Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Prospective validation of a virtual clinic pathway in the management of choroidal naevi: the NAEVUS study Report no. 1: safety assessment.

BACKGROUND: Choroidal naevi are a common incidental finding prompting specialist referrals to ocular oncology. Rarely, such lesions have sufficient suspicious features to diagnose a small melanoma. The aim of the study is to show that 'virtual' imaging-based pathways are a safe and efficient option to manage such referrals. METHODS: A prospective cohort study at the Manchester Royal Eye Hospital and Moorfields Eye Hospital between June 2016 and July 2017 of the management decision of 400 patients reviewed by an ophthalmologist in a face-to-face consultation (gold standard) supported by fundus photography, optical coherence tomography, autofluorescence (AF) and B-mode ultrasound. The images were also read independently by blinded graders (non-medical) and blinded ophthalmologists, and a management decision was made based on image review alone (virtual pathway). The two pathways were compared for safety. RESULTS: The agreement for management decisions between face-to-face and virtual pathways was 83.1% (non-medical) and 82.6% (medical). There were more over-referrals in the virtual pathway (non-medical 24.3%, medical 23.3% of gold standard discharge) and only two under-referrals (10.5% of gold standard referrals), both borderline cases with minimal clinical risk. The agreement for risk factors of growth (orange pigment, subretinal fluid, hyper-AF) ranged between 82.3% and 97.3%. CONCLUSIONS: We prospectively validated a virtual clinic model for the safe management of choroidal naevi. Such a model of care is feasible with low rate of under-referral. An over-referral rate of almost 24% from the vitrual pathway needs to be factored into designing such pathways in conjunction with evidence on their cost-effectiveness.

Stillbirth rates, service outcomes and costs of implementing NHS England's Saving Babies' Lives care bundle in maternity units in England: A cohort study.

OBJECTIVE: To assess implementation of the Saving Babies Lives (SBL) Care Bundle, a collection of practice recommendations in four key areas, to reduce stillbirth in England. DESIGN: A retrospective cohort study of 463,630 births in 19 NHS Trusts in England using routinely collected electronic data supplemented with case note audit (n = 1,658), and surveys of service users (n = 2,085) and health care professionals (n = 1,064). The primary outcome was stillbirth rate. Outcome rates two years before and after the nominal SBL implementation date were derived as a measure of change over the implementation period. Data were collected on secondary outcomes and process outcomes which reflected implementation of the SBL care bundle. RESULTS: The total stillbirth rate, declined from 4.2 to 3.4 per 1,000 births between the two time points (adjusted Relative Risk (aRR) 0.80, 95% Confidence Interval (95% CI) 0.70 to 0.91, P<0.001). There was a contemporaneous increase in induction of labour (aRR 1.20 (95%CI 1.18-1.21), p<0.001) and emergency Caesarean section (aRR 1.10 (95%CI 1.07-1.12), p<0.001). The number of ultrasound scans performed (aRR 1.25 (95%CI 1.21-1.28), p<0.001) and the proportion of small for gestational age infants detected (aRR 1.59 (95%CI 1.32-1.92), p<0.001) also increased. Organisations reporting higher levels of implementation had improvements in process measures in all elements of the care bundle. An economic analysis estimated the cost of implementing the care bundle at ~£140 per birth. However, neither the costs nor changes in outcomes could be definitively attributed to implementation of the SBL care bundle. CONCLUSIONS: Implementation of the SBL care bundle increased over time in the majority of sites. Implementation was associated with improvements in process outcomes. The reduction in stillbirth rates in participating sites exceeded that reported nationally in the same timeframe. The intervention should be refined to identify women who are most likely to benefit and minimise unwarranted intervention. TRIAL REGISTRATION: The study was registered on (NCT03231007); www.clinicaltrials.gov.

Assessment of the quality, content and perceived utility of local maternity guidelines in hospitals in England implementing the saving babies' lives care bundle to reduce stillbirth.

INTRODUCTION: The UK Department of Health have targeted a reduction in stillbirth by 50% by 2025; to achieve this, the first version of the Saving Babies' Lives Care Bundle (SBLCB) was developed by NHS England in 2016 to improve four key areas of antenatal and intrapartum care. Clinical practice guidelines are a key means by which quality improvement initiatives are disseminated to front-line staff. METHODS: Seventy-five clinical practice guidelines covering the four areas of antenatal and intrapartum care in the first version of SBLCB were obtained from 19 maternity providers. The content and quality of guidelines were evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Maternity health professionals in participating organisations were invited to participate in an anonymous survey to determine perceptions toward and experiences of the use of clinical practice guidelines using a series of Likert scales. RESULTS: Unit guidelines showed considerable variation in quality with median scores of 50%-58%. Only 4 (5.6%) guidelines were recommended for use in clinical practice without modifications, 54 (75.0%) were recommended for use subject to modifications and 12 (16.7%) were not recommended for use. The lowest scoring domains were 'rigour of development', 'stakeholder involvement' and 'applicability'. A significant minority of unit guidelines omitted recommendations from national guidelines. The majority of staff believed that clinical practice guidelines standardised and improved the quality of care but over 30% had insufficient time to use them and 24% stated they were unable to implement recommendations. CONCLUSION: To successfully implement initiatives such as the SBLCB change is needed to local clinical practice guidelines to reduce variation in quality and to ensure they are consistent with national recommendations . In addition, to improve clinical practice, adequate time and resources need to be in place to deliver and evaluate care recommended in the SBLCB.

Routine versus As-Needed Bevacizumab with 12-Weekly Assessment Intervals for Neovascular Age-Related Macular Degeneration: 92-Week Results of the GMAN Trial.

PURPOSE: To evaluate the efficacy and safety of intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD) using 2 different treatment regimens in which patients were assessed clinically at up to 12-week intervals. DESIGN: Randomized, controlled, noninferiority trial. PARTICIPANTS: A total of 331 patients with nAMD. METHODS: Patients were treated with 1.25 mg intravitreal bevacizumab and followed up to 92 weeks. They were randomized into 2 arms. All patients received 3 loading doses 4 weeks apart and thereafter were assessed every 12 weeks until the end of the study. One arm received a routine treatment at each 12-week assessment, and the other arm was treated at these assessments on an as-needed basis. After the loading doses, patients in either arm who showed signs of disease activity had an additional assessment after 6 weeks and at that visit had top-up treatments on an as-needed basis. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) at 92 weeks. RESULTS: At 92 weeks, patients who had treatments every 12 weeks had superior BCVA to those treated on an as-needed basis every 12 weeks (P = 0.008), with the regular treatment arm gaining a mean BCVA of 5.5 letters and the as-needed treatment arm gaining 0.6 letters. The regular treatment arm of the study showed significantly improved outcomes with respect to 5-, 10-, and 15-letter changes in BCVA from baseline compared with the as-needed treatment arm, as well as superior reading speed. In patients who completed the study, up to but not including week 92, the mean number of treatments was 10.8 for the regular treatment arm and 9.1 for the as-needed treatment arm. CONCLUSIONS: A treatment regimen with regular bevacizumab injections every 12 weeks after loading doses supplemented with as-needed top-up treatments produced a stable improvement in BCVA from baseline. The improvement in BCVA was broadly similar to that obtained in other studies using anti-vascular endothelial growth factor drugs with more frequent assessments and treatments.

Sociodemographic factors predicting mother's cervical screening and daughter's HPV vaccination uptake.

BACKGROUND: Achieving high human papillomavirus (HPV) vaccine coverage may reduce inequalities in cervical cancer prevention by mitigating the inequalities seen in the cervical screening programme. This paper assesses whether the same sociodemographic factors are associated with both cervical screening and HPV vaccination. METHODS: Girls' HPV vaccination records were linked by address to cervical screening records for their mothers in the North West of England. Index of Multiple Deprivation scores (2010) and census ethnicity data (2001) were used to investigate the association between deprivation and ethnic composition of area of residence with HPV vaccination and cervical screening uptake, along with potential differences between Primary Care Trusts (PCTs), which were responsible for vaccine delivery. RESULTS: Deprivation was not associated with routine (12-13-year-olds) vaccination initiation, but girls living in the most deprived quintile were significantly less likely to complete the three vaccine doses (OR 0.75; 95% CI 0.63 to 0.88). Mother-daughter pairs failing to engage in either screening or vaccination were also more likely to live in deprived areas (routine vaccination OR for most deprived quintile: 2.35; 95% CI 2.00 to 2.77). There were differences between PCTs after controlling for demographic effects (OR 1.35; 95% CI 1.23 to 1.52). CONCLUSIONS: Ensuring completion of the vaccine schedule is critical for organisations responsible for vaccine delivery in order to reduce cancer risk among girls living in deprived areas. There remains a small minority of mothers and daughters from disadvantaged backgrounds who do not participate in either cervical screening or HPV vaccination.

The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine.

BACKGROUND: Thiopurine-methyl transferase (TPMT) testing prior to the prescription of azathioprine in autoimmune diseases is one of the few examples of a pharmacogenetic test that has made the transition from research into clinical practice. TPMT testing could lead to improved prescribing of azathioprine resulting in a reduction in adverse drug reactions as well as an improvement in effectiveness. When allocating scarce resources robust evidence on cost-effectiveness is required. OBJECTIVE: This study aimed to evaluate the cost-effectiveness of a TPMT genotyping test to inform azathioprine prescribing in autoimmune diseases. The secondary aim of this study was to demonstrate the complexity of undertaking a trial-based evaluation of a pharmacogenetic test. METHODS: A prospective economic evaluation was conducted alongside the TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study, a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT genotyping before azathioprine (n = 167) or current practice (n = 166). Assuming the UK health service perspective and a time horizon of 4 months, resource-use and health status data were collected prospectively for all recruited patients. RESULTS: The mean incremental cost for TPMT genotyping and subsequent care pathways compared with current practice for the 4-month follow-up was -£421.06 (95% confidence interval -£925.15 to £89.75). Mean incremental quality-adjusted life-years were close to zero but negative: -0.008 (95% confidence interval -0.017 to 0.0002). Assuming a threshold of £20,000 per quality-adjusted life-year, the expected incremental net benefit of introducing the test is £256.89 (95% CI -£425.94 to £932.86). CONCLUSIONS: TPMT genotyping potentially offers a less expensive alternative than current practice, but it may also have a small but negative effect on health status. These findings are associated with significant uncertainty, and the causal effect of TPMT genotyping on changes in health status and health care resource use remains uncertain. The results from this study therefore pose a difficult challenge to decision makers.

The school nurse, the school and HPV vaccination: a qualitative study of factors affecting HPV vaccine uptake.

School nurses in the United Kingdom are largely responsible for delivering the human papillomavirus (HPV) vaccine to 12-13 year old girls. In order to assess the impact of HPV vaccination on school nurses' roles, we gave a questionnaire to all 33 school nurses who offered Cervarix ™ in two Primary Care Trusts one year ahead of the national vaccine programme. Key organisational issues raised by the school nurses were the size of the team and its skill mix. A few found their schools uncooperative and were dissatisfied with mechanisms for problem resolution. On average, nurses spent an additional 69 h (0.80 h per child) on vaccine-related activities. In semi-qualitative interviews (n=17), school nurses complained of work overload and described the difficulties of establishing good relationships with some of their schools. Nurses expected schools to take some responsibility for ensuring good uptake and were frustrated when help was not forthcoming. We conclude that variation in uptake between schools in part reflects a difficult relationship with the school nurse which may be attributed to characteristics of the school, schools' attitudes towards health interventions, organisational problems, multiple school nurse roles and/or personal ability. Some of these issues will need to be addressed to ensure continued high vaccine coverage as HPV vaccination becomes a less prioritised, routine activity.

Evaluation of a primary care musculoskeletal clinical assessment service: a preliminary study.

OBJECTIVES: To evaluate the clinical effectiveness of a primary care musculoskeletal clinical assessment service (MCAS). The MCAS is a triage and treatment service for the management of patients with musculoskeletal conditions. DESIGN: Prospective observational cohort study. PARTICIPANTS: Consecutive patients with musculoskeletal disorders referred to the MCAS from primary care over a 6-month period. INTERVENTIONS: Patients were managed within the service in accordance with usual MCAS management/treatment pathways. MAIN OUTCOME MEASURES: Previously validated self-administered questionnaires were selected as outcome measures in order to facilitate the use of postal responses. These comprised two generic health status questionnaires (Short Form 36, EuroQol EQ-5D), a pain assessment using a visual analogue scale and two measures of patient satisfaction (Perceived Improvement Evaluation, Deyo and Diehl satisfaction questionnaire). Outcome measures were taken at baseline, and 3 and 12 months after recruitment. RESULTS: In total, 217 patients were recruited into the study. Significant improvement was demonstrated with EuroQol at 3 and 12 months (P=0.043 and 0.035, respectively) and the pain visual analogue scale at 3 and 12 months (P=0.001 and 0.002, respectively). No significant differences were demonstrated with Short Form 36 (P=0.73 and 0.87). The mean patient-perceived improvement was 33% at 3 months and 46% at 12 months. Results showed high levels of patient satisfaction, with 72% of patients indicating total satisfaction with all aspects of the MCAS. CONCLUSIONS: Nationally, models similar to the MCAS have been developed to help improve care for patients and achieve the 18-week access target. This preliminary study shows the possible benefits of adopting this model of care, and identifies the need for further research.

Ultrasound assessment of caudal catheter position in infants.

The positioning of caudally inserted epidural catheters is crucial to their effectiveness. However, level assessment can be difficult and time consuming. We report the use of ultrasound to assess the catheter position in three patients aged between 1 and 10 months. The advantages and disadvantages of this technique are discussed in relation to other methods of assessing caudal catheter placement.