Strategies to secure surgical research funding: fellowships and grants.

Innovation and advances in surgery are entirely dependent on research. Fellowships and grants are the principal means by which surgical research projects are funded. However, these are scarce and highly competitive. This article offers guidance through the application process for the aspiring academic surgeon. Approaching the application in a timely and structured manner, seeking advice from current and previous award-holders and members of review panels, and obtaining preliminary data are key ingredients to success

Increasing prevalence of male homosexual partnerships and practices in Britain 1990-2000: evidence from national probability surveys.

OBJECTIVES: To estimate the prevalence and timing of homosexual experience among British men; to explore the patterns of sexual practices and partnerships in 2000, and behavioural and attitudinal changes between 1990 and 2000 among men who have sex with men (MSM). DESIGN: Two large, stratified probability sample surveys of the general population. METHODS: Trained interviewers administered a combination of face-to-face and self-completion questionnaires to men aged 16 to 44 years resident in Britain (n = 6000 in 1990 and n = 4762 in 2000). RESULTS: In 2000, 2.8% of British men reported sex with men in the past 5 years. 46.0% of MSM reported five or more partners in the past 5 years, and 59.8% reported unprotected anal intercourse in the past year. A total of 33.0% of MSM reported one or more female partner(s) in the past year. In comparison with 1990, there was a significant increase in the proportion of MSM in the population in 2000, and among these men, in the proportion reporting receptive anal intercourse in the past year [age-adjusted odds ratio (OR), 2.08; 95% confidence interval (CI), 1.08-4.00], but no significant change in self-perceived HIV-risk (age-adjusted OR, 1.11; 95% CI, 0.49-2.51) or HIV testing in past 5 years (age-adjusted OR, 1.14; 95% CI, 0.57-2.25). CONCLUSIONS: Evidence of increasing prevalence of homosexual intercourse among the British male population coupled with increases in some HIV-risk behaviours among MSM suggests overall increasing numbers at risk in the population. Although these changes may partly reflect an increased willingness to report these behaviours, our results are consistent with increasing incidence of sexually transmitted infections and behavioural surveillance data

Sexual behaviour in Britain: partnerships, practices, and HIV risk behaviours.

BACKGROUND: Sexual behaviour is a major determinant of sexual and reproductive health. We did a National Survey of Sexual Attitudes and Lifestyles (Natsal 2000) in 1999-2001 to provide population estimates of behaviour patterns and to compare them with estimates from 1990-91 (Natsal 1990). METHODS: We did a probability sample survey of men and women aged 16-44 years who were resident in Britain, using computer-assisted interviews. Results were compared with data from respondents in Natsal 1990. FINDINGS: We interviewed 11161 respondents (4762 men, 6399 women). Patterns of heterosexual and homosexual partnership varied substantially by age, residence in Greater London, and marital status. In the past 5 years, mean numbers of heterosexual partners were 3.8 (SD 8.2) for men, and 2.4 (SD 4.6) for women; 2.6% (95% CI 2.2-3.1) of both men and women reported homosexual partnerships; and 4.3% (95% CI 3.7-5.0) of men reported paying for sex. In the past year, mean number of new partners varied from 2.04 (SD 8.4) for single men aged 25-34 years to 0.05 (SD 0.3) for married women aged 35-44 years. Prevalence of many reported behaviours had risen compared with data from Natsal 1990. Benefits of greater condom use were offset by increases in reported partners. Changes between surveys were generally greater for women than men and for respondents outside London. INTERPRETATION: Our study provides updated estimates of sexual behaviour patterns. The increased reporting of risky sexual behaviours is consistent with changing cohabitation patterns and rising incidence of sexually transmitted infections. Observed differences between Natsal 1990 and Natsal 2000 are likely to result from a combination of true change and greater willingness to report sensitive behaviours in Natsal 2000 due to improved survey methodology and more tolerant social attitudes

Ethnic variations in sexual behaviour in Great Britain and risk of sexually transmitted infections: a probability survey.

BACKGROUND: Ethnic variations in the rate of diagnosed sexually transmitted infections (STIs) have been reported in many developed countries. We used data from the second British National Survey of Sexual Attitudes and Lifestyles (Natsal 2000) to investigate the frequency of high-risk sexual behaviours and adverse sexual health outcomes in five ethnic groups in Great Britain. METHODS: We did a stratified probability sample survey of 11161 men and women aged 16-44 years, resident in Great Britain, using computer-assisted interviews. Additional sampling enabled us to do more detailed analyses for 949 black Caribbean, black African, Indian, and Pakistani respondents. We used logistic regression to assess reporting of STI diagnoses in the past 5 years, after controlling for demographic and behavioural variables. FINDINGS: We noted striking variations in number of sexual partnerships by ethnic group and between men and women. Reported numbers of sexual partnerships in a lifetime were highest in black Caribbean (median 9 [IQR 4-20]) and black African (9 [3-20]) men, and in white (5 [2-9]) and black Caribbean (4 [2-7]) women. Indian and Pakistani men and women reported fewer sexual partnerships, later first intercourse, and substantially lower prevalence of diagnosed STIs than did other groups. We recorded a significant association between ethnic origin and reported STIs in the past 5 years with increased risk in sexually active black Caribbean (OR 2.74 [95% CI 1.22-6.15]) and black African (2.95 [1.45-5.99]) men compared with white men, and black Caribbean (2.41 [1.35-4.28]) women compared with white women. Odds ratios changed little after controlling for age, number of sexual partnerships, homosexual and overseas partnerships, and condom use at last sexual intercourse. INTERPRETATION: Individual sexual behaviour is a key determinant of STI transmission risk, but alone does not explain the varying risk across ethnic groups. Our findings suggest a need for targeted and culturally competent prevention interventions

Standard wound management versus negative-pressure wound therapy in the treatment of adult patients having surgical incisions for major trauma to the lower limb — a two-arm parallel group superiority randomised controlled trial : protocol for Wound Healing in Surgery for Trauma (WHIST)

Introduction Patients with closed high-energy injuries associated with major trauma have surprisingly high rates of surgical site infection in incisions created during fracture fixation. One factor that may reduce the risk of surgical site infection is the type of dressing applied over the closed surgical incision. In this multicentre randomised clinical trial, negative-pressure wound therapy will be compared with standard dressings with outcomes of deep infection, quality of life, pain and disability. Methods and analysis Adult patients presenting to hospital within 72 hours of sustaining major trauma, requiring a surgical incision to treat a fractured lower limb, are eligible for inclusion. Randomisation, stratified by trial centre, open/closed fracture at presentation and Injury Severity Score (ISS) ≤15 versus ISS ≥16 will be administered via a secure web-based service using minimisation. The random allocation will be to either standard wound management or negative-pressure wound therapy. Trial participants will usually have clinical follow-up at the local fracture clinic for a minimum of 6 months, as per standard National Health Service practice. Diagnosis of deep infection will be recorded at 30 days. Functional, pain and quality of life outcome data will be collected using the Disability Rating Index, Douleur Neuropathique Questionnaire and Euroqol - 5 Dimension - 5 level (EQ-5D-5L) questionnaires at 3 months and 6 months postinjury. Further data will be captured on resource use and any late postoperative complications. Longer term outcomes will be assessed annually for 5 years and reported separately. Ethics and dissemination National Research Ethics Committee approved this study on 16 February 2016 16/WM/0006. The National Institute for Health Research Health Technology Assessment monograph and a manuscript to a peer-reviewed journal will be submitted on completion of this trial. The results of this trial will inform clinical practice on the clinical and cost-effectiveness of the treatment of this injury

Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study. [version 2; peer review: 2 approved]

Dupuytren’s disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates. The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disease. The first part is a dose-ranging study where nodules of participants already scheduled for surgery will be injected with either placebo (saline) or varying doses of adalimumab. The excised tissue will then be analysed for markers of myofibroblast activity. The second part of the study will recruit participants with early stage disease. They will be randomised 1: 1 to receive either adalimumab or placebo at 3 month intervals over 1 year and will then be followed for a further 6 months. Outcome measures will include nodule hardness, size and disease progression. The trial will also determine the cost-effectiveness of adalimumb treatment for this group of participants

Optimising measurement of health-related characteristics of the built environment: Comparing data collected by foot-based street audits, virtual street audits and routine secondary data sources.

The role of the neighbourhood environment in influencing health behaviours continues to be an important topic in public health research and policy. Foot-based street audits, virtual street audits and secondary data sources are widespread data collection methods used to objectively measure the built environment in environment-health association studies. We compared these three methods using data collected in a nationally representative epidemiological study in 17 British towns to inform future development of research tools. There was good agreement between foot-based and virtual audit tools. Foot based audits were superior for fine detail features. Secondary data sources measured very different aspects of the local environment that could be used to derive a range of environmental measures if validated properly. Future built environment research should design studies a priori using multiple approaches and varied data sources in order to best capture features that operate on different health behaviours at varying spatial scales

Cost-effectiveness of adalimumab for early-stage Dupuytren's disease : an economic evaluation based on a randomized controlled trial and individual-patient simulation model.

This is the final version. Available from British Editorial Society of Bone & Joint Surgery via the DOI in this record. Data sharing: Aggregate data will be shared at the end of the trial with external researchers who provide a methodologically sound proposal to the trial team (and will be required to sign a data sharing access agreement with the sponsor) and in accordance with the guidelines of the sponsor and funders. Model code may also be available in due course, on request. Study documents including participant consent form can also be made available. Requests for data or study documents should be directed to the corresponding author and will be considered by the chief investigator in conjunction with other members of the trial management group and the trials unit.AIMS: To estimate the potential cost-effectiveness of adalimumab compared with standard care alone for the treatment of early-stage Dupuytren's disease (DD) and the value of further research from an NHS perspective. METHODS: We used data from the Repurposing anti-TNF for Dupuytren's disease (RIDD) randomized controlled trial of intranodular adalimumab injections in patients with early-stage progressive DD. RIDD found that intranodular adalimumab injections reduced nodule hardness and size in patients with early-stage DD, indicating the potential to control disease progression. A within-trial cost-utility analysis compared four adalimumab injections with no further treatment against standard care alone, taking a 12-month time horizon and using prospective data on EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and resource use from the RIDD trial. We also developed a patient-level simulation model similar to a Markov model to extrapolate trial outcomes over a lifetime using data from the RIDD trial and a literature review. This also evaluated repeated courses of adalimumab each time the nodule reactivated (every three years) in patients who initially responded. RESULTS: The within-trial economic evaluation found that adalimumab plus standard care cost £503,410 per quality-adjusted life year (QALY) gained versus standard care alone over a 12-month time horizon. The model-based extrapolation suggested that, over a lifetime, repeated courses of adalimumab could cost £14,593 (95% confidence interval £7,534 to £42,698) per QALY gained versus standard care alone. If the NHS was willing to pay £20,000/QALY gained, there is a 77% probability that adalimumab with retreatment is the best value for money. CONCLUSION: Repeated courses of adalimumab are likely to be a cost-effective treatment for progressive early-stage DD. The value of perfect parameter information that would eliminate all uncertainty around the parameters estimated in RIDD and the duration of quiescence was estimated to be £105 per patient or £272 million for all 2,584,411 prevalent cases in the UK. Cite this article: Bone Jt Open 2022;3(11):898-906.Wellcome TrustDepartment of Health UK180 Therapeutics LPNational Institute for Health and Care Researc

Cost-effectiveness of adalimumab for early-stage Dupuytren’s disease

Aims: To estimate the potential cost-effectiveness of adalimumab compared with standard care alone for the treatment of early-stage Dupuytren’s disease (DD) and the value of further research from an NHS perspective. Methods: We used data from the Repurposing anti-TNF for Dupuytren’s disease (RIDD) randomized controlled trial of intranodular adalimumab injections in patients with early-stage progressive DD. RIDD found that intranodular adalimumab injections reduced nodule hardness and size in patients with early-stage DD, indicating the potential to control disease progression. A within-trial cost-utility analysis compared four adalimumab injections with no further treatment against standard care alone, taking a 12-month time horizon and using prospective data on EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and resource use from the RIDD trial. We also developed a patient-level simulation model similar to a Markov model to extrapolate trial outcomes over a lifetime using data from the RIDD trial and a literature review. This also evaluated repeated courses of adalimumab each time the nodule reactivated (every three years) in patients who initially responded. Results: The within-trial economic evaluation found that adalimumab plus standard care cost £503,410 per quality-adjusted life year (QALY) gained versus standard care alone over a 12-month time horizon. The model-based extrapolation suggested that, over a lifetime, repeated courses of adalimumab could cost £14,593 (95% confidence interval £7,534 to £42,698) per QALY gained versus standard care alone. If the NHS was willing to pay £20,000/QALY gained, there is a 77% probability that adalimumab with retreatment is the best value for money. Conclusion: Repeated courses of adalimumab are likely to be a cost-effective treatment for progressive early-stage DD. The value of perfect parameter information that would eliminate all uncertainty around the parameters estimated in RIDD and the duration of quiescence was estimated to be £105 per patient or £272 million for all 2,584,411 prevalent cases in the UK

Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to G(ALERT)

A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue repair, so far with limited success. An alternative approach, which may be more effective and far less costly, is to promote tissue regeneration by targeting endogenous stem cells. However, ways of enhancing endogenous stem cell function remain poorly defined. Injury leads to the release of danger signals which are known to modulate the immune response, but their role in stem cell-mediated repair in vivo remains to be clarified. Here we show that high mobility group box 1 (HMGB1) is released following fracture in both humans and mice, forms a heterocomplex with CXCL12, and acts via CXCR4 to accelerate skeletal, hematopoietic, and muscle regeneration in vivo. Pretreatment with HMGB1 2 wk before injury also accelerated tissue regeneration, indicating an acquired proregenerative signature. HMGB1 led to sustained increase in cell cycling in vivo, and using Hmgb1 -/- mice we identified the underlying mechanism as the transition of multiple quiescent stem cells from G0 to GAlert HMGB1 also transitions human stem and progenitor cells to GAlert Therefore, exogenous HMGB1 may benefit patients in many clinical scenarios, including trauma, chemotherapy, and elective surgery