Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

A multicomponent intervention to reduce daily sitting time in office workers: the SMART Work & Life three-arm cluster RCT.

Background: Office workers spend 70-85% of their time at work sitting. High levels of sitting have been linked to poor physiological and psychological health. Evidence shows the need for fully powered randomised controlled trials, with long-term follow-up, to test the effectiveness of interventions to reduce sitting time. Objective: Our objective was to test the clinical effectiveness and cost-effectiveness of the SMART Work & Life intervention, delivered with and without a height-adjustable workstation, compared with usual practice at 12-month follow-up. Design: A three-arm cluster randomised controlled trial. Setting: Councils in England. Participants: Office workers. Intervention: SMART Work & Life is a multicomponent intervention that includes behaviour change strategies, delivered by workplace champions. Clusters were randomised to (1) the SMART Work & Life intervention, (2) the SMART Work & Life intervention with a height-adjustable workstation (i.e. SMART Work & Life plus desk) or (3) a control group (i.e. usual practice). Outcome measures were assessed at baseline and at 3 and 12 months. Main outcome measures: The primary outcome was device-assessed daily sitting time compared with usual practice at 12 months. Secondary outcomes included sitting, standing, stepping time, physical activity, adiposity, blood pressure, biochemical measures, musculoskeletal issues, psychosocial variables, work-related health, diet and sleep. Cost-effectiveness and process evaluation data were collected. Results: A total of 78 clusters (756 participants) were randomised [control, 26 clusters (n = 267); SMART Work & Life only, 27 clusters (n = 249); SMART Work & Life plus desk, 25 clusters (n = 240)]. At 12 months, significant differences between groups were found in daily sitting time, with participants in the SMART Work & Life-only and SMART Work & Life plus desk arms sitting 22.2 minutes per day (97.5% confidence interval -38.8 to -5.7 minutes/day; p = 0.003) and 63.7 minutes per day (97.5% confidence interval -80.0 to -47.4 minutes/day; p < 0.001), respectively, less than the control group. Participants in the SMART Work & Life plus desk arm sat 41.7 minutes per day (95% confidence interval -56.3 to -27.0 minutes/day; p < 0.001) less than participants in the SMART Work & Life-only arm. Sitting time was largely replaced by standing time, and changes in daily behaviour were driven by changes during work hours on workdays. Behaviour changes observed at 12 months were similar to 3 months. At 12 months, small improvements were seen for stress, well-being and vigour in both intervention groups, and for pain in the lower extremity and social norms in the SMART Work & Life plus desk group. Results from the process evaluation supported these findings, with participants reporting feeling more energised, alert, focused and productive. The process evaluation also showed that participants viewed the intervention positively; however, the extent of engagement varied across clusters. The average cost of SMART Work & Life only and SMART Work & Life plus desk was £80.59 and £228.31 per participant, respectively. Within trial, SMART Work & Life only had an incremental cost-effectiveness ratio of £12,091 per quality-adjusted life-year, with SMART Work & Life plus desk being dominated. Over a lifetime, SMART Work & Life only and SMART Work & Life plus desk had incremental cost-effectiveness ratios of £4985 and £13,378 per quality-adjusted life-year, respectively. Limitations: The study was carried out in one sector, limiting generalisability. Conclusions: The SMART Work & Life intervention, provided with and without a height-adjustable workstation, was successful in changing sitting time. Future work: There is a need for longer-term follow-up, as well as follow-up within different organisations. Trial registration: Current Controlled Trials ISRCTN11618007.

Office workers spend a large proportion of their day sitting. High levels of sitting have been linked to diseases, such as type 2 diabetes, heart disease and some cancers. The SMART Work & Life intervention is designed to reduce office workers' sitting time inside and outside work. The SMART Work & Life intervention involves organisational, environmental, group and individual strategies to encourage a reduction in sitting time and was designed to be delivered with and without a height-adjustable workstation (which allows the user to switch between sitting and standing while working). To test whether or not the SMART Work & Life intervention worked, we recruited 756 office workers from councils in Leicester/Leicestershire, Greater Manchester and Liverpool, UK. Participants were from 78 office groups. One-third of the participants received the intervention, one-third received the intervention with a height-adjustable workstation and one-third were a control group (and carried on as usual). Workplace champions in each office group were given training and resources to deliver the intervention. Data were collected at the start of the study, with follow-up measurements at 3 and 12 months. We measured sitting time using a small device worn on the thigh and collected data on weight, body fat, blood pressure, blood sugar and cholesterol levels. We asked participants about their health and work and spoke to participants to find out what they thought of the intervention. Our results showed that participants who received the intervention without workstation sat for 22 minutes less per day, and participants who received the intervention with workstation sat for 64 minutes less per day, than participants in the control group. Levels of stress, well-being, vigour (i.e. personal and emotional energy and cognitive liveliness) and pain in the lower extremity appeared to improve in the intervention groups. Participants viewed the intervention positively and reported several benefits, such as feeling more energised, alert, focused and productive; however, the extent to which participants engaged with the intervention varied across groups.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

The Cost-Effectiveness of the SMART Work & Life Intervention for Reducing Sitting Time.

Sedentary behaviours continue to increase and are associated with heightened risks of morbidity and mortality. We assessed the cost-effectiveness of SMART Work & Life (SWAL), an intervention designed to reduce sitting time inside and outside of work, both with (SWAL-desk) and without (SWAL-only) a height-adjustable workstation compared to usual practice (control) for UK office workers. Health outcomes were assessed in quality-adjusted life-years (QALY) and costs in pound sterling (2019-2020). Discounted costs and QALYs were estimated using regression methods with multiply imputed data from the SMART Work & Life trial. Absenteeism, productivity and wellbeing measures were also evaluated. The average cost of SWAL-desk was £228.31 and SWAL-only £80.59 per office worker. Within the trial, SWAL-only was more effective and costly compared to control (incremental cost-effectiveness ratio (ICER): £12,091 per QALY) while SWAL-desk was dominated (least effective and most costly). However, over a lifetime horizon, both SWAL-only and SWAL-desk were more effective and more costly than control. Comparing SWAL-only to control generated an ICER of £4985 per QALY. SWAL-desk was more effective and costly than SWAL-only, generating an ICER of £13,378 per QALY. Findings were sensitive to various worker, intervention, and extrapolation-related factors. Based on a lifetime horizon, SWAL interventions appear cost-effective for office-workers conditional on worker characteristics, intervention cost and longer-term maintenance in sitting time reductions.

The cost-effectiveness of a proportionate parenting programme for primary caregivers and their child: an economic evaluation using evidence from the E-SEE Trial.

BACKGROUND: Behavioural and mental disorders have become a public health crisis; averting mental ill-health in early years can achieve significant longer-term health benefits and cost savings. This study assesses whether the Enhancing Social-Emotional Health and Wellbeing in the Early Years (E-SEE-Steps)-a proportionate universal delivery model comprising the Incredible Babies book (IY-B) and the Incredible Years Infant (IY-I) and Toddler (IY-T) parenting programmes is cost-effective compared to services as usual (SAU) for the primary caregiver, child and dyad. METHODS: Using UK data for 339 primary caregivers from the E-SEE trial, we conducted a within-trial economic evaluation assessing the cost-effectiveness of E-SEE Steps. Health outcomes were expressed in quality-adjusted life-years (QALY) and costs in UK pounds sterling (2018-19). Missing data were populated via multiple imputation and costs and QALYs discounted at 3.5% per annum. Cost-effectiveness results were conducted for primary caregivers, children and dyad using econometric modelling to control for patient co-variables. Uncertainty was explored through scenario and sensitivity analyses. RESULTS: The average cost of E-SEE Steps intervention was £458.50 per dyad. E-SEE Steps was associated with modest gains in primary caregiver HRQoL but minor decrements in child HRQoL compared to SAU. For primary caregivers, E-SEE Steps was more effective (0.034 QALYs) and more costly (£446) compared to SAU, with a corresponding incremental cost-effectiveness ratio (ICER) of £13,011 per QALY. In children, E-SEE Steps was strictly dominated with poorer outcomes (-0.005 QALYs) and greater costs (£178) relative to SAU. QALY gains in primary caregivers exceeded those QALY losses found in children, meaning E-SEE Steps was more effective (0.031 QALYs) and costly (£621) for the dyad (ICER: £20,062 per QALY). All scenario analyses found E-SEE Steps cost-effective for the dyad at a £30,000 per QALY threshold. Sensitivity analyses found significant cost reductions from expansions in programme delivery and attendance. CONCLUSIONS: E-SEE Steps achieved modest health gains in primary caregivers but small negative effects on children and was more costly than SAU. E-SEE Steps appears cost-effective for the dyad, but the results should be interpreted with caution given the potential detrimental impact on children. TRIAL REGISTRATION: ISRCTN11079129 ; Pre participant trial enrolment, 11/05/2015.

A randomized controlled trial of a proportionate universal parenting program delivery model (E-SEE Steps) to enhance child social-emotional wellbeing.

BACKGROUND: Evidence for parenting programs to improve wellbeing in children under three is inconclusive. We investigated the fidelity, impact, and cost-effectiveness of two parenting programs delivered within a longitudinal proportionate delivery model ('E-SEE Steps'). METHODS: Eligible parents with a child ≤ 8 weeks were recruited into a parallel two-arm, assessor blinded, randomized controlled, community-based, trial with embedded economic and process evaluations. Post-baseline randomization applied a 5:1 (intervention-to-control) ratio, stratified by primary (child social-emotional wellbeing (ASQ:SE-2)) and key secondary (maternal depression (PHQ-9)) outcome scores, sex, and site. All intervention parents received the Incredible Years® Baby Book (IY-B), and were offered the targeted Infant (IY-I)/Toddler (IY-T) program if eligible, based on ASQ:SE-2/PHQ-9 scores. Control families received usual services. Fidelity data were analysed descriptively. Primary analysis applied intention to treat. Effectiveness analysis fitted a marginal model to outcome scores. Cost-effectiveness analysis involved Incremental Cost-Effectiveness Ratios (ICERs). RESULTS: The target sample (N = 606) was not achieved; 341 mothers were randomized (285:56), 322 (94%) were retained to study end. Of those eligible for the IY-I (n = 101), and IY-T (n = 101) programs, 51 and 21 respectively, attended. Eight (of 14) groups met the 80% self-reported fidelity criteria. No significant differences between arms were found for adjusted mean difference scores; ASQ:SE-2 (3.02, 95% CI: -0.03, 6.08, p = 0.052), PHQ-9 (-0.61; 95% CI: -1.34, 0.12, p = 0.1). E-SEE Steps had higher costs, but improved mothers' Health-related Quality of Life (0.031 Quality Adjusted Life Year (QALY) gain), ICER of £20,062 per QALY compared to control. Serious adverse events (n = 86) were unrelated to the intervention. CONCLUSIONS: E-SEE Steps was not effective, but was borderline cost-effective. The model was delivered with varying fidelity, with lower-than-expected IY-T uptake. Changes to delivery systems and the individual programs may be needed prior to future evaluation. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number: ISRCTN11079129.

An Analysis of Antibacterial Drug Development Trends in the United States, 1980-2019.

We present a longitudinal analysis of investigational new drug applications (INDs) for new, systemic antibacterial drugs under active development between 1980 and 2019, evaluating the characteristics of these investigational drugs and the outcomes of these drug development programs. The number of INDs in active development declined by two-thirds, from 39 active INDs at its peak in 1987 to a low 13 in 2001, with decreased development of new cephalosporin, quinolone, and macrolide drugs and reduced participation from large pharmaceutical firms. Antibacterial drug development activity rebounded substantially from 2002 to 2009, primarily led by involvement of small pharmaceutical companies. As of 31 December 2019, the number of active INDs has declined to an 11-year low, and the number of antibacterial INDs initiated with the US Food and Drug Administration during 2010-2019 was lower than any of the previous 3 decades. Antibacterial drug development programs initiated in the 1980s and 1990s had high success rates, with >40% of INDs obtaining marketing approval, in a median time of about 6 years from IND receipt to approval. For drug development programs initiated between 2000 and 2009, we found that IND-to-approval rates reduced to 23%, with median development times for approved antibacterial drugs increasing to 8.2 years. The majority of INDs in development as of 31 December 2019 come from already established drug classes, most in early stages of development, and few are sponsored by large pharmaceutical companies.

Geographic Shifts in Antibacterial Drug Clinical Trial Enrollment: Implications for Generalizability.

BACKGROUND: As drug development has globalized, trials have increasingly enrolled participants from all parts of the world rather than just the United States and Western Europe. For antibacterial drug trials, understanding enrollment trends and regional differences is important for generalizability considerations. METHODS: We retrospectively analyzed 42 phase 3 trials submitted to the US Food and Drug Administration after 2001 for complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), community-acquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infection (ABSSSI) (n = 29 282 participants). Enrollment numbers, demographics, clinical characteristics, and microbiological data were compared to identify temporal and geographic trends. RESULTS: For cUTI, cIAI, and CABP trials, Eastern European enrollment greatly increased over the study period. For ABSSSI trials, North American enrollment increased. Demographic characteristics and regional microbiology among regions were broadly similar with several exceptions. For cIAI trials, Eastern European participants had the lowest proportion of participants with prior antibacterial drug therapy. For ABSSSI trials, North American participants more commonly reported intravenous drug use. Microbiological differences relative to North America included a greater proportion of Klebsiella pneumoniae among Asian cIAI isolates (17.8% vs 9.0%, P = .0057), a higher proportion of cephalosporin resistance in South American Enterobacteriaceae cUTI isolates (26.8% vs 15.7%, P = .044), and a lower proportion of Staphylococcus aureus in Eastern European ABSSSI isolates (43.7% vs 61.9%, P < .0001). CONCLUSIONS: Geographic trends in recruitment for recent antibacterial clinical trials differ by indication. Regional similarities in demographic characteristics and microbiology across regions lessen concerns regarding generalizability due to shifting enrollment trends.

Cost-effectiveness of cardiovascular imaging for stable coronary heart disease.

OBJECTIVE: To assess the cost-effectiveness of management strategies for patients presenting with chest pain and suspected coronary heart disease (CHD): (1) cardiovascular magnetic resonance (CMR); (2) myocardial perfusion scintigraphy (MPS); and (3) UK National Institute for Health and Care Excellence (NICE) guideline-guided care. METHODS: Using UK data for 1202 patients from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial, we conducted an economic evaluation to assess the cost-effectiveness of CMR, MPS and NICE guidelines. Health outcomes were expressed as quality-adjusted life-years (QALYs), and costs reflected UK pound sterling in 2016-2017. Cost-effectiveness results were presented as incremental cost-effectiveness ratios and incremental net health benefits overall and for low, medium and high pretest likelihood of CHD subgroups. RESULTS: CMR had the highest estimated QALY gain overall (2.21 (95% credible interval 2.15, 2.26) compared with 2.07 (1.92, 2.20) for NICE and 2.11 (2.01, 2.22) for MPS) and incurred comparable costs (overall £1625 (£1431, £1824) compared with £1753 (£1473, £2032) for NICE and £1768 (£1572, £1989) for MPS). Overall, CMR was the cost-effective strategy, being the dominant strategy (more effective, less costly) with incremental net health benefits per patient of 0.146 QALYs (-0.18, 0.406) compared with NICE guidelines at a cost-effectiveness threshold of £15 000 per QALY (93% probability of cost-effectiveness). Results were similar in the pretest likelihood subgroups. CONCLUSIONS: CMR-guided care is cost-effective overall and across all pretest likelihood subgroups, compared with MPS and NICE guidelines.

Effects of Bladder Cancer on UK Healthcare Costs and Patient Health-Related Quality of Life: Evidence From the BOXIT Trial.

BACKGROUND: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial. MATERIAL AND METHODS: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification. RESULTS: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152). CONCLUSION: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC.

The cost-effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa.

INTRODUCTION: Many HIV-positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced-prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3 . We investigated the cost-effectiveness of this enhanced-prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. METHODS: The REALITY trial enrolled from June 2013 to April 2015. A decision-analytic model was developed to estimate the cost-effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard-prophylaxis, enhanced-prophylaxis, standard-prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced-prophylaxis (CrAg-positive) or standard-prophylaxis (CrAg-negative), the second to enhanced-prophylaxis (CrAg-positive) or enhanced-prophylaxis without fluconazole (CrAg-negative) and the third to standard-prophylaxis with fluconazole (CrAg-positive) or without fluconazole (CrAg-negative). The model estimated costs, life-years and quality-adjusted life-years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. RESULTS: Enhanced-prophylaxis was cost-effective at cost-effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost-effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm3 population providing enhanced-prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced-prophylaxis components. Enhanced-prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced-prophylaxis still conveyed health gains in CrAg-negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost-effective unless the price of CrAg testing fell below US$2.30. CONCLUSIONS: The REALITY enhanced-prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost-effective. Efforts should continue to ensure that components are accessed at lowest available prices.

The Clinical and Cost Effectiveness of Inotuzumab Ozogamicin for the Treatment of Adult Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Pfizer, the manufacturer of inotuzumab ozogamicin (henceforth inotuzumab), to submit clinical- and cost-effectiveness evidence for inotuzumab as part of NICE's single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned as the independent evidence review group (ERG). The clinical-effectiveness data were from a multicentre randomised controlled trial that compared inotuzumab with standard of care (SoC), where SoC was the investigator's choice of chemotherapy. Inotuzumab demonstrated statistically significant improvements in response rates or in the proportion of patients progressing to haematopoietic stem cell transplant (HSCT) but failed to meet the second primary objective of longer overall survival. Treatment-emergent adverse events were more frequent in the SoC arm, except veno-occlusive disease, which was more frequent in the inotuzumab arm. The company's economic model split patients into three post-hoc subgroups and used a partitioned survival approach within each group, with a cure assumption 3 years after receiving HSCT. In contrast with the trial results, the economic model estimated substantial improvement in survival with inotuzumab compared with SoC, providing an additional 5.2 life-years and 2.2 quality-adjusted life-years (QALYs) using a discount rate of 1.5% per annum. The ERG's critique highlighted a number of concerns, including the use of a post-hoc post-randomisation patient subset for extrapolation, the choice of a 1.5% discount rate, the complexity of the parametric modelling, the assumption of further treatment benefit post-HSCT, the nature of the cure assumption, and the length of inpatient stay while receiving treatment. The combination of the ERG's adjustments resulted in an incremental cost-effectiveness ratio (ICER) of £122,174 per QALY gained using Kaplan-Meier survival estimates and £114,078 per QALY gained with parametric survival models fit to the trial data. The final determination of the appraisal followed four NICE Appraisal Committee meetings, an appeal by the company and other stakeholders, two patient access schemes, and a company response to each appraisal consultation. The final ICER post-consultation was between £33,749 and £37,497 per QALY gained compared with SoC (excluding the confidential discount for blinatumomab received as subsequent therapy). The Appraisal Committee concluded that the ICER for inotuzumab was within the range usually considered cost effective for end-of-life care and recommended inotuzumab within its licensed indication.

Strimvelis® for Treating Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Evaluation.

The Centre for Reviews and Dissemination and Centre for Health Economics Technology Assessment Group at the University of York was commissioned by the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) programme to act as the independent Evidence Review Group (ERG) for an appraisal of Strimvelis®, a gene therapy treatment for adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID). This paper describes the manufacturing company's submission of clinical and economic evidence, the ERG's review and the resulting NICE guidance. For Strimvelis® compared with haematopoietic stem cell transplant (HSCT) from a matched unrelated donor (MUD) and HSCT from a haploidentical donor, the company base-case deterministic incremental cost-effectiveness ratios (ICERs) were £36,360 and £14,645 per quality-adjusted life-year (QALY) gained, respectively (using a discount rate of 1.5%). Although overall survival in patients receiving Strimvelis® was substantially higher than historical comparator data on HSCT from a MUD or haploidentical donor, the ERG was concerned that the estimated treatment benefit remained highly uncertain. The ERG critiqued some assumptions in the cost-effectiveness model, including that all patients return to general population mortality and morbidity after a successful procedure; that all patients receive a matched sibling donor following an unsuccessful engraftment; and that differences in wait times exist between the treatments. Incorporating a number of changes to the model, the ERG's base-case ICERs were £86,815 per QALY gained for Strimvelis® compared with HSCT from a MUD and £16,704 per QALY gained compared with HSCT from a haploidentical donor (using a discount rate of 1.5%). The ICER for Strimvelis® compared with HSCT from a MUD was highly sensitive to the difference in procedural mortality and could exceed NICE's £100,000 per QALY gained threshold for HSTs, if HSCT survival rates have improved since the most recent data. The evaluation committee concluded that the most plausible ICERs were lower than £100,000 per QALY gained and that Strimvelis® should be recommended for treatment of ADA-SCID where a matched related donor is unavailable.

Evaluation of ReminX as a Behavioral Intervention for Mild to Moderate Dementia.

Dementia is a growing global challenge that is difficult to treat. Pharmaceutical treatment approaches have had limited success, leading to an increased focus on nonpharmaceutical approaches to the treatment of dementia. A clinical pilot study was performed to evaluate whether ReminX digital therapeutic software, based on reminiscence therapy, has the potential to improve emotional functioning in patients with Alzheimer's disease and related dementias. ReminX allows the uploading of pictures and narration to create slideshow stories depicting important moments in the patient's life. Fourteen patients were evaluated in their home, and their emotional health was assessed both before and after using ReminX. Results indicated that patients reported significantly less anxiety, depression, and overall emotional distress after having viewed their story. Furthermore, patient's caregivers also reported that the patient appeared less emotionally distressed. The effect sizes for the significant results ranged from 0.76 to 0.91. These effect sizes, which were larger than anticipated, suggest that digitally-delivered reminiscence therapy can have an immediate and positive impact on emotional functioning in patients with dementia. In addition, the accessibility, scalability, and ease of use of the software platform suggests that this technology holds great promise as a product for use in both the home and senior care settings.

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.

BACKGROUND: The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS: We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS: We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION: Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING: World Health Organization.

Facilitating Antibacterial Drug Development in a Time of Great Need.

The continued development of new antibacterial drugs is critical to meet patient and public health needs. In this editorial, authors from the US Food and Drug Administration and European Medicines Agency reflect on the role of public-private partnerships and the development of clinical trials networks as agents to guide and perform quality studies of antibacterial drugs.

How to connect time-lapse recorded trajectories of motile microorganisms with dynamical models in continuous time.

We provide a tool for data-driven modeling of motility, data being time-lapse recorded trajectories. Several mathematical properties of a model to be found can be gleaned from appropriate model-independent experimental statistics, if one understands how such statistics are distorted by the finite sampling frequency of time-lapse recording, by experimental errors on recorded positions, and by conditional averaging. We give exact analytical expressions for these effects in the simplest possible model for persistent random motion, the Ornstein-Uhlenbeck process. Then we describe those aspects of these effects that are valid for any reasonable model for persistent random motion. Our findings are illustrated with experimental data and Monte Carlo simulations.