Hyperthermic intraoperative peritoneal chemotherapy and cytoreductive surgery for people with peritoneal metastases: a systematic review and cost-effectiveness analysis.

Background: We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost-utility analysis. Methods: We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost-utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results: The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations: We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions: In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work: More randomised controlled trials are necessary. Study registration: This study is registered as PROSPERO CRD42019130504. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Cancers of the bowel, ovary or stomach can spread to the lining of the abdomen ('peritoneal metastases'). Chemotherapy (the use of drugs that aim to kill cancer cells) given by injection or tablets ('systemic chemotherapy') is one of the main treatment options. There is uncertainty about whether adding cytoreductive surgery (cytoreductive surgery; an operation to remove the cancer) and 'hyperthermic intraoperative peritoneal chemotherapy' (warm chemotherapy delivered into the lining of the abdomen during cytoreductive surgery) are beneficial. We reviewed all the information from medical literature published until 14 April 2022, to answer the above uncertainty. We found the following from eight trials, including about 1000 participants. In people with peritoneal metastases from bowel cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably does not provide any benefits and increases harm compared to cytoreductive surgery + systemic chemotherapy, while cytoreductive surgery + systemic chemotherapy appears to increase survival compared to systemic chemotherapy alone. There is uncertainty about the best treatment for people with peritoneal metastases from stomach cancer. In women with peritoneal metastases from ovarian cancer who require systemic chemotherapy before cytoreductive surgery to shrink the cancer to allow surgery ('advanced ovarian cancer'), hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably increases survival compared to cytoreductive surgery + systemic chemotherapy. In people who can withstand a major operation and in whom cancer can be removed, cytoreductive surgery + systemic chemotherapy should be offered to people with peritoneal metastases from bowel cancer, while hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered to women with peritoneal metastases from 'advanced ovarian cancer'. Uncertainty in treatment continues for gastric cancer. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Pelvic Floor Muscle Training for Stress Urinary Incontinence, Fecal Incontinence, and Pelvic Organ Prolapse: A Health Technology Assessment.

Background: Stress urinary incontinence, fecal incontinence, and pelvic organ prolapse are common forms of pelvic floor dysfunction. Pelvic floor muscle training is used to improve pelvic floor function, through a program of exercises. We conducted a health technology assessment of pelvic floor muscle training for people with stress urinary incontinence, fecal incontinence, or pelvic organ prolapse, which included an evaluation of effectiveness, safety, and the budget impact of publicly funding pelvic floor muscle training, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of included studies using the ROBIS tool, for systematic reviews, and the Cochrane Risk of Bias tool, for randomized controlled trials, and we assessed the quality of the body of evidence according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search but did not conduct a primary economic evaluation. We also analyzed the budget impact of publicly funding pelvic floor muscle training in adults with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse in Ontario. To contextualize the potential value of pelvic floor muscle training as a treatment, we spoke with people with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse. Results: We included 6 studies (4 systematic reviews and 2 randomized controlled trials) in the clinical evidence review. In comparison with no treatment, pelvic floor muscle training significantly improved symptom severity and increased patient satisfaction in women with stress urinary incontinence or pelvic organ prolapse (GRADE: Moderate). For men with stress urinary incontinence after prostatectomy, pelvic floor muscle training yielded mixed results for symptom improvement (GRADE: Very low). For adults with fecal incontinence, pelvic floor muscle training did not improve symptoms in comparison with standard care (GRADE: Very low).In the economic literature review, we included 6 cost-utility analyses that had evaluated the cost-effectiveness of pelvic floor muscle training as a treatment for people with pelvic organ prolapse or urinary incontinence. We did not identify any economic studies on pelvic floor muscle training for women or men with fecal incontinence or men with pelvic organ prolapse. The analyses included in our review found that, for women with stress urinary incontinence, pelvic floor muscle training was likely cost-effective in comparison with other nonsurgical interventions. For men with urinary incontinence after prostate surgery, pelvic floor muscle training was likely not cost-effective in comparison with standard care. For women with pelvic organ prolapse, the cost-effectiveness of pelvic floor muscle training in comparison with no active treatment was uncertain.The average cost of pelvic floor muscle training was approximately $763 per patient. Publicly funding pelvic floor muscle training for women with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse would result in additional costs over 5 years of $185.3 million, $275.6 million, and $85.8 million, respectively. Publicly funding pelvic floor muscle training for men with stress urinary incontinence and fecal incontinence would result in additional costs over 5 years of $10.8 million and $131.1 million, respectively. The people we spoke with reported that stress urinary incontinence, fecal incontinence, and pelvic organ prolapse limited their social and physical activities, taking a huge emotional toll. Many were hesitant or even fearful of surgery, and most people with experience of pelvic floor muscle training reported that it relieved most or all of their symptoms and allowed them to return to normal daily activities. Conclusions: Pelvic floor muscle training is likely more effective (with respect to symptom improvement and patient satisfaction) than no treatment for women with stress urinary incontinence or pelvic organ prolapse. Pelvic floor muscle training may yield mixed results with respect to symptom improvement for men with stress urinary incontinence after prostatectomy and have little to no effect on symptom improvement for adults with fecal incontinence. We estimate that publicly funding pelvic floor muscle training for adults with pelvic floor dysfunction (stress urinary incontinence, fecal incontinence, and pelvic organ prolapse) in Ontario would result in a substantial budget increase over the next 5 years. People with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse shared the negative impact these conditions have on their social and physical life and valued pelvic floor muscle training as a nonsurgical treatment option.

Impact of a social media-delivered distance learning program on mhGAP training among primary care providers in Jalisco, Mexico.

BACKGROUND: The World Health Organization's (WHO) Mental Health Gap Action Programme (mhGAP) aims to provide evidence-based guidelines for the management of mental, neurological, and substance use disorders in non-specialized healthcare settings. However, implementing these guidelines remains a challenge due to various factors, including limited training opportunities for primary care providers. This study con the effectiveness of a social media-delivered distance education program on the mhGAP intervention guide, to overcome barriers of technology access and digital literacy, providing a familiar and accessible platform for primary care providers in Jalisco. METHODS: A quasi-experimental study with a pre-test/post-test design was conducted. Primary care providers from Jalisco were invited to participate in a distance education program on the mhGAP intervention guide. The program consisted of online modules, webinars, and discussion forums facilitated by mental health experts. Knowledge assessments were conducted before and after the intervention using a standardized questionnaire. Participant satisfaction and perceived utility were also evaluated through surveys and focus group discussions. RESULTS: A total of 1,096 primary care providers completed the program. The mean knowledge score significantly improved from 58.2% (SD = 12.8%) in the pre-test to 81.4% (SD = 9.6%) in the post-test (p < 0.001), with a large effect size (Cohen's d = 2.04). Subgroup analyses revealed consistent knowledge gains across different demographic and professional characteristics. Participant satisfaction was high, with 92% rating the program's overall quality as "good" or "excellent." Qualitative findings highlighted the benefits of accessibility, flexibility, interactivity, and practical applicability of the distance education approach. CONCLUSIONS: The social media-delivered distance education program on the mhGAP intervention guide effectively improved the knowledge of primary care providers in Jalisco, Mexico. Participants reported high levels of satisfaction and perceived utility. This study demonstrates the potential of distance education strategies to disseminate evidence-based guidelines and enhance mental health service delivery in primary care settings, particularly in resource-limited areas.

Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation.

Background: Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. Methods: We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. Results: We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. Limitations: Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. Conclusions: There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. Study registration: This study is registered as PROSPERO CRD42020171098. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Lynch syndrome is an inherited condition which puts people at a higher risk of getting bowel cancer, womb cancer and ovarian cancer. Although people with Lynch syndrome are more likely to get these cancers, they are more likely to survive cancer if they get it. People diagnosed with Lynch syndrome get regular testing (surveillance) using a camera to check for bowel cancer or polyps. For womb and ovarian cancer, surveillance may also be an option, but it is less well studied in these cancers. This means that many women are not offered surveillance. Women with Lynch syndrome are recommended to have risk-reducing surgery when their risk starts rising, if they do not want any more children. We wanted to find out whether surveillance for womb and ovarian cancer would work and would be good value for money. Doctors and patients have said that these are important research questions. We searched for published research on this subject and found a lot of studies, but these studies were often small or not well designed, so they could only tell us a limited amount. Studies did not always measure the things that patients want to know. There was some evidence that people having surveillance might live longer than people not having surveillance, but there was also some evidence that risk-reducing surgery is better than surveillance. Surveillance has detected some cancers which had no symptoms, but there are also cancers diagnosed soon after a surveillance visit where nothing was found. People often find surveillance painful, but experiences vary. Our work shows that surveillance and surgery could be good value for money for many women with Lynch syndrome. We need better research to help patients and doctors decide whether surveillance is right for them.

Image directed redesign of bladder cancer treatment pathways: the BladderPath RCT.

Background: Transurethral resection of bladder tumour has been the mainstay of bladder cancer staging for > 60 years. Staging inaccuracies are commonplace, leading to delayed treatment of muscle-invasive bladder cancer. Multiparametric magnetic resonance imaging offers rapid, accurate and non-invasive staging of muscle-invasive bladder cancer, potentially reducing delays to radical treatment. Objectives: To assess the feasibility and efficacy of the introducing multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour in the staging of suspected muscle-invasive bladder cancer. Design: Open-label, multistage randomised controlled study in three parts: feasibility, intermediate and final clinical stages. The COVID pandemic prevented completion of the final stage. Setting: Fifteen UK hospitals. Participants: Newly diagnosed bladder cancer patients of age ≥ 18 years. Interventions: Participants were randomised to Pathway 1 or 2 following visual assessment of the suspicion of non-muscle-invasive bladder cancer or muscle-invasive bladder cancer at the time of outpatient cystoscopy, based upon a 5-point Likert scale: Likert 1-2 tumours considered probable non-muscle-invasive bladder cancer; Likert 3-5 possible muscle-invasive bladder cancer. In Pathway 1, all participants underwent transurethral resection of bladder tumour. In Pathway 2, probable non-muscle-invasive bladder cancer participants underwent transurethral resection of bladder tumour, and possible muscle-invasive bladder cancer participants underwent initial multiparametric magnetic resonance imaging. Subsequent therapy was determined by the treating team and could include transurethral resection of bladder tumour. Main outcome measures: Feasibility stage: proportion with possible muscle-invasive bladder cancer randomised to Pathway 2 which correctly followed the protocol. Intermediate stage: time to correct treatment for muscle-invasive bladder cancer. Results: Between 31 May 2018 and 31 December 2021, of 638 patients approached, 143 participants were randomised; 52.1% were deemed as possible muscle-invasive bladder cancer and 47.9% probable non-muscle-invasive bladder cancer. Feasibility stage: 36/39 [92% (95% confidence interval 79 to 98%)] muscle-invasive bladder cancer participants followed the correct treatment by pathway. Intermediate stage: median time to correct treatment was 98 (95% confidence interval 72 to 125) days for Pathway 1 versus 53 (95% confidence interval 20 to 89) days for Pathway 2 [hazard ratio 2.9 (95% confidence interval 1.0 to 8.1)], p = 0.040. Median time to correct treatment for all participants was 37 days for Pathway 1 and 25 days for Pathway 2 [hazard ratio 1.4 (95% confidence interval 0.9 to 2.0)]. Limitations: For participants who underwent chemotherapy, radiotherapy or palliation for multiparametric magnetic resonance imaging-diagnosed stage T2 or higher disease, it was impossible to conclusively know whether these were correct treatments due to the absence of histopathologically confirmed muscle invasion, this being confirmed radiologically in these cases. All patients had histological confirmation of their cancers. Due to the COVID-19 pandemic, we were unable to realise the final stage. Conclusion: The multiparametric magnetic resonance imaging-directed pathway led to a substantial 45-day reduction in time to correct treatment for muscle-invasive bladder cancer, without detriment to non-muscle-invasive bladder cancer participants. Consideration should be given to the incorporation of multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour into the standard pathway for all patients with suspected muscle-invasive bladder cancer. The improved decision-making accelerated time to treatment, even though many patients subsequently needed transurethral resection of bladder tumour. A proportion of patients can avoid transurethral resection of bladder tumour completely, reducing costs and morbidity, given the much lower cost of magnetic resonance imaging and biopsy compared to transurethral resection of bladder tumour. Future work: Further work to cross-correlate with the recently developed Vesical Imaging-Reporting and Data System will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required. Incorporation of liquid deoxyribonucleic acid-based biomarkers may further improve the quality of decision-making and should also be investigated further. Study registration: This study is registered as ISRCTN 35296862. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135775) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information.

The BladderPath trial explored how to accelerate diagnosis and avoid unnecessary surgery for patients with bladder cancer which had grown into the muscle wall of the bladder, referred to as muscle-invasive bladder cancer. Following initial outpatient diagnosis, bladder cancer patients currently undergo inpatient or day-case surgical tumour removal using a telescope (transurethral resection of bladder tumour). This surgery is fundamental to the treatment of early bladder cancer (non-muscle-invasive). However, for muscle-invasive disease, the main role of transurethral resection of bladder tumour is to confirm that the tumour has grown into the bladder muscle, and this is often inaccurate; the actual correct treatment for muscle-invasive bladder cancer patients should include chemotherapy, radiotherapy and/or bladder removal. For these patients, having transurethral resection of bladder tumour may delay this correct treatment and impact survival. Additionally, for patients determined to need palliative care due to advanced disease, the transurethral resection of bladder tumour may represent over-treatment. A magnetic resonance imaging scan with contrast agent (called multiparametric magnetic resonance imaging) gives a clearer picture of the bladder than normal scans, allowing distinction between invasive and non-invasive tumours. The BladderPath trial investigated adding multiparametric magnetic resonance imaging for patients with suspected muscle-invasive bladder cancer and the effect on treatment times. Subsequent therapy could include transurethral resection of bladder tumour if clinically determined as necessary by the treating team. Trial participants were randomly allocated either to the standard pathway (Pathway 1: all underwent transurethral resection of bladder tumour) or to a new pathway (Pathway 2). In Pathway 2, urologists conducting the initial outpatient diagnostic bladder inspections used a scale to assess whether tumours appeared to be either probably non-muscle-invasive or possibly muscle-invasive. Participants whose tumours appeared possibly muscle-invasive had initial multiparametric magnetic resonance imaging as their next investigation instead of transurethral resection of bladder tumour. We then compared the duration of time from initial diagnosis to receiving the correct treatment for participants in each pathway. Of the 143 participants, 75 (52.1%) were diagnosed as possibly muscle invasive. In Pathway 1, the duration for half of the participants in the group to have received their correct treatment for muscle-invasive bladder cancer was 98 days, which reduced to 53 days in Pathway 2. Furthermore, the duration for half of all the participants in the two groups to have received their correct treatment was 37 days for Pathway 1 and 31 days for Pathway 2. In summary, use of initial multiparametric magnetic resonance imaging in suspected muscle-invasive bladder cancer participants substantially reduced the time to correct treatment (surgery, radiotherapy, chemotherapy or instigation of palliative care) and avoided unnecessary surgery. There was no negative impact on participants with non-invasive disease. Adopting multiparametric magnetic resonance imaging into the pathway ahead of transurethral resection of bladder tumour for patients with suspected muscle-invasive bladder cancer is recommended.

The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation.

Background: Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research: The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy. Design: Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources: Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods: We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results: We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations: A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions: Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work: Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration: The study is registered as PROSPERO CRD42018111005. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.

Testosterone is a hormone which is vital for sexual activity, bone growth and muscle development in men. Men with low testosterone levels may experience problems with erections and may suffer from brittle bones (osteoporosis), weakness, feeling down (low mood) and tiredness. The manifestations of low testosterone can be treated with testosterone replacement therapy. However, there is current uncertainty about the positive effects of testosterone replacement therapy and its safety. We brought together results from all available medical studies that looked at the use of testosterone replacement therapy in men with low testosterone and contacted the doctors who led these studies to gather further information on their participants. We found 35 studies (5601 participants) conducted in different countries, 17 of which provided additional information on their participants. We did not find any evidence to show that testosterone replacement therapy increases the risk of heart problems, or any evidence to show that some men who take testosterone replacement therapy benefit more than others. Men with low testosterone reported having low mood, poor concentration and lack of energy; however, medical studies often failed to prove that these manifestations improved with testosterone replacement therapy. Most medical studies were conducted among white men in North America using questionnaires designed specifically for them; therefore, the results may not reflect the experiences of men in other countries and from more diverse ethnic backgrounds. There is too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS. We think our findings offer some reassurance to doctors and patients that testosterone replacement therapy does not increase the risk of heart problems. New studies are needed to find out whether some groups of men (such as older or younger men) are more likely to benefit from testosterone replacement therapy more than others. It is also important to develop tools which better reflect the experience of men from a diverse range of social and ethnic backgrounds. To inform men with low testosterone about our findings, we are creating a website with dedicated YouTube video clips.

Feasibility of in-home monitoring for people with glaucoma: the I-TRAC mixed-methods study.

Background: Glaucoma is a chronic disease of the optic nerve and a leading cause of severe visual loss in the UK. Once patients have been diagnosed, they need regular monitoring at hospital eye services. Recent advances in technology mean patients with glaucoma can now monitor their disease at home. This could be more convenient for patients and potentially reduce costs and increase capacity for the NHS. However, it is uncertain whether self-monitoring would be acceptable or possible for patients with glaucoma. Objectives: The objectives were to: identify which patients are most appropriate for home monitoring; understand views of key stakeholders (patients, clinicians, researchers) on whether home glaucoma monitoring is feasible and acceptable; develop a conceptual framework for the economic evaluation of home glaucoma monitoring; and explore the need for and provide evidence on the design of a future study to evaluate the clinical and cost-effectiveness of digital technologies for home monitoring of glaucoma. Design: In-home Tracking of glaucoma: Reliability, Acceptability, and Cost (I-TRAC) was a multiphase mixed-methods feasibility study with key components informed by theoretical and conceptual frameworks. Setting: Expert glaucoma specialists in the UK recruited through professional glaucoma societies; study site staff and patient participants recruited through three UK hospital eye services (England, Scotland, Northern Ireland); and UK research teams recruited though existing networks. Intervention: Home tonometer that measures intraocular pressure and a tablet computer with a visual function application. Patients were asked to use the technology weekly for 12 weeks. Results: Forty-two patients were recruited. Retention and completion of follow-up procedures was successful, with 95% (n = 40) completing the 3-month follow-up clinic visits. Adherence to the interventions was generally high [adherence to both devices (i.e. ≥ 80% adherence) was 55%]. Overall, patients and healthcare professionals were cautiously optimistic about the acceptability of digital technologies for home monitoring of patients with glaucoma. While most clinicians were supportive of the potential advantages glaucoma home monitoring could offer, concerns about the technologies (e.g. reliability and potential to miss disease progression) and how they would fit into routine care need to be addressed. Additionally, clarity is required on defining the ideal population for this intervention. Plans for how to evaluate value for money in a future study were also identified. However, the study also highlighted several unknowns relating to core components of a future evaluative study that require addressing before progression to a definitive effectiveness trial. Limitations: The main limitation relates to our sample and its generalisability, for example, the over-representation of educated persons of white ethnicity who were generally experienced with technology and research motivated. Conclusions: The In-home Tracking of glaucoma: Reliability, Acceptability, and Cost study has demonstrated 'cautious optimism' when considering patients' and healthcare professionals' views on the acceptability of digital technologies for home monitoring of patients with glaucoma. However, the study also highlighted several unknowns relating to the research question and design of a future evaluative study that require addressing before progression to a randomised controlled trial. Future work: Further research is required to determine the appropriate population (i.e. low vs. high risk of progression) and further refine the intervention components and delivery for planning of future evaluation studies. Study registration: This study is registered as Research Registry #6213. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129248) and is published in full in Health Technology Assessment; Vol. 28, No. 44. See the NIHR Funding and Awards website for further award information.

The In-home Tracking of glaucoma: Reliability, Acceptability, and Cost study explored whether glaucoma patients who would normally be monitored in hospital could do some monitoring themselves at home, and whether self-monitoring at home would be acceptable or possible for them. We delivered In-home Tracking of glaucoma: Reliability, Acceptability, and Cost in four phases by: Surveying expert glaucoma specialists to understand which patients would benefit most from home monitoring. Providing glaucoma patients with an iPad tablet and a device which measures eye pressure to use once a week for 3 months. The patients who participated and the clinical staff delivering the study were interviewed about their experiences. Interviewing researchers with experience of running large studies testing digital technologies to monitor patients' health at home to understand challenges. Reviewing other researchers' work and comparing it with ours to help us understand whether home monitoring of glaucoma could be good value for money. Overall, patients and healthcare professionals were cautiously optimistic about the digital technologies for home monitoring of glaucoma. Most patient participants were able to use the technologies, and half told us they preferred home monitoring. Most clinicians recognised the potential advantages of glaucoma home monitoring but had concerns about the technologies (specifically reliability and the risk of missing disease progression) and how they would fit into routine care. Plans for how to evaluate value for money in a future study were identified. The study did not aim to identify whether the digital technology was better than what happens currently; a different study design with many more patients would be required to answer that question. The study did identify several important questions to answer before designing a future larger study; for example, how to ensure diverse patient participation. These questions should be the focus of future research in this area.

Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.

Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis.

Background: Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient's risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. Objectives: The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. Methods: The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. Results: The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Conclusions: Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration: This study is registered as PROSPERO CRD4202128587. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Renal cell carcinoma is the most common type of kidney cancer. Several drug treatment options are available for NHS patients with advanced or metastatic disease, and the choice of treatment varies depending on a patient's risk of disease progression. A new drug combination, lenvatinib plus pembrolizumab, may soon become available to treat NHS patients. This review explored whether treatment with lenvatinib plus pembrolizumab offered value for money to the NHS. We reviewed the effectiveness of treatment with lenvatinib plus pembrolizumab versus other NHS treatment options. We also estimated the costs and benefits of treatment with lenvatinib plus pembrolizumab versus current NHS treatments for patients with higher and lower risks of disease progression. Compared with current NHS treatments, treatment with lenvatinib plus pembrolizumab may increase the time that people with a higher risk of disease progression (i.e. worsening disease) were alive. However, for patients with a lower risk of disease progression, the available evidence is limited and only shows that treatment with lenvatinib plus pembrolizumab may prolong the time that patients have a stable level of disease. For all patients, compared to all current NHS treatments, treatment with lenvatinib plus pembrolizumab is very expensive. Compared with current NHS treatments for untreated renal cell carcinoma, using published prices (which do not include any discounts that are offered to the NHS), treatment with lenvatinib plus pembrolizumab may not provide good value for money to the NHS.

Artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer: an evidence synthesis early value assessment.

Background: Lung cancer is one of the most common types of cancer in the United Kingdom. It is often diagnosed late. The 5-year survival rate for lung cancer is below 10%. Early diagnosis may improve survival. Software that has an artificial intelligence-developed algorithm might be useful in assisting with the identification of suspected lung cancer. Objectives: This review sought to identify evidence on adjunct artificial intelligence software for analysing chest X-rays for suspected lung cancer, and to develop a conceptual cost-effectiveness model to inform discussion of what would be required to develop a fully executable cost-effectiveness model for future economic evaluation. Data sources: The data sources were MEDLINE All, EMBASE, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, Epistemonikos, ACM Digital Library, World Health Organization International Clinical Trials Registry Platform, clinical experts, Tufts Cost-Effectiveness Analysis Registry, company submissions and clinical experts. Searches were conducted from 25 November 2022 to 18 January 2023. Methods: Rapid evidence synthesis methods were employed. Data from companies were scrutinised. The eligibility criteria were (1) primary care populations referred for chest X-ray due to symptoms suggestive of lung cancer or reasons unrelated to lung cancer; (2) study designs that compared radiology specialist assessing chest X-ray with adjunct artificial intelligence software versus radiology specialists alone and (3) outcomes relating to test accuracy, practical implications of using artificial intelligence software and patient-related outcomes. A conceptual decision-analytic model was developed to inform a potential full cost-effectiveness evaluation of adjunct artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer. Results: None of the studies identified in the searches or submitted by the companies met the inclusion criteria of the review. Contextual information from six studies that did not meet the inclusion criteria provided some evidence that sensitivity for lung cancer detection (but not nodule detection) might be higher when chest X-rays are interpreted by radiology specialists in combination with artificial intelligence software than when they are interpreted by radiology specialists alone. No significant differences were observed for specificity, positive predictive value or number of cancers detected. None of the six studies provided evidence on the clinical effectiveness of adjunct artificial intelligence software. The conceptual model highlighted a paucity of input data along the course of the diagnostic pathway and identified key assumptions required for evidence linkage. Limitations: This review employed rapid evidence synthesis methods. This included only one reviewer conducting all elements of the review, and targeted searches that were conducted in English only. No eligible studies were identified. Conclusions: There is currently no evidence applicable to this review on the use of adjunct artificial intelligence software for the detection of suspected lung cancer on chest X-ray in either people referred from primary care with symptoms of lung cancer or people referred from primary care for other reasons. Future work: Future research is required to understand the accuracy of adjunct artificial intelligence software to detect lung nodules and cancers, as well as its impact on clinical decision-making and patient outcomes. Research generating key input parameters for the conceptual model will enable refinement of the model structure, and conversion to a full working model, to analyse the cost-effectiveness of artificial intelligence software for this indication. Study registration: This study is registered as PROSPERO CRD42023384164. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135755) and is published in full in Health Technology Assessment; Vol. 28, No. 50. See the NIHR Funding and Awards website for further award information.

Lung cancer is one of the most common types of cancer in the United Kingdom. Early diagnosis may improve survival, as lung cancer is often diagnosed late. Chest X-rays can be used to identify features of lung cancer. There can be delays in getting X-rays, and sometimes features of lung cancer are not seen on them. Artificial intelligence software may help by finding features of cancer on chest X-rays and highlighting them. A radiologist will look at the X-rays and information from the software. There is a lack of information about how lung cancer diagnosis could change if artificial intelligence software is used and what the costs may be to the National Health Service. This project looked at the use of artificial intelligence software in the detection of lung cancer in people referred from primary care. Software companies were invited to provide evidence. There were no studies that looked at this topic among people from primary care. We summarised the closest evidence we could find instead. All of this had flaws, so we could not tell if the results were accurate or helpful to this review. It was not clear if artificial intelligence helped to find cancers or improve people's health. We made a theoretical model to discuss the best way to assess if artificial intelligence software might be cost-effective in detecting lung cancer and what evidence would be needed to do this in a fully working model. Costs and alternative pricing models provided by five companies were used to calculate the cost of adding artificial intelligence software to review chest X-rays in people referred from their general practitioner, for the first 5 years, based on one National Health Service trust. Future studies are needed to identify the impact of adjunct artificial intelligence on test accuracy, clinical decision-making and patient outcomes (e.g. mortality and morbidity).

Workplace Well-Being in Industry 5.0: A Worker-Centered Systematic Review.

The paradigm of Industry 5.0 pushes the transition from the traditional to a novel, smart, digital, and connected industry, where well-being is key to enhance productivity, optimize man-machine interaction and guarantee workers' safety. This work aims to conduct a systematic review of current methodologies for monitoring and analyzing physical and cognitive ergonomics. Three research questions are addressed: (1) which technologies are used to assess the physical and cognitive well-being of workers in the workplace, (2) how the acquired data are processed, and (3) what purpose this well-being is evaluated for. This way, individual factors within the holistic assessment of worker well-being are highlighted, and information is provided synthetically. The analysis was conducted following the PRISMA 2020 statement guidelines. From the sixty-five articles collected, the most adopted (1) technological solutions, (2) parameters, and (3) data analysis and processing were identified. Wearable inertial measurement units and RGB-D cameras are the most prevalent devices used for physical monitoring; in the cognitive ergonomics, and cardiac activity is the most adopted physiological parameter. Furthermore, insights on practical issues and future developments are provided. Future research should focus on developing multi-modal systems that combine these aspects with particular emphasis on their practical application in real industrial settings.

Chair-based yoga programme for older adults with multimorbidity: RCT with embedded economic and process evaluations.

Background: Older adults with multimorbidity experience impaired health-related quality of life and treatment burden. Yoga has the potential to improve several aspects of health and well-being. The British Wheel of Yoga's Gentle Years Yoga© programme was developed specifically for older adults, including those with chronic conditions. A pilot trial demonstrated feasibility of using Gentle Years Yoga in this population, but there was limited evidence of its effectiveness and cost-effectiveness. Objective: To determine the effectiveness and cost-effectiveness of the Gentle Years Yoga programme in addition to usual care versus usual care alone in older adults with multimorbidity. Design: Pragmatic, multisite, individually randomised controlled trial with embedded economic and process evaluations. Setting: Participants were recruited from 15 general practices in England and Wales from July 2019 with final follow-up in October 2022. Participants: Community-dwelling adults aged 65 years and over with multimorbidity, defined as two or more chronic health conditions from a predefined list. Interventions: All participants continued with any usual care provided by primary, secondary, community and social services. The intervention group was offered a 12-week programme of Gentle Years Yoga. Main outcome measures: The primary outcome and end point were health-related quality of life measured using the EuroQol-5 Dimensions, five-level version utility index score over 12 months. Secondary outcomes were health-related quality of life, depression, anxiety, loneliness, incidence of falls, adverse events and healthcare resource use. Results: The mean age of the 454 randomised participants was 73.5 years; 60.6% were female, and participants had a median of three chronic conditions. The primary analysis included 422 participants (intervention, n = 227 of 240, 94.6%; usual care, n = 195 of 214, 91.1%). There was no statistically or clinically significant difference in the EuroQol-5 Dimensions, five-level version utility index score over 12 months: the predicted mean score for the intervention group was 0.729 (95% confidence interval 0.712 to 0.747) and for usual care it was 0.710 [95% confidence interval (CI) 0.691 to 0.729], with an adjusted mean difference of 0.020 favouring intervention (95% CI -0.006 to 0.045, p = 0.14). No statistically significant differences were observed in secondary outcomes, except for the pain items of the Patient-Reported Outcomes Measurement Information System-29. No serious, related adverse events were reported. The intervention cost £80.85 more per participant (95% CI £76.73 to £84.97) than usual care, generated an additional 0.0178 quality-adjusted life-years per participant (95% CI 0.0175 to 0.0180) and had a 79% probability of being cost-effective at the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained. The intervention was acceptable to participants, with seven courses delivered face to face and 12 online. Limitations: Self-reported outcome data raise the potential for bias in an unblinded trial. The COVID-19 pandemic affected recruitment, follow-up and the mode of intervention delivery. Conclusions: Although the Gentle Years Yoga programme was not associated with any statistically significant benefits in terms of health-related quality of life, mental health, loneliness or falls, the intervention was safe, acceptable to most participants and highly valued by some. The economic evaluation suggests that the intervention could be cost-effective. Future work: Longer-term cost-effectiveness modelling and identifying subgroups of people who are most likely to benefit from this type of intervention. Trial registration: This trial is registered as ISRCTN13567538. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/94/36) and is published in full in Health Technology Assessment; Vol. 28, No. 53. See the NIHR Funding and Awards website for further award information.

It is common for older adults to have two or more long-term health conditions. These conditions affect quality of life differently, with some people feeling well and others needing healthcare support. The Gentle Years Yoga programme was developed to improve quality of life for older adults, including those with long-term health conditions. We wanted to see how well the programme worked and if it offered good value for money for the NHS. We tested whether offering a 12-week course of Gentle Years Yoga improved the quality of life and reduced anxiety, depression, loneliness and falls for people aged 65 years and over who had two or more long-term health conditions. We recruited 454 people through general practices across England and Wales, with 240 people selected at random to be invited to take part in the Gentle Years Yoga programme and the other 214 to continue with their usual care and not be offered Gentle Years Yoga. The average age of participants was 74 years, nearly two-thirds were female and the number of long-term health conditions participants had ranged from two to nine (average was three). They completed four questionnaires over a 12-month period. We also interviewed some of the participants and the yoga teachers to find out how the approach worked in practice. The yoga was delivered either face to face or online. We did not find any significant benefits in terms of quality of life, anxiety, depression, loneliness or falls. At interview, some yoga participants noted no or a modest impact on their health or lifestyle, while others described Gentle Years Yoga as transformative, having substantial impacts and improvements on their physical health and emotional well-being. Because running the yoga classes was relatively inexpensive and some insignificant benefits were seen, the Gentle Years Yoga programme may be good value for money.

An international consensus panel on the potential value of Digital Surgery.

OBJECTIVES: The use of digital technology in surgery is increasing rapidly, with a wide array of new applications from presurgical planning to postsurgical performance assessment. Understanding the clinical and economic value of these technologies is vital for making appropriate health policy and purchasing decisions. We explore the potential value of digital technologies in surgery and produce expert consensus on how to assess this value. DESIGN: A modified Delphi and consensus conference approach was adopted. Delphi rounds were used to generate priority topics and consensus statements for discussion. SETTING AND PARTICIPANTS: An international panel of 14 experts was assembled, representing relevant stakeholder groups: clinicians, health economists, health technology assessment experts, policy-makers and industry. PRIMARY AND SECONDARY OUTCOME MEASURES: A scoping questionnaire was used to generate research questions to be answered. A second questionnaire was used to rate the importance of these research questions. A final questionnaire was used to generate statements for discussion during three consensus conferences. After discussion, the panel voted on their level of agreement from 1 to 9; where 1=strongly disagree and 9=strongly agree. Consensus was defined as a mean level of agreement of >7. RESULTS: Four priority topics were identified: (1) how data are used in digital surgery, (2) the existing evidence base for digital surgical technologies, (3) how digital technologies may assist surgical training and education and (4) methods for the assessment of these technologies. Seven consensus statements were generated and refined, with the final level of consensus ranging from 7.1 to 8.6. CONCLUSION: Potential benefits of digital technologies in surgery include reducing unwarranted variation in surgical practice, increasing access to surgery and reducing health inequalities. Assessments to consider the value of the entire surgical ecosystem holistically are critical, especially as many digital technologies are likely to interact simultaneously in the operating theatre.

SATURN: assessing the feasibility of utilising existing registries for real-world evidence data collection to meet patients, regulatory, health technology assessment and payer requirements.

BACKGROUND: SATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries. METHODS: The approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry's Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy. RESULTS: The results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability-readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype-phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations. CONCLUSIONS: This robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that aligns with the requirements from the European Medicines Agency (EMA) and HTAs. More data variables will continue to be developed and refined along the way with more registries participating in SATURN. As a result, SATURN will become a meaningful and truly collaborative core dataset, which will also contribute to advancing understanding of OI diagnosis, treatment, and care.

Effectiveness of Distance Educational Programs for parents of children diagnosed with Autism Spectrum Disorder: an integrative review. / Eficácia de Programas Educativos à Distância para pais de crianças com diagnóstico de Transtorno do Espectro Autista: uma revisão integrativa.

OBJECTIVE: to analyze the scientific literature on distance education programs for parents/caregivers in the development of children with Autism Spectrum Disorder (ASD). RESEARCH METHOD: the PICO strategy was used to identify the research problem. The databases Medline, ERIC, LILACs, EMBASE, CINAHL, Web of Science, and Scopus were searched using specific descriptors and free terms. There were no restrictions on time or language. Articles on online educational programs for parents of children with ASD were selected, focusing on the impact of these programs on the development of children up to six years old. SELECTION CRITERIA: studies were selected based on standard eligibility criteria, including full-text reading after initial screening using the RAYYAN software. Primary studies such as clinical trials and systematic reviews evaluating distance education programs for parents of children with ASD were included. DATA ANALYSIS: the RAYYAN software was used for initial study selection. Articles were hierarchically organized based on title and abstract, followed by full-text reading to apply eligibility criteria. RESULTS: the initial search yielded 1019 articles, of which 192 were identified as duplicates. After initial screening and full-text reading, 37 articles were analyzed, of which six were deemed eligible to answer the research question. Among the eligible studies, one was a systematic review and five were experimental studies. Experimental studies highlighted positive impacts on areas such as daily routines, behavioral flexibility, and communication. The systematic review provided preliminary evidence that distance education programs for parents can enhance knowledge about ASD, increase adherence to interventions, and foster the development of social and communication skills in children. CONCLUSION: the findings suggest that remote parent guidance programs may effectively improve knowledge about ASD, increase parent adherence to interventions, and promote the development of social and communication skills in children with ASD.

OBJETIVO: analisar a produção científica sobre programas educativos à distância para pais/responsáveis no desenvolvimento de crianças com Transtorno do Espectro Autista (TEA). ESTRATÉGIA DE PESQUISA: utilizou-se a estratégia PICO para identificar o problema de pesquisa. Foram consultadas as bases de dados Medline, ERIC, LILACs, EMBASE, CINAHL, Web of Science e Scopus utilizando descritores e termos livres específicos. não houve restrição de tempo ou idioma. Foram selecionados artigos sobre programas educativos online destinados a pais de crianças com TEA, com foco no impacto desses programas no desenvolvimento de crianças de até seis anos. CRITÉRIOS DE SELEçÃO: os estudos foram selecionados com base em critérios de elegibilidade padrões, incluindo a leitura completa dos artigos após a triagem inicial realizada com o software RAYYAN. Foram incluídos estudos primários, como ensaios clínicos e revisões sistemáticas que avaliaram programas educativos à distância para pais de crianças com TEA. ANÁLISE DOS DADOS: utilizou-se o software RAYYAN para a seleção inicial dos estudos. Os artigos foram organizados hierarquicamente com base no título e resumo, seguido pela leitura integral para aplicação dos critérios de elegibilidade. RESULTADOS: a busca inicial resultou em 1019 artigos, dos quais 192 foram identificados como duplicados. Após a seleção inicial e a leitura completa, 37 artigos foram analisados, dos quais seis foram considerados elegíveis para responder à pergunta de pesquisa. Entre os estudos elegíveis, um era uma revisão sistemática e cinco eram estudos experimentais. Os estudos experimentais destacaram impactos positivos em áreas como rotinas diárias, flexibilidade comportamental e comunicação. A revisão sistemática indicou evidências preliminares de que os programas educativos à distância para pais podem melhorar o conhecimento sobre TEA, aumentar a adesão às intervenções e promover o desenvolvimento de habilidades sociais e de comunicação nas crianças. CONCLUSÃO: os resultados sugerem que programas remotos de orientação para pais podem ser eficazes para melhorar o conhecimento sobre TEA, aumentar a adesão dos pais às intervenções e promover o desenvolvimento de habilidades sociais e de comunicação em crianças com TEA.

Prevalence, incidence and associated factors of musculoskeletal disorders before and during the Covid-19 pandemic in faculty members: a comparative cross-sectional study.

BACKGROUND: The COVID-19 pandemic has led to the broad acceptance of distance education (DE), with university professors and students conducting the teaching-learning process remotely from their homes. The propose of this study to investigate the prevalence of musculoskeletal disorders (MSDs) before and during the COVID-19 pandemic and identify risk factors associated with DE that may contribute to an increased incidence of these disorders among university professors. METHODS: This cross-sectional analytical study took a comparative approach and involved 310 university professors in Iran. Data were gathered using an online questionnaire. Initially, demographic and occupational information of the professors, hours of physical activity, and hours spent using electronic devices were recorded. Participants were then asked to report MSDs in various body areas throughout the previous year and the previous seven days. Finally, MSDs risk factors such as workstation ergonomics during computer, laptop, smartphone, and tablet use, as well as working postures during online teaching or offline content development during the COVID-19 pandemic, were examined. RESULTS: The majority of the participants were male (66.13%), with a PhD (46.77%) and a faculty member position (74.2%). On average, the use of computers and laptops increased by 2.67 h and 2.72 h, respectively, during the pandemic compared to before the pandemic. This increase was statistically significant (P < 0.001). MSDs incidence increased significantly before and during the COVID pandemic was observed in the areas of the neck, shoulders, lower and upper back, arms, forearms, wrists and fingers (P < 0.05). The highest cumulative incidence (Cin) of MSDs was related to the neck (Cin = 24.20%), upper back (Cin = 21.29%), low back (Cin = 18.06%) and fingers (Cin = 16.13%). The prevalence of MSDs during the COVID pandemic was significantly associated with employment status (P = 0.042), work experience (P = 0.016), age (P = 0.027), increase in the use of computers/ laptops (P < 0.001), decrease of the smartphone/tablet distance from the body (P = 0.047), workstation (smartphone-tablet, computer, laptop) (P < 0.05), head position (smartphone-tablet) (P = 0.029), display height (computer/laptop) (P = 0.045) and physical activity (P = 0.006). CONCLUSIONS: It appears that the increased duration of smartphone, computer, and laptop use, combined with decreased physical activity and detrimental changes in ergonomic conditions of workstations during the quarantine period caused by the COVID-19 pandemic, has resulted in a shift from dynamic to static tasks and an increase in the prevalence and incidence of MSDs among university professors.

Strategies for Implementing GlobalConsent to Prevent Sexual Violence in University Men (SCALE): study protocol for a national implementation trial.

BACKGROUND: Globally, women 15-24 years are at heightened risk of sexual violence victimization, a risk factor for adverse mental, physical, and behavioral health outcomes. Sexual violence is common at universities and most often perpetrated by men, yet few evidence-based prevention strategies targeting men have been tested in low- and middle-income countries. GlobalConsent is a six-module, web-based educational program adapted from an efficacious U.S.-based program. Nine months post-treatment in a randomized trial in Vietnam, GlobalConsent reduced men's sexually violent behavior (odds ratio [OR] = 0.71, 95%CI 0.50-1.00) and increased prosocial intervening behavior (OR = 1.51, 1.00-2.28) relative to an attention-control. Evidence regarding optimal implementation strategies for scale up is needed. METHODS: We will randomize six medical universities in North, Central, and South Vietnam to deliver GlobalConsent using two different packages of implementation strategies that vary in intensity. Higher-intensity strategies will include greater (1) pre- and post-implementation engagement with university leaders and faculty and (2) greater pre-implementation outreach, follow-up, and incentives for students to promote engagement and completion of GlobalConsent. Higher intensity universities will receive additional training and support for their added activities. We will compare implementation drivers and outcomes, intervention effectiveness, and cost-effectiveness across the two implementation bundles. Our mixed-methods comparative interrupted time series design includes (1) qualitative interviews and quantitative surveys with university leaders and implementation teams to assess implementation barriers and facilitators; (2) repeated surveys with leaders and faculty, implementation teams, and male students to assess multilevel implementation drivers and outcomes; (3) repeated surveys with male students to assess behavioral outcomes (sexual violence and intervening behavior) and mediating variables (knowledge, attitudes, affect, and capacities); and (4) time diaries and cost tracking to assess cost-effectiveness of the two implementation-strategies bundles. DISCUSSION: This project is the first to assess packages of implementation strategies to deliver an efficacious web-based sexual violence prevention program for undergraduate men across all regions of Vietnam and synergizes with a violence-prevention training initiative (D43TW012188). This approach will produce rigorous evidence about how to disseminate GlobalConsent nationally, which holds promise to reduce gender-based health inequities linked to sexual violence as GlobalConsent is brought to scale. TRIAL REGISTRATION: NCT06443541. Retrospectively registered with ClinicalTrials.gov. Registered on June 05, 2024.

Feasibility and Acceptability of Ecological Momentary Assessment to Assess Suicide Risk among Young People with Mood Disorder in China.

Suicidal thoughts and behaviors (STBs) are increasing among young people (aged 12-24 years) in China. Although Ecological Momentary Assessment (EMA) has been increasingly used to study STBs worldwide, no study has been conducted on young people with mood disorders (MD) in China. This mixed-method study aimed to evaluate the feasibility and acceptability of suicide risk monitoring in 75 young people with MD. Participants completed five to eight daily EMA surveys and wore smart bands for the EMA study. Semi-structured interviews were used to collect feedback. High adherence to EMA surveys (73.0 %) and smart bands (87.4 %) indicated feasibility. Participants reported an overall positive experience with the EMA study (helpful, friendly, and acceptable). Additionally, the reasons they were willing to comply with the EMA study were: (1) seeing the possibility of returning to "normal," and (2) experiencing the process of returning. However, a small proportion of participants had negative experiences (e.g., annoyance and missing prompts). The results of this mixed-methods study provide preliminary support for the feasibility and acceptability of using EMA (combined smartphones and wearable sensor devices) to assess suicidality among young people with MD in the Chinese cultural and social context.

The maze of real-world evidence frameworks: from a desert to a jungle! An environmental scan and comparison across regulatory and health technology assessment agencies.

Aim: Regulatory and health technology assessment (HTA) agencies have increasingly published frameworks, guidelines, and recommendations for the use of real-world evidence (RWE) in healthcare decision-making. Variations in the scope and content of these documents, with updates running in parallel, may create challenges for their implementation especially during the market authorization and reimbursement phases of a medicine's life cycle. This environmental scan aimed to comprehensively identify and summarize the guidance documents for RWE developed by most well-established regulatory and reimbursement agencies, as well as other organizations focused on healthcare decision-making, and present their similarities and differences. Methods: RWE guidance documents, including white papers from regulatory and HTA agencies, were reviewed in March 2024. Data on scope and recommendations from each body were extracted by two reviewers and similarities and differences were summarized across four topics: study planning, choosing fit-for-purpose data, study conduct, and reporting. Post-authorization or non-pharmacological guidance was excluded. Results: Forty-six documents were identified across multiple agencies; US FDA produced the most RWE-related guidance. All agencies addressed specific and often similar methodological issues related to study design, data fitness-for-purpose, reliability, and reproducibility, although inconsistency in terminologies on these topics was noted. Two HTA bodies (National Institute for Health and Care Excellence [NICE] and Canada's Drug Agency) each centralized all related RWE guidance under a unified framework. RWE quality tools and checklists were not consistently named and some differences in preferences were noted. European Medicines Agency, NICE, Haute Autorité de Santé, and the Institute for Quality and Efficiency in Health Care included specific recommendations on the use of analytical approaches to address RWE complexities and increase trust in its findings. Conclusion: Similarities in agencies' expectations on RWE studies design, quality elements, and reporting will facilitate evidence generation strategy and activities for manufacturers facing multiple, including global, regulatory and reimbursement submissions and re-submissions. A strong preference by decision-making bodies for local real-world data generation may hinder opportunities for data sharing and outputs from international federated data networks. Closer collaboration between decision-making agencies towards a harmonized RWE roadmap, which can be centrally preserved in a living mode, will provide manufacturers and researchers clarity on minimum acceptance requirements and expectations, especially as novel methodologies for RWE generation are rapidly emerging.

Lessons on the use of real-world data in medical device research: findings from the National Evaluation System for Health Technology Test-Cases.

Aim: Although the US FDA encourages manufacturers of medical devices to submit real-world evidence (RWE) to support regulatory decisions, the ability of real-world data (RWD) to generate evidence suitable for decision making remains unclear. The 2017 Medical Device User Fee Amendments (MDUFA IV), authorized the National Evaluation System for health Technology Coordinating Center (NESTcc) to conduct pilot projects, or 'Test-Cases', to assess whether current RWD captures the information needed to answer research questions proposed by industry stakeholders. We synthesized key lessons about the challenges conducting research with RWD and the strategies used by research teams to enhance their ability to generate evidence from RWD based on 18 Test-Cases conducted between 2020 and 2022. Materials & methods: We reviewed study protocols and reports from each Test-Case team and conducted 49 semi-structured interviews with representatives of participating organizations. Interview transcripts were coded and thematically analyzed. Results: Challenges that stakeholders encountered in working with RWD included the lack of unique device identifiers, capturing key data elements and their appropriate meaning in structured data, limited reliability of diagnosis and procedure codes in structured data, extracting information from unstructured electronic health record (EHR) data, limited capture of long-term study end points, missing data and data sharing. Successful strategies included using manufacturer and supply chain data, leveraging clinical registries and registry reporting processes to collect and aggregate data, querying standardized EHR data, implementing natural language processing algorithms and using multidisciplinary research teams. Conclusion: The Test-Cases identified numerous challenges working with RWD but also opportunities to address these challenges and improve researchers' ability to use RWD to generate evidence on medical devices.