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.

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.

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.

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.

Devices for remote continuous monitoring of people with Parkinson's disease: a systematic review and cost-effectiveness analysis.

Background: Parkinson's disease is a brain condition causing a progressive loss of co ordination and movement problems. Around 145,500 people have Parkinson's disease in the United Kingdom. Levodopa is the most prescribed treatment for managing motor symptoms in the early stages. Patients should be monitored by a specialist every 6-12 months for disease progression and treatment of adverse effects. Wearable devices may provide a novel approach to management by directly monitoring patients for bradykinesia, dyskinesia, tremor and other symptoms. They are intended to be used alongside clinical judgement. Objectives: To determine the clinical and cost-effectiveness of five devices for monitoring Parkinson's disease: Personal KinetiGraph, Kinesia 360, KinesiaU, PDMonitor and STAT-ON. Methods: We performed systematic reviews of all evidence on the five devices, outcomes included: diagnostic accuracy, impact on decision-making, clinical outcomes, patient and clinician opinions and economic outcomes. We searched MEDLINE and 12 other databases/trial registries to February 2022. Risk of bias was assessed. Narrative synthesis was used to summarise all identified evidence, as the evidence was insufficient for meta-analysis. One included trial provided individual-level data, which was re-analysed. A de novo decision-analytic model was developed to estimate the cost-effectiveness of Personal KinetiGraph and Kinesia 360 compared to standard of care in the UK NHS over a 5-year time horizon. The base-case analysis considered two alternative monitoring strategies: one-time use and routine use of the device. Results: Fifty-seven studies of Personal KinetiGraph, 15 of STAT-ON, 3 of Kinesia 360, 1 of KinesiaU and 1 of PDMonitor were included. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in clinical outcomes when measured using the Unified Parkinson's Disease Rating Scale. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical impact. The evidence for Kinesia 360, KinesiaU and PDMonitor is insufficient to draw any conclusions on their value in clinical practice. The base-case results for Personal KinetiGraph compared to standard of care for one-time and routine use resulted in incremental cost-effectiveness ratios of £67,856 and £57,877 per quality-adjusted life-year gained, respectively, with a beneficial impact of the Personal KinetiGraph on Unified Parkinson's Disease Rating Scale domains III and IV. The incremental cost-effectiveness ratio results for Kinesia 360 compared to standard of care for one-time and routine use were £38,828 and £67,203 per quality-adjusted life-year gained, respectively. Limitations: The evidence was limited in extent and often low quality. For all devices, except Personal KinetiGraph, there was little to no evidence on the clinical impact of the technology. Conclusions: Personal KinetiGraph could reasonably be used in practice to monitor patient symptoms and modify treatment where required. There is too little evidence on STAT-ON, Kinesia 360, KinesiaU or PDMonitor to be confident that they are clinically useful. The cost-effectiveness of remote monitoring appears to be largely unfavourable with incremental cost-effectiveness ratios in excess of £30,000 per quality-adjusted life-year across a range of alternative assumptions. The main driver of cost-effectiveness was the durability of improvements in patient symptoms. Study registration: This study is registered as PROSPERO CRD42022308597. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135437) and is published in full in Health Technology Assessment; Vol. 28, No. 30. See the NIHR Funding and Awards website for further award information.

Parkinson's disease is a brain condition causing loss of co-ordination and movement problems. Levodopa is the most prescribed treatment for early disease. Patients should be seen by a specialist every 6­12 months to assess their treatment needs. Wearable devices (like smart watches) may aid management by directly monitoring patients for disease symptoms including tremor and slowness of movement (bradykinesia), or side effects of treatment like involuntary movement (dyskinesia). This assessment considered the clinical and economic value of five wearable devices: Personal KinetiGraph, STAT-ON, Kinesia 360, KinesiaU and PDMonitor. We searched medical databases to find all studies of the five devices. We assessed the quality of these studies and reviewed their results. We found 77 studies of the devices. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in symptoms. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical value. There was insufficient evidence for Kinesia 360, KinesiaU and PDMonitor to draw any conclusions. An economic analysis was conducted to investigate whether using any of these technologies is economically viable. The economic analysis found that the quality-of-life benefits generated by remote monitoring devices were small relative to the additional costs of implementing them in the NHS. As such, none of the remote monitoring devices were good value for money when compared with the current standard of care.

Gene location and DNA density determine transcription factor distributions in Escherichia coli.

The diffusion coefficient of the transcription factor LacI within living Escherichia coli has been measured directly by in vivo tracking to be D = 0.4 µm(2)/s. At this rate, simple models of diffusion lead to the expectation that LacI and other proteins will rapidly homogenize throughout the cell. Here, we test this expectation of spatial homogeneity by single-molecule visualization of LacI molecules non-specifically bound to DNA in fixed cells. Contrary to expectation, we find that the distribution depends on the spatial location of its encoding gene. We demonstrate that the spatial distribution of LacI is also determined by the local state of DNA compaction, and that E. coli can dynamically redistribute proteins by modifying the state of its nucleoid. Finally, we show that LacI inhomogeneity increases the strength with which targets located proximally to the LacI gene are regulated. We propose a model for intranucleoid diffusion that can reconcile these results with previous measurements of LacI diffusion, and we discuss the implications of these findings for gene regulation in bacteria and eukaryotes.

Using deep sequencing to characterize the biophysical mechanism of a transcriptional regulatory sequence.

Cells use protein-DNA and protein-protein interactions to regulate transcription. A biophysical understanding of this process has, however, been limited by the lack of methods for quantitatively characterizing the interactions that occur at specific promoters and enhancers in living cells. Here we show how such biophysical information can be revealed by a simple experiment in which a library of partially mutated regulatory sequences are partitioned according to their in vivo transcriptional activities and then sequenced en masse. Computational analysis of the sequence data produced by this experiment can provide precise quantitative information about how the regulatory proteins at a specific arrangement of binding sites work together to regulate transcription. This ability to reliably extract precise information about regulatory biophysics in the face of experimental noise is made possible by a recently identified relationship between likelihood and mutual information. Applying our experimental and computational techniques to the Escherichia coli lac promoter, we demonstrate the ability to identify regulatory protein binding sites de novo, determine the sequence-dependent binding energy of the proteins that bind these sites, and, importantly, measure the in vivo interaction energy between RNA polymerase and a DNA-bound transcription factor. Our approach provides a generally applicable method for characterizing the biophysical basis of transcriptional regulation by a specified regulatory sequence. The principles of our method can also be applied to a wide range of other problems in molecular biology.

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.

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.

Site-specific chromosomal integration of large synthetic constructs.

We have developed an effective, easy-to-use two-step system for the site-directed insertion of large genetic constructs into arbitrary positions in the Escherichia coli chromosome. The system uses lambda-Red mediated recombineering accompanied by the introduction of double-strand DNA breaks in the chromosome and a donor plasmid bearing the desired insertion fragment. Our method, in contrast to existing recombineering or phage-derived insertion methods, allows for the insertion of very large fragments into any desired location and in any orientation. We demonstrate this method by inserting a 7-kb fragment consisting of a venus-tagged lac repressor gene along with a target lacZ reporter into six unique sites distributed symmetrically about the chromosome. We also demonstrate the universality and repeatability of the method by separately inserting the lac repressor gene and the lacZ target into the chromosome at separate locations around the chromosome via repeated application of the protocol.

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.

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.

'Dicty dynamics': Dictyostelium motility as persistent random motion.

We model the motility of Dictyostelium cells in a systematic data-driven manner. We deduce a minimal dynamical model that reproduces the statistical features of experimental trajectories. These are trajectories of the centroid of the cell perimeter, which is more sensitive to pseudopod activity than the usual tracking by centroid or nucleus. Our data account for cell individuality and dictate a model that extends the cell-type specific models recently derived for mammalian cells. Two generalized Langevin equations model stochastic periodic pseudopod motion parallel and orthogonal to the amoeba's direction of motion. This motion propels the amoeba with a random periodic left-right waddle in a direction that has a long persistence time. The model fully accounts for the statistics of the experimental trajectories, including velocity power spectra and auto-correlations, non-Gaussian velocity distributions, and multiplicative noise. Thus, we find neither need nor place in our data for an interpretation in terms of anomalous diffusion. The model faithfully captures cell individuality as different parameter values in the model, and serves as a basis for integrating the local mechanics of cell motion with our observed long-term behavior.