infections (AnTIC): a randomised, open-label trial.

BACKGROUND: Repeated symptomatic urinary tract infections (UTIs) affect 25% of people who use clean intermittent self-catheterisation (CISC) to empty their bladder. We aimed to determine the benefits, harms, and cost-effectiveness of continuous low-dose antibiotic prophylaxis for prevention of recurrent UTIs in adult users of CISC. METHODS: In this randomised, open-label, superiority trial, we enrolled participants from 51 UK National Health Service organisations. These participants were community-dwelling (as opposed to hospital inpatient) users of CISC with recurrent UTIs. We randomly allocated participants (1:1) to receive either antibiotic prophylaxis once daily (prophylaxis group) or no prophylaxis (control group) for 12 months by use of an internet-based system with permuted blocks of variable length. Trial and laboratory staff who assessed outcomes were masked to allocation but participants were aware of their treatment group. The primary outcome was the incidence of symptomatic, antibiotic-treated UTIs over 12 months. Participants who completed at least 6 months of follow-up were assumed to provide a reliable estimate of UTI incidence and were included in the analysis of the primary outcome. Change in antimicrobial resistance of urinary and faecal bacteria was monitored as a secondary outcome. The AnTIC trial is registered at ISRCTN, number 67145101; and EudraCT, number 2013-002556-32. FINDINGS: Between Nov 25, 2013, and Jan 29, 2016, we screened 1743 adult users of CISC for eligibility, of whom 404 (23%) participants were enrolled between Nov 26, 2013, and Jan 31, 2016. Of these 404 participants, 203 (50%) were allocated to receive prophylaxis and 201 (50%) to receive no prophylaxis. 1339 participants were excluded before randomisation. The primary analysis included 181 (89%) adults allocated to the prophylaxis group and 180 (90%) adults in the no prophylaxis (control) group. 22 participants in the prophylaxis group and 21 participants in the control group were not included in the primary analysis because they were missing follow-up data before 6 months. The incidence of symptomatic antibiotic-treated UTIs over 12 months was 1·3 cases per person-year (95% CI 1·1-1·6) in the prophylaxis group and 2·6 (2·3-2·9) in the control group, giving an incidence rate ratio of 0·52 (0·44-0·61; p<0·0001), indicating a 48% reduction in UTI frequency after treatment with prophylaxis. Use of prophylaxis was well tolerated: we recorded 22 minor adverse events in the prophylaxis group related to antibiotic prophylaxis during the study, predominantly gastrointestinal disturbance (six participants), skin rash (six participants), and candidal infection (four participants). However, resistance against the antibiotics used for UTI treatment was more frequent in urinary isolates from the prophylaxis group than in those from the control group at 9-12 months of trial participation (nitrofurantoin 12 [24%] of 51 participants from the prophylaxis group vs six [9%] of 64 participants from the control group with at least one isolate; p=0·038), trimethoprim (34 [67%] of 51 vs 21 [33%] of 64; p=0·0003), and co-trimoxazole (26 [53%] of 49 vs 15 [24%] of 62; p=0·002). INTERPRETATION: Continuous antibiotic prophylaxis is effective in reducing UTI frequency in CISC users with recurrent UTIs, and it is well tolerated in these individuals. However, increased resistance of urinary bacteria is a concern that requires surveillance if prophylaxis is started. FUNDING: UK National Institute for Health Research.

Continuous low-dose antibiotic prophylaxis to prevent urinary tract infection in adults who perform clean intermittent self-catheterisation: the AnTIC RCT.

BACKGROUND: People carrying out clean intermittent self-catheterisation (CISC) to empty their bladder often suffer repeated urinary tract infections (UTIs). Continuous once-daily, low-dose antibiotic treatment (antibiotic prophylaxis) is commonly advised but knowledge of its effectiveness is lacking. OBJECTIVE: To assess the benefit, harms and cost-effectiveness of antibiotic prophylaxis to prevent UTIs in people who perform CISC. DESIGN: Parallel-group, open-label, patient-randomised 12-month trial of allocated intervention with 3-monthly follow-up. Outcome assessors were blind to allocation. SETTING: UK NHS, with recruitment of patients from 51 sites. PARTICIPANTS: Four hundred and four adults performing CISC and predicted to continue for ≥ 12 months who had suffered at least two UTIs in the previous year or had been hospitalised for a UTI in the previous year. INTERVENTIONS: A central randomisation system using random block allocation set by an independent statistician allocated participants to the experimental group [once-daily oral antibiotic prophylaxis using either 50 mg of nitrofurantoin, 100 mg of trimethoprim (Kent Pharmaceuticals, Ashford, UK) or 250 mg of cefalexin (Sandoz Ltd, Holzkirchen, Germany); n = 203] or the control group of no prophylaxis (n = 201), both for 12 months. MAIN OUTCOME MEASURES: The primary clinical outcome was relative frequency of symptomatic, antibiotic-treated UTI. Cost-effectiveness was assessed by cost per UTI avoided. The secondary measures were microbiologically proven UTI, antimicrobial resistance, health status and participants' attitudes to antibiotic use. RESULTS: The frequency of symptomatic antibiotic-treated UTI was reduced by 48% using prophylaxis [incidence rate ratio (IRR) 0.52, 95% confidence interval (CI) 0.44 to 0.61; n = 361]. Reduction in microbiologically proven UTI was similar (IRR 0.49, 95% CI 0.39 to 0.60; n = 361). Absolute reduction in UTI episodes over 12 months was from a median (interquartile range) of 2 (1-4) in the no-prophylaxis group (n = 180) to 1 (0-2) in the prophylaxis group (n = 181). The results were unchanged by adjustment for days at risk of UTI and the presence of factors giving higher risk of UTI. Development of antimicrobial resistance was seen more frequently in pathogens isolated from urine and Escherichia coli from perianal swabs in participants allocated to antibiotic prophylaxis. The use of prophylaxis incurred an extra cost of £99 to prevent one UTI (not including costs related to increased antimicrobial resistance). The emotional and practical burden of CISC and UTI influenced well-being, but health status measured over 12 months was similar between groups and did not deteriorate significantly during UTI. Participants were generally unconcerned about using antibiotics, including the possible development of antimicrobial resistance. LIMITATIONS: Lack of blinding may have led participants in each group to use different thresholds to trigger reporting and treatment-seeking for UTI. CONCLUSIONS: The results of this large randomised trial, conducted in accordance with best practice, demonstrate clear benefit for antibiotic prophylaxis in terms of reducing the frequency of UTI for people carrying out CISC. Antibiotic prophylaxis use appears safe for individuals over 12 months, but the emergence of resistant urinary pathogens may prejudice longer-term management of recurrent UTI and is a public health concern. Future work includes longer-term studies of antimicrobial resistance and studies of non-antibiotic preventative strategies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67145101 and EudraCT 2013-002556-32. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 22, No. 24. See the NIHR Journals Library website for further project information.

The Impact of Autoimmune Hepatitis and Its Treatment on Health Utility.

Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health-related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient-reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK-AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) and clinical data forms. The EQ-5D-5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ-5D-5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. CONCLUSION: Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid-free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH. (Hepatology 2018; 00:000-000).

The Changing Landscape of HIV Prevention in the United States: Health Department Experiences and Local Adaptations in Response to the National HIV/AIDS Strategy and High-Impact Prevention Approach.

OBJECTIVE: HIV prevention has changed substantially in recent years due to changes in national priorities, biomedical advances, and health care reform. Starting in 2010, motivated by the National HIV/AIDS Strategy (NHAS) and the Centers for Disease Control and Prevention's (CDC's) High-Impact Prevention (HIP), health departments realigned resources so that cost-effective, evidence-based interventions were targeted to groups at risk in areas most affected by HIV. This analysis describes how health departments in diverse settings were affected by NHAS and HIP. METHODS: We conducted interviews and a consultation with health departments from 16 jurisdictions and interviewed CDC project officers who monitored programs in 5 of the jurisdictions. Participants were asked to describe changes since NHAS and HIP and how they adapted. We used inductive qualitative analysis to identify themes of change. RESULTS: Health departments improved their HIV prevention practices in different ways. They aligned jurisdictional plans with NHAS and HIP goals, increased local data use to monitor program performance, streamlined services, and strengthened partnerships to increase service delivery to persons at highest risk for infection/transmission. They shifted efforts to focus more on the needs of people with diagnosed HIV infection, increased HIV testing and routine HIV screening in clinical settings, raised provider and community awareness about preexposure prophylaxis, and used nontraditional strategies to successfully engage out-of-care people with diagnosed HIV infection. However, staff-, provider-, and data-related barriers that could slow scale-up of priority programs were consistently reported by participants, potentially impeding the ability to meet national goals. CONCLUSION: Findings suggest progress toward NHAS and HIP goals has been made in some jurisdictions but highlight the need to monitor prevention programs in different contexts to identify areas for improvement and increase the likelihood of national success. Health departments and federal funders alike can benefit from the routine sharing of successes and challenges associated with local policy implementation, considering effects on the overall portfolio of programs.

Improving Linkage, Retention, and Reengagement in HIV Care in 12 Metropolitan Areas.

The Centers for Disease Control and Prevention developed the Enhanced Comprehensive HIV Prevention Planning (ECHPP) project to support 12 health departments' improvement of their HIV prevention and care portfolios in response to new national guidelines. We systematically analyzed 3 years of progress reports to learn how grantees put into practice local intervention strategies intended to link people to, and keep them in, HIV care. All grantees initiated seven activities to support these strategies: (1) improve surveillance data systems, (2) revise staffing duties and infrastructures, (3) update policies and procedures, (4) establish or strengthen partnerships, (5) identify persons not in care, (6) train personnel, and (7) create ways to overcome obstacles to receiving care. Factors supporting ECHPP grantee successes were thorough planning, attention to detail, and strong collaboration among health department units, and between the health department and external stakeholders. Other jurisdictions may consider adopting similar strategies when planning and enhancing HIV linkage, retention, and reengagement efforts in their areas. ECHPP experiences, lessons learned, and best practices may be relevant when applying new public health policies that affect community and health care practices jurisdiction-wide.

Shifting Resources and Focus to Meet the Goals of the National HIV/AIDS Strategy: The Enhanced Comprehensive HIV Prevention Planning Project, 2010-2013.

In September 2010, CDC launched the Enhanced Comprehensive HIV Prevention Planning (ECHPP) project to shift HIV-related activities to meet goals of the 2010 National HIV/AIDS Strategy (NHAS). Twelve health departments in cities with high AIDS burden participated. These 12 grantees submitted plans detailing jurisdiction-level goals, strategies, and objectives for HIV prevention and care activities. We reviewed plans to identify themes in the planning process and initial implementation. Planning themes included data integration, broad engagement of partners, and resource allocation modeling. Implementation themes included organizational change, building partnerships, enhancing data use, developing protocols and policies, and providing training and technical assistance for new and expanded activities. Pilot programs also allowed grantees to assess the feasibility of large-scale implementation. These findings indicate that health departments in areas hardest hit by HIV are shifting their HIV prevention and care programs to increase local impact. Examples from ECHPP will be of interest to other health departments as they work toward meeting the NHAS goals.