Protocol for the "magnitude of cigarette substitution after initiation of e-cigarettes and its impact on biomarkers of exposure and potential harm in dual users" (MAGNIFICAT) study.

Introduction: Many smokers who use e-cigarettes (ECs) to quit continue smoking alongside vaping. The impact on health among individuals who simultaneously smoke conventional cigarettes (CCs) and use ECs remains unclear. The varying patterns of dual use present differing levels of overall toxin exposure and relative risks concerning smoking-related diseases. Understanding these complexities is vital to assessing the implications for human health. Objective: Herein we describe a protocol designed to analyze the impact of different level of substituting CCs with ECs on exposure to toxicants. We'll use biomarkers to measure this exposure and assess harm reduction in dual users through clinical endpoints, harm-related biomarkers, and behavioral correlations. We expect to observe progressive changes with varying patterns of dual use. Methods and analyses: For this purpose, we planned to recruit a group of 250 smokers who will be asked to reduce their CC consumption by adopting ECs (intervention group). A separate group of 50 smokers will continue to smoke CC (reference group). Study groups will be followed up for 6 months during which biospecimens will be collected for biomarker analyses, and clinical endpoints will be assessed. The trial is structured to characterize subjects' usage patterns over time using robust biomarkers of exposure and a standardized mobile phone application to facilitate the precise categorization of dual users along the risk continuum based on their usage behaviors. Subject recruitment will start in February 2024 and enrolment is expected to be completed by August 2024. Results will be reported early in 2025. Study findings may provide valuable insights into health benefits or risks associated with varying patterns of dual use. Ethics and dissemination: The study protocol and informed consent forms will be approved by the local Ethical Review Boards. Study results will be disseminated through articles published in reputable, peer-reviewed, open access, scientific journals, presentations at conferences, and the University website.

Prevalence of comorbidities with the potential to increase the risk of nonadherence to topical ocular hypotensive medication in patients with open-angle glaucoma.

OBJECTIVE: To evaluate the prevalence of comorbidities that may limit or prevent adherence to topical ocular hypotensive therapy in patients with open-angle glaucoma (OAG). METHODS: The UK Clinical Practice Research Datalink (CPRD) database of primary and secondary care and prescription records was analyzed to identify patients with a first (index) diagnosis of OAG during 2016-2020. The primary care records of these patients were screened for diagnostic terms linked to prespecified (qualifying) comorbidities considered to have the potential to impact patients' ability to instill eye drops. The prevalence of each of 10 categories of qualifying comorbidity recorded within the period from 5 years before to 2 years after the index OAG diagnosis was analyzed. RESULTS: A total of 100,968 patients with OAG were included in the analysis. Among the patients in the OAG cohort, 13,962 (13.8%) were aged 40-54 years, 32,145 (31.8%) were aged 55-69 years, 42,042 (41.6%) were aged 70-84 years, and 12,819 (12.7%) were aged 85+ years. Within the OAG population, 82.7%, 14.6%, and 2.7% of patients had no category, one category, and two or more categories of qualifying comorbidity, respectively. Qualifying comorbidities were most common in older patients. The most prevalent qualifying comorbidities were categorized as degenerative, traumatic, or pathological central nervous system disorder disrupting cognitive function (5.2%), movement disorder (4.4%), and low vision (4.1%). The prevalence of arthropathies and injuries affecting upper limbs (including arthritis in the hands) was 2.4%. CONCLUSIONS: The presence of comorbidities should be considered when determining whether eye drops are suitable treatment for glaucoma. Neurodegenerative disease affecting cognition and memory, motor disease, and low vision are common comorbidities that may impact adherence to eye drops, and affected patients may benefit from non-drop treatment modalities.

A multicenter prospective randomized controlled trial investigating the effects of combustion-free nicotine alternatives on cardiovascular risk factors and metabolic parameters in individuals with type 2 diabetes who smoke: the DiaSmokeFree study protocol.

Stopping smoking is crucial for public health and especially for individuals with diabetes. Combustion-free nicotine alternatives like e-cigarettes and heated tobacco products are increasingly being used as substitutes for conventional cigarettes, contributing to the decline in smoking prevalence. However, there is limited information about the long-term health impact of those products in patients with diabetes. This randomized controlled trial aims to investigate whether switching from conventional cigarettes to combustion-free nicotine alternatives will lead to a measurable improvement in cardiovascular risk factors and metabolic parameters over a period of 2 years in smokers with type 2 diabetes. The multicenter study will be conducted in seven sites across four countries. A total of 576 smokers with type 2 diabetes will be randomly assigned (1:2 ratio) to either standard of care with brief cessation advice (Control Arm) or combustion-free nicotine alternatives use (Intervention Arm). The primary end point is the change in the proportion of patients with metabolic syndrome between baseline and the 2-year follow-up. Additionally, the study will analyze the absolute change in the sum of the individual factors of metabolic syndrome at each study time point. Patient recruitment has started in September 2021 and enrollment is expected to be completed by December 2023. Results will be reported in 2026. This study may provide valuable insights into cardiovascular and metabolic health benefits or risks associated with using combustion-free nicotine alternatives for individuals with type 2 diabetes who are seeking alternatives to tobacco cigarette smoking. The study protocol, informed consent forms, and relevant documents were approved by seven ethical review boards. Study results will be disseminated through articles published in high-quality, peer-reviewed journals and presentations at conferences.

A cost-consequences and budget impact analysis of blue light-guided cystoscopy with Hexvix in patients diagnosed with non-muscle-invasive bladder cancer in France.

AIMS: French guidelines for the management of non-muscle-invasive bladder cancer recommend that blue-light cystoscopy should be used in patients where the risk of missing residual tumor is highest. Despite evidence for its cost-effectiveness, budgetary concerns have limited uptake in France. The aim of this analysis was to model the cost-consequences of adopting the recommendations in a French urology unit. MATERIALS AND METHODS: A budget impact model was developed in Excel, using a decision tree approach derived from guidelines issued by L'Academie franÒ«aise d'urologie. Risk profiles were derived from an analysis of studies using white-light cystoscopy; estimates for the impact of blue-light cystoscopy were derived from a published Cochrane Review. Costs were based on published tariff prices from L'Agence Technique de L'Information sur L'Hospitalisation. The model allowed results to be tailored to activity levels and projected blue-light usage in the chosen urology unit. RESULTS: Two scenarios were evaluated, based on a 3-year time horizon. Full implementation of all recommendations within a large public hospital was estimated to yield incremental costs of €269 per procedure (∼10% increase overall); a more targeted approach within a smaller private hospital yielded incremental costs of €133 per procedure (5% increase overall). LIMITATIONS: The basis of the model is a change in the time to first recurrence. There are no data available for subsequent recurrences or progression, both of which could have an influence on expenditure. Secondly, recurrence rates for blue-light cystoscopy were not specifically available for each patient group identified in the guidelines: extrapolation of data may have resulted in bias. Finally, the data were derived from clinical trials, which may not be generalisable to real-world clinical practice. CONCLUSIONS: The model has shown that the additional expenditure required to implement blue-light cystoscopy is modest and not disproportionate to the overall cost of care.

Focal therapy versus radical prostatectomy and external beam radiotherapy as primary treatment options for non-metastatic prostate cancer: results of a cost-effectiveness analysis.

AIMS: Focal therapy treats individual areas of tumour in non-metastatic prostate cancer in patients unsuitable for active surveillance. The aim of this work was to evaluate the cost-effectiveness of focal therapy versus prostatectomy and external beam radiotherapy (EBRT). MATERIALS AND METHODS: A Markov cohort health state transition model with four health states (stable disease, local recurrence, metastatic disease and death) was created, evaluating costs and utilities over a 10-year time horizon for patients diagnosed with non-metastatic prostate cancer. National Health Service (NHS) for England perspective was used, based on direct healthcare costs. Clinical transition probabilities were derived from prostate cancer registries in patients undergoing radical prostatectomy, EBRT and focal therapy using cryotherapy (Boston Scientific) or high-intensity focused ultrasound (HIFU) (Sonablate). Propensity score matching was used to ensure that at-risk populations were comparable. Variables included age, prostate-specific antigen (PSA), International Society of Urological Pathology (ISUP) grade group, maximum cancer core length (mm), T-stage and year of treatment. RESULTS: Focal therapy was associated with a lower overall cost and higher quality-adjusted life year (QALY) gains than either prostatectomy or EBRT, dominating both treatment strategies. Positive incremental net monetary benefit (NMB) values confirm focal therapy as cost-effective versus the alternatives at a willingness to pay (WTP) threshold of £30,000/QALY. One-way deterministic sensitivity analyses revealed consistent results. LIMITATIONS: Data used to calculate the transition probabilities were derived from a limited number of hospitals meaning that other potential treatment options were excluded. Limited data were available on later outcomes and none on quality of life data, therefore, literature-based estimates were used. CONCLUSIONS: Cost-effectiveness modelling demonstrates use of focal therapy (cryotherapy or HIFU) is associated with greater QALY gains at a lower overall cost than either radical prostatectomy or EBRT, representing good value for money in the NHS.

Focal therapy can be used for the primary treatment of individual areas of cancer in those patients with prostate cancer whose disease has not spread (localized or non-metastatic prostate cancer) and whose disease is unsuitable for active monitoring. Focal therapy in these patients results in similar control of the cancer to more invasive therapies, such as surgical removal of the prostate and radiotherapy, with the benefit of fewer sexual, urinary and rectal side effects. This work considered whether using focal therapy (either freezing the cancer cells using cryotherapy or using high-intensity focused ultrasound [HIFU] to destroy cancer cells) was good value for money in the National Health Service (NHS) compared with surgery or radiotherapy. An economic model was developed which considered the relative impact of treatment with focal therapies, surgery or radiotherapy within the NHS in England. Previously collected information from people undergoing treatment for their prostate cancer, together with published literature and clinical opinion, was used within the model to predict the treatment pathway, costs incurred and the results of treatment in terms of patient benefits (effectiveness and quality of life). The model showed that focal therapy using either cryotherapy or HIFU was associated with a lower overall cost and higher patient benefit than either surgery or radiotherapy, indicating that focal therapy represents good value for money in the NHS.

Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of leflunomide (L) added to the standard-of-care (SOC) treatment in COVID-19 patients hospitalised with moderate/critical clinical symptoms. DESIGN: Prospective, open-label, multicentre, stratified, randomised clinical trial. SETTING: Five hospitals in UK and India, from September 2020 to May 2021. PARTICIPANTS: Adults with PCR confirmed COVID-19 infection with moderate/critical symptoms within 15 days of onset. INTERVENTION: Leflunomide 100 mg/day (3 days) followed by 10-20 mg/day (7 days) added to standard care. PRIMARY OUTCOMES: The time to clinical improvement (TTCI) defined as two-point reduction on a clinical status scale or live discharge prior to 28 days; safety profile measured by the incidence of adverse events (AEs) within 28 days. RESULTS: Eligible patients (n=214; age 56.3±14.9 years; 33% female) were randomised to SOC+L (n=104) and SOC group (n=110), stratified according to their clinical risk profile. TTCI was 7 vs 8 days in SOC+L vs SOC group (HR 1.317; 95% CI 0.980 to 1.768; p=0.070). Incidence of serious AEs was similar between the groups and none was attributed to leflunomide. In sensitivity analyses, excluding 10 patients not fulfilling the inclusion criteria and 3 who withdrew consent before leflunomide treatment, TTCI was 7 vs 8 days (HR 1.416, 95% CI 1.041 to 1.935; p=0.028), indicating a trend in favour of the intervention group. All-cause mortality rate was similar between groups, 9/104 vs 10/110. Duration of oxygen dependence was shorter in the SOC+L group being a median 6 days (IQR 4-8) compared with 7 days (IQR 5-10) in SOC group (p=0.047). CONCLUSION: Leflunomide, added to the SOC treatment for COVID-19, was safe and well tolerated but had no major impact on clinical outcomes. It may shorten the time of oxygen dependence by 1 day and thereby improve TTCI/hospital discharge in moderately affected COVID-19 patients. TRIAL REGISTRATION NUMBERS: EudraCT Number: 2020-002952-18, NCT05007678.

Cost-effectiveness analysis of the Parkinson's KinetiGraph and clinical assessment in the management of Parkinson's disease.

AIMS: The Parkinson's KinetiGraph (PKG) is a wrist-worn movement recording system that collates continuous, objective, data during daily activities in people with Parkinson's disease (PD) providing a report for clinicians. This study explores the cost-effectiveness of adding the PKG to routine PD assessments. METHODS: A de novo Markov model of three health states: uncontrolled, controlled and death compared PKG plus routine assessment by a Movement Disease Specialist (MDS) versus routine assessment. Uncontrolled and controlled states were based on the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II and III scores. The transition between health states was dependent on improvement in MDS-UPDRS II and III, and transition to death state on all cause-mortality and PD-specific relative mortality risk. Markov cycle length was yearly beyond year 1 and lifetime horizon 22 years. LIMITATIONS: PKG evidence incorporated in this analysis is based on findings from one clinical trial. Health state utilities were mapped and the probability of patients progressing from uncontrolled to controlled health state at the second visit and beyond was derived from a bootstrap method which assumed a normal distribution for MDS-UPDRS. RESULTS: The addition of the PKG to usual PD assessments is a cost-effective intervention. PKG plus routine assessment is associated with lower total costs compared to routine assessment (£141,950 versus £159,312) and improved quality-adjusted life years (7.88 versus 7.61), resulting in an incremental cost-effectiveness ratio of -£64,978.99 and a net monetary benefit of £22,706.37 using a £20,000 threshold. Results were robust across sensitivity and scenario analyses. CONCLUSIONS: Management of PD involves monitoring and evaluation of symptoms to assess disease progression and ensure appropriate treatment choices. Adding the PKG to clinical assessment in routine care allows for improved and objective identification of PD motor symptoms which can be used in clinical decision making to improve patient outcomes.

Hospital doctors caring for people with Parkinson's disease (PwP) regularly monitor and assess their patients' symptoms, relying on patient recall and patient-completed diaries to find out about current symptoms, which can be unreliable. The Parkinson's KinetiGraph (PKG) is a wrist-worn device that collects continuous information on movement in PwP. A report is then provided to the patient's Consultant helping them to understand the PwP's symptoms and make decisions about changing medication to improve symptom control.An economic model compared asking patients to wear a PKG device for 6 days before their check-up appointment with their Consultant with usual check-up without the PKG. Information from a clinical trial exploring the use of PKG provided data on Movement Disorder Society ­ Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II and III scores, which were used in the model to predict improvements in quality of life and whether PwP had controlled or uncontrolled disease.The model showed that addition of PKG to usual check-ups is a cost-effective approach. Use of the PKG reduced costs (£141,950 versus £159,312 for usual check-ups) and had a positive impact on quality and quantity of life as measured by quality adjusted life years (7.88 versus 7.61).This study shows that adding the PKG to routine check-ups allows Consultants to accurately assess movement (or motor) symptoms in PwP, which can then be used to ensure optimal mediation choice and improve patient outcomes.

The effect of laboratory-verified smoking on SARS-CoV-2 infection: results from the Troina sero-epidemiological survey.

Previous research yielded conflicting results on the association between cigarette smoking and risk of SARS-CoV-2 infection. Since the prevalence of smoking is high globally, the study of its impact on COVID-19 pandemic may have considerable implications for public health. This study is the first to investigate the association between the SARS-CoV-2 antibody sero-positivity and biochemically verified smoking status, to refine current estimates on this association. SARS-CoV-2-specific IgG and serum cotinine levels (a well-known marker of tobacco exposure) were assessed in a large sero-epidemiological survey conducted in the town of Troina (Sicily, Italy). A propensity score matching was carried out to reduce the effect of possible factors on SARS-CoV-2 infection risk among study participants. Of the 1785 subjects included in our study, one-third was classified as current smokers, based on serum cotinine levels. The overall proportion of subjects with positive serology for SARS-CoV-2 IgG was 5.4%. The prevalence of SARS-CoV-2 antibody positivity and previous COVID-19 diagnosis were reduced in smokers. This reduced prevalence persisted after adjusting for possible confounders (such as sex, age, previous infection, chronic conditions, and risk group) at regression analyses, and the point estimates based on the PS-matched models resulted consistent with those for the unmatched population. This study found a lower proportion of positive SARS-CoV-2 serology among current smokers, using direct laboratory measures of tobacco exposure and thus avoiding possible bias associated with self-reported smoking status. Results may also serve as a reference for future clinical research on potential pharmaceutical role of nicotine or nicotinic-cholinergic agonists against COVID-19.

Disproportionate Mitral Regurgitation Determines Survival in Acute Heart Failure.

Objectives: To assess the prevalence and impact of mitral regurgitation (MR) on survival in patients presenting to hospital in acute heart failure (AHF) using traditional echocardiographic assessment alongside more novel indices of proportionality. Background: It remains unclear if the severity of MR plays a significant role in determining outcomes in AHF. There is also uncertainty as to the clinical relevance of indexing MR to left ventricular volumes. This concept of disproportionality has not been assessed in AHF. Methods: A total of 418 consecutive patients presenting in AHF over 12 months were recruited and followed up for 2 years. MR was quantitatively assessed within 24 h of recruitment. Standard proximal isovelocity surface area (PISA) and a novel proportionality index of effective regurgitant orifice/left ventricular end-diastolic volume (ERO/LVEDV) >0.14 mm2/ml were used to identify severe and disproportionate MR. Results: Every patient had MR. About 331/418 (78.9%) patients were quantifiable by PISA. About 165/418 (39.5%) patients displayed significant MR. A larger cohort displayed disproportionate MR defined by either a proportionality index using ERO/LVEDV > 0.14 mm2/ml or regurgitant volumes/LVEDV > 0.2 [217/331 (65.6%) and 222/345 (64.3%), respectively]. The LVEDV was enlarged in significant MR-129.5 ± 58.95 vs. 100.0 ± 49.91 ml in mild, [p < 0.0001], but remained within the normal range. Significant MR was associated with a greater mortality at 2 years {44.2 vs. 34.8% in mild MR [hazard ratio (HR) 1.39; 95% CI: 1.01-1.92, p = 0.04]}, which persisted with adjustment for comorbid conditions (HR; 1.43; 95% CI: 1.04-1.97, p = 0.03). Disproportionate MR defined by ERO/LVEDV >0.14 mm2/ml was also associated with worse outcome [42.4 vs. 28.3% (HR 1.62; 95% CI 1.12-2.34, p = 0.01)]. Conclusions: MR was a universal feature in AHF and determines outcome in significant cases. Furthermore, disproportionate MR, defined either by effective regurgitant orifice (ERO) or volumetrically, is associated with a worse prognosis despite the absence of adverse left ventricular (LV) remodeling. These findings outline the importance of adjusting acute volume overload to LV volumes and call for a review of the current standards of MR assessment. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02728739, identifier NCT02728739.

Seroepidemiological Survey on the Impact of Smoking on SARS-CoV-2 Infection and COVID-19 Outcomes: Protocol for the Troina Study.

BACKGROUND: After the global spread of SARS-CoV-2, research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain. OBJECTIVE: In this context, this study aims at quantifying the proportion of SARS-CoV-2 antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between the biochemically verified smoking status and SARS-CoV-2 infection. METHODS: The research design involves a 6-month prospective cohort study with a serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19-related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (ie, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2-specific antibodies and serum cotinine, being the latter of the principal metabolite of nicotine, which will be used to assess participants' smoking status. RESULTS: The study is ongoing. It aims to find a higher antibody prevalence in individuals at high risk for viral exposure (ie, health care personnel) and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19. CONCLUSIONS: The added value of this research is that the current smoking status of the population to be studied will be biochemically verified to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide an actionable metric to study the role of smoking in SARS-CoV-2 infection and COVID-19 outcomes, and therefore to implement the most appropriate public health measures to control the pandemic. Results may also serve as a reference for future clinical research, and the methodology could be exploited in public health sectors and policies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32285.

Right ventricular ejection fraction as predictor of outcome in acute heart failure using RV ellipsoid model: A retrospective analysis of a prospective cross-sectional study.

OBJECTIVES: The right ventricular (RV) function is an important prognostic factor in acute and chronic heart failure (HF). Echocardiography is an essential imaging modality with established parameters for RV function which are useful and easy to perform. However, these fail to reflect global RV volumes due to reliability on one acoustic window. It is therefore attractive to calculate RV volumes and ejection fraction (RVEF/E) using an ellipsoid geometric model which has been validated against MRI in healthy adults but not in the HF patients. DESIGN: This is a retrospective analysis of a prospective cross-sectional study enrolling 418 consecutive patients with symptoms of HF according to a predefined study protocol. All patients underwent echocardiographic assessment of RV function using Tricuspid Annular Plane Systolic Excursion (TAPSE) and RV fractional area change (RVFAC) and RVEF/E. SETTING: Single centre study with multiple locations for acute in-patients including high dependency units. PARTICIPANTS: Patients with acute or exacerbation of chronic HF older than 18 y.o. MAIN OUTCOME MEASURES: Ability of RVEF/E to predict patient outcomes compared with two established parameters of RV function over two-year follow-up period. Primary outcome measure was all-cause mortality. RESULTS: RVEF/E is equal to TAPSE & RVFAC in predicting outcome (p ≤ 0.01 vs p ≤ 0.01) and provides additional benefit of RV volume estimation based on standard 2D echo measurements. CONCLUSIONS: In this study we have shown that RVEF/E derived from ellipsoid model is not inferior to well established measures of RV function as a prognostic indicator of outcome in the acute HF.

Implications of incidental findings from lung screening for primary care: data from a UK pilot.

Regional lung cancer screening (LCS) is underway in England, involving a "lung health check" (LHC) and low-dose CT scan for those at high risk of cancer. Incidental findings from LHCs or CTs are usually referred to primary care. We describe the proportion of participants referred from the West London LCS pilot to primary care, the indications for referral, the number of general practitioner (GP) attendances and consequent changes to patient management, and provide an estimated cost-burden analysis for primary care. A small proportion (163/1542, 10.6%) of LHC attendees were referred to primary care, primarily for suspected undiagnosed chronic obstructive pulmonary disease (55/163, 33.7%) or for QRISK® (63/163, 38.7%) assessment. Ninety one of 159 (57.2%) participants consenting to follow-up attended GP appointments; costs incurred by primary care were estimated at £5.69/LHC participant. Patient management changes occurred in only 36/159 (22.6%) referred participants. LHCs result in a small increase to primary care workload provided a strict referral protocol is adhered to. Changes to patient management arising from incidental findings referrals are infrequent.

International randomised controlled trial evaluating metabolic syndrome in type 2 diabetic cigarette smokers following switching to combustion-free nicotine delivery systems: the DIASMOKE protocol.

INTRODUCTION: Reducing exposure to cigarette smoke is an imperative for public health and for patients with diabetes. Increasingly, combustion-free nicotine delivery systems (C-F NDS) such as e-cigarettes and heated tobacco products are substituting conventional cigarettes and accelerating the downward trends in smoking prevalence. However, there is limited information about the long-term health impact in patients with diabetes who use C-F NDS. This randomised trial of type 2 diabetic cigarette smokers will test the hypothesis that following a switch from conventional cigarettes to C-F NDS a measurable improvement in metabolic syndrome (MetS) factors will be shown over the course of 2 years. METHODS AND ANALYSIS: The study is multicentre and thus will take place in five locations in four countries in an ambulatory setting. A total of 576 patients with diabetes will be randomised (1:2 ratio) to either a control arm (Study Arm A), in which they will be offered referral to smoking cessation programmes or to an intervention arm (Study Arm B) assigned to C-F NDS use. Participants will be at least 23 years old and of any gender. Patient recruitment will start in February 2021 and is expected to be completed by December 2021. Primary outcome measures include fasting plasma glucose, blood pressure, triglycerides, high-density lipoprotein and waist circumference, while secondary feature absolute change in the sum of the individual factors of MetS and change in each individual factor of MetS measured at each study time point. ETHICS AND DISSEMINATION: The approval of research ethics committee (REC) regarding the trial protocol, informed consent forms and other relevant documents is required to commence the study. Substantial amendments to the study protocol cannot be implemented until the REC grants a favourable opinion. The results of the study are intended to be published as articles in high quality peer-reviewed journals and disseminated through conference papers. TRIAL REGISTRATION NUMBER: NCT04231838. Pre-results stage.

Updated cost-effectiveness analysis of palivizumab (Synagis) for the prophylaxis of respiratory syncytial virus in infant populations in the UK.

AIMS: Respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and severe infection can result in hospitalization. The passive immunization, palivizumab, is used as prophylaxis against RSV, however, use in the UK is restricted to populations at high risk of hospitalization. This study assesses the cost-effectiveness (CE) of palivizumab in premature infants with and without risk factors for hospitalization (congenital heart disease [CHD], bronchopulmonary dysplasia [BPD]). METHODS: A decision tree model, based on earlier CE analyses, was updated using data derived from targeted literature reviews and advice gained from a Round Table meeting. All costs were updated to 2019 prices. One-way and probabilistic sensitivity analyses were performed to assess the degree of uncertainty surrounding the results. RESULTS: Palivizumab is dominant (i.e. clinically superior and cost saving) when used in premature infants born ≤35 weeks gestational age (wGA) without CHD or BPD and aged <6 months at the start of the RSV season, infants aged <24 months with CHD and infants aged <24 months requiring treatment for BPD within the last 6 months. LIMITATIONS: One-way sensitivity analysis suggests that these results are highly sensitive to the efficacy of prophylaxis, number of doses, impact of long-term respiratory sequalae, rate of hospitalization and mortality due to RSV. A conservative approach has been taken toward long-term respiratory sequalae due to uncertainty around epidemiology and etiology and a lack of recent cost and utility data. CONCLUSIONS: Palivizumab prophylaxis is cost-effective in preventing severe RSV infection requiring hospital admission in a wider population than currently recommended in UK guidelines. Prophylaxis in premature infants born <29 wGA, 29-32 wGA and 33-35 wGA without CHD or BPD aged <6 months at the start of the RSV season is not funded under current guidance, however, prophylaxis has been demonstrated to be cost-effective in this analysis.

Budget impacts associated with improving diagnosis and treatment of atrial fibrillation in high-risk stroke patients.

Aim: Estimate the 3-year budget impact in England from 2016/17 of improving nonvalvular atrial fibrillation management in high-risk stroke patients. Materials & methods: The Academic Health Science Network's AF Business Case Model was used to identify detection, protection (risk assessment and treatment initiation) and perfection (optimized treatment) gaps and to project the budget impact of closing these. Results: Closing all gaps over 3 years could prevent 27,550 strokes. Overall, perfection gap savings were £136,650,962 and protection gap savings were £58,146,171. Detection by screening in year one could cost £149,048,676, but with stroke-prevention savings would be £47,081,047 at 3 years. Thus, total potential savings were £194,797,133 and the cost-adjusted budget impact was £147,716,086. Conclusion: The detection and perfection gaps are key areas for investment.

Cost-utility analysis of levodopa carbidopa intestinal gel (Duodopa) in the treatment of advanced Parkinson's disease in patients in Scotland and Wales.

AIMS: To carry out a cost-utility analysis comparing the cost-effectiveness of levodopa carbidopa intestinal gel (LCIG) with standard of care (SOC) in patients with advanced Parkinson's Disease (aPD) unsuitable for apomorphine or deep brain stimulation (DBS). LCIG is the only treatment option in this small, but clinically important, population. METHODS: A Markov model with 25 disease states based on disease stage and off-time status plus death. Patients enter the model with aPD spending >50% of their waking day in the off-state. Patients progress through the model in 6-monthly cycles for 20 years to approximate lifetime treatment and capture long-term costs and effects of therapy. Inputs are based on LCIG clinical trials for clinical outcomes and health state utilities, the literature for health state transitions and use UK-based input data wherever possible (drug costs, disease/adverse event management costs, discontinuation rates, mortality rates). LIMITATIONS: Data collection can be challenging in this small, elderly population with advanced disease, therefore some model inputs were estimated, rather than collected directly. It was assumed that a reduction in off-time was the only benefit after the first year of treatment with LCIG; this is a conservative approach, since there may be additional clinical benefits. RESULTS: There is a considerable incremental gain in quality adjusted life years (QALYs) for patients treated with LCIG of 1.26 QALY with an associated incremental cost-effectiveness ratio (ICER) of £52,110. If the impact on caregivers is included, the ICER reduces to £47,266. CONCLUSIONS: In cases where there is an orphan population, with no alternative treatment options, HTA assessments have a broader decision-making framework and the ICER is interpreted in this context. In the setting of a very small population, with considerable unmet need, LCIG represents value for money, as reflected by funding approval across the UK.

The role of tivozanib in advanced renal cell carcinoma therapy.

INTRODUCTION: The efficacy of VEGF-targeting therapies in clinical trials led to their recommendation in clinical guidelines for use across the advanced or metastatic renal cell carcinoma (RCC) treatment landscape, however, tolerability (including off-target effects) has remained a challenge. Tivozanib is a selective inhibitor of all three VEGFRs, with limited off-target interaction, which demonstrates efficacy with improved tolerability relative to multikinase VEGFR-TKIs. Areas covered: Covered here is the clinical development of tivozanib in advanced RCC, including the pivotal Phase III, multicenter, open-label, randomized clinical study comparing tivozanib with sorafenib for the treatment of VEGF- and mTOR therapy-naïve advanced RCC patients. Also covered are ongoing trials, exploring the efficacy and safety of tivozanib in the setting of refractory disease and the utility of tivozanib in combination with checkpoint inhibitors for advanced RCC. Combination of a VEGFR-TKI and immunotherapy is promising in advanced RCC, if the treatment regimens have acceptable tolerability. Here the selectivity of tivozanib may contribute to an acceptable tolerability profile when used in combination therapy. Expert commentary: The approval of tivozanib provides an additional option for the first-line treatment of advanced or metastatic RCC patients in Europe and allows use of a VEGFR-TKI with selectivity for VEGFRs in this setting.

Optimizing choice of oral interferon-free treatment for genotype 1 hepatitis C virus using testing for NS5A resistance: a cost-utility analysis from the perspective of the Italian National Health Service.

BACKGROUND: Patients with genotype-1 hepatitis C virus infection who have failed to respond to standard therapy or who relapse following treatment may be considered for an interferon-free regimen incorporating a nonstructural protein 5A (NS5A) inhibitor. Sustained virologic response (SVR) with these regimens is typically >90%, but this is reduced in patients with NS5A resistance. European Association for Study of the Liver guidelines recommend simeprevir + sofosbuvir ± ribavirin (SMV+SOF±R) for re-treating patients failing an NS5A inhibitor-containing regimen. An alternative strategy would be to test for NS5A resistance prior to treatment, with therapy optimized based on the results. This study investigates the cost-effectiveness of this strategy. MATERIALS AND METHODS: A Markov model was used to estimate disease progression for treatment-experienced genotype 1 patients with severe fibrosis or compensated cirrhosis. Targeted treatment with either SMV+SOF±R or sofosbuvir + ledipasvir ± ribavirin (SOF+LDV±R) based on pretreatment NS5A resistance testing was compared to routine SOF+LDV±R without testing. Treatment duration was 12 or 24 weeks for patients with severe fibrosis or compensated cirrhosis (Metavir F3/F4). SVR data for the treatment options were based on the results of published clinical trials. The analysis was carried out from the perspective of the Italian National Health Service. RESULTS: Optimized treatment using NS5A resistance testing yielded 0.163 additional QALYs and increased costs of €2,789 per patient versus no testing. The incremental cost-effectiveness ratio (ICER) was €17,078/QALY. Sensitivity analysis identified the SVR attributable to each of the treatment regimens as the most sensitive determinant of ICER (range: €10,055/QALY-€43,501/QALY across plausible range). Probabilistic sensitivity analysis demonstrated that, at a willingness-to-pay threshold of €30,000/QALY, the probability that NS5A-directed treatment will be cost-effective is 81.4%. CONCLUSION: Optimizing therapy with either SMV+SOF±R or SOF+LDV±R based on pretreatment NS5A resistance testing was cost-effective from the perspective of the Italian National Health Service, in treatment-experienced patients with severe fibrosis or compensated cirrhosis.

Evidence-based recommendations on androgen deprivation therapy for localized and advanced prostate cancer.

INTRODUCTION: The management of prostate cancer (PC) is still evolving. Although, androgen deprivation therapy (ADT) is an established treatment option, particularly in patients with disseminated disease, important data regarding hormonal manipulation have recently emerged. The aim of this paper is to review the evidence on ADT, make recommendations and address areas of controversy associated with its use in men with PC. MATERIAL AND METHODS: An expert panel was convened. Areas related to the hormonal management of patients with PC requiring evidence review were identified and questions to be addressed by the panel were determined. Appropriate literature review was performed and included a search of online databases, bibliographic reviews and consultation with experts. RESULTS: The panel was able to provide recommendations on: 1) which patients with localised PC should receive androgen deprivation in conjunction with radiotherapy (RT); 2) what standard initial treatment should be used in metastatic hormone-naïve PC (MHNPC); 3) efficacy of androgen deprivation agents; 4) whether ADT should be continued in patients with castration resistant PC (CRPC). However, no recommendations could be made for combined ADT and very high-dose RT in patients with an intermediate-risk disease. CONCLUSIONS: ADT remains the cornerstone of treatment for both metastatic hormone-naïve and castration-resistant PC. According to the expert panel's opinion, based on the ERG report, luteinizing hormone-releasing hormone agonists might not be equivalent but this needs to be confirmed in long-term data. The combined use of ADT and RT improves outcome and survival in men with high-risk localised disease. The benefits in patients with intermediate-risk disease, particularly those subject to escalated dose RT are controversial.