CpG-island fragments from the HNRPA2B1/CBX3 genomic locus reduce silencing and enhance transgene expression from the hCMV promoter/enhancer in mammalian cells

BACKGROUND: The hCMV promoter is very commonly used for high level expression of transgenes in mammalian cells, but its utility is hindered by transcriptional silencing. Large genomic fragments incorporating the CpG island region of the HNRPA2B1 locus are resistant to transcriptional silencing. RESULTS: In this report we describe studies on the use of a novel series of vectors combining the HNRPA2B1 CpG island with the hCMV promoter for expression of transgenes in CHO-K1 cells. We show that the CpG island gives at least twenty-fold increases in the levels of EGFP and EPO observed in pools of transfectants, and that transgene expression levels remain high in such pools for more than 100 generations. These novel vectors also allow facile isolation of clonal CHO-K1 cell lines showing stable, high-level transgene expression. CONCLUSION: Vectors incorporating the hnRPA2B1 CpG island give major benefits in transgene expression from the hCMV promoter, including substantial improvements in the level and stability of expression. The utility of these vectors for the improved production of recombinant proteins in CHO cells has been demonstrated

Design and feasibility testing of a novel group intervention for young women who binge drink in groups

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial

Controlled attenuation parameter in NAFLD identifies risk of suboptimal glycaemic and metabolic control

To examine the relationship between steatosis quantified by controlled attenuation parameter (CAP) values and glycaemic/metabolic control. 230 patients, recruited from an Endocrine clinic or primary care underwent routine Hepatology assessment, with liver stiffness measurements and simultaneous CAP. Multivariable logistic regression was performed to identify potential predictors of Metabolic Syndrome (MetS), HbA1c ≥ 7%, use of insulin, hypertriglyceridaemia and CAP ≥ 300 dB/m. Patients were 56.7 ± 12.3 years of age with a high prevalence of MetS (83.5%), T2DM (81.3%), and BMI ≥ 40 kg/m (18%). Median CAP score was 344 dB/m, ranging from 128 to 400 dB/m. BMI (aOR 1.140 95% CI 1.068-1.216), requirement for insulin (aOR 2.599 95% CI 1.212-5.575), and serum ALT (aOR 1.018 95% CI 1.004-1.033) were independently associated with CAP ≥ 300 dB/m. Patients with CAP interquartile range

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Evaluation of the guide to action care home fall prevention programme in care homes for older people: A multi-centre, single blinded, cluster randomised controlled trial (FINCH)

BackgroundFalls in care home residents are common, unpleasant, costly and difficult to prevent. Trial DesignThe objective was to evaluate the clinical and cost effectiveness of the Guide to Action for Falls Prevention Care Homes, GtACH) in which care home staff were trained and supported in the systematic use of a multi-domain decision support tool and identify issues affecting subsequent implementation. A two-arm parallel design, multi-centre, cluster randomised controlled trial of the GtACH programme and usual falls prevention in older care home residents was conducted with embedded process evaluation and economic evaluation. MethodThe study was conducted in care homes from ten UK sites. The primary trial outcome was the rate of falls per resident participant occurring during the 90-day period between 91 days and 180 days post-randomisation. The primary outcome for the cost effectiveness analysis was the cost per fall averted and for the cost utility analysis was the incremental cost per QALY. Secondary outcomes included the rate of falls over days 0-90 and 181-360 post randomisation, activity levels, dependency, and fractures. Care homes were randomised on a 1:1 basis to the GtACH programme or usual care, via a secure web-based randomisation service. Research assistants (RAs), resident participants and staff informants were blind to allocation at recruitment. RAs were blind to allocation at follow up. Data from NHS Digital were extracted blindly. The number of falls per resident was compared between groups using a negative binomial regression model (GEE).Results84 care homes were randomised, 39 to GtACH and 45 to usual care. 1657 residents consented and provided baseline measures, mean age 85 years, 32% men. GtACH training was delivered to 1051 staff (71% of eligible staff) over 146 group sessions. Primary RCT outcome data were available for 630 of the GtACH participants and 712 usual care participants. The primary RCT outcome result showed an unadjusted Incidence Rate Ratio (IRR) of 0.57 (95% CI 0.45-0.71, p<0.01) in favour of the GtACH programme. Fall rates were also lower in the GtACH group in the period 0-90 days, but there were no other differences between groups in the secondary outcomes. Care home staff valued the training, the systematic strategies and the specialist peer support, but there was limited incorporation of the GtACH documentation into routine care home practice. No adverse events were recorded. The incremental cost per DEMQoL-based QALY was £20,889.42 and £4,543.69 per EQ-5D based QALY. Mean falls were 1.889 (sd 3.662) in the GtACH arm and 2.747 (sd 7.414) in the usual care arm. Therefore, 0.858 falls were averted. The base case incremental cost per fall averted was £190.62ConclusionThe GtACH programme significantly reduced the rate of falls in the study care homes, without restricting residents’ activity levels or increasing their dependency and was cost effective at current thresholds in the UK NHS. Widespread implementation of the programme is justified. Trial registrationTrial registration number: ISRCTN34353836. Protocol V6 14 November 2017Funding DetailsThe National Institute for Health Research (NIHR) HTA programm

Multifactorial falls prevention programme compared with usual care in UK care homes for older people: Multicentre cluster randomised controlled trial with economic evaluation

Objectives: To determine the clinical and cost effectiveness of a multifactorial fall prevention programme compared with usual care in long term care homes. Design: Multicentre, parallel, cluster randomised controlled trial. Setting: Long term care homes in the UK, registered to care for older people or those with dementia. Participants: 1657 consenting residents and 84 care homes. 39 were randomised to the intervention group and 45 were randomised to usual care. Interventions: Guide to Action for Care Homes (GtACH): a multifactorial fall prevention programme or usual care. Main outcome measures: Primary outcome measure was fall rate at 91-180 days after randomisation. The economic evaluation measured health related quality of life using quality adjusted life years (QALYs) derived from the five domain five level version of the EuroQoL index (EQ-5D-5L) or proxy version (EQ-5D-5L-P) and the Dementia Quality of Life utility measure (DEMQOL-U), which were self-completed by competent residents and by a care home staff member proxy (DEMQOL-P-U) for all residents (in case the ability to complete changed during the study) until 12 months after randomisation. Secondary outcome measures were falls at 1-90, 181-270, and 271-360 days after randomisation, Barthel index score, and the Physical Activity Measure-Residential Care Homes (PAM-RC) score at 91, 180, 270, and 360 days after randomisation. Results: Mean age of residents was 85 years. 32% were men. GtACH training was delivered to 1051/1480 staff (71%). Primary outcome data were available for 630 participants in the GtACH group and 712 in the usual care group. The unadjusted incidence rate ratio for falls between 91 and 180 days was 0.57 (95% confidence interval 0.45 to 0.71, P<0.001) in favour of the GtACH programme (GtACH: six falls/1000 residents v usual care: 10 falls/1000). Barthel activities of daily living indices and PAM-RC scores were similar between groups at all time points. The incremental cost was £108 (95% confidence interval −£271.06 to 487.58), incremental QALYs gained for EQ-5D-5L-P was 0.024 (95% confidence interval 0.004 to 0.044) and for DEMQOL-P-U was 0.005 (−0.019 to 0.03). The incremental costs per EQ-5D-5L-P and DEMQOL-P-U based QALY were £4544 and £20 889, respectively. Conclusions: The GtACH programme was associated with a reduction in fall rate and cost effectiveness, without a decrease in activity or increase in dependency. Trial registration: ISRCTN34353836

A multidomain decision support tool to prevent falls in older people: the FinCH cluster RCT

BackgroundFalls in care home residents are common, unpleasant, costly and difficult to prevent.ObjectivesThe objectives were to evaluate the clinical effectiveness and cost-effectiveness of the Guide to Action for falls prevention in Care Homes (GtACH) programme.DesignA multicentre, cluster, parallel, 1 : 1 randomised controlled trial with embedded process evaluation and economic evaluation. Care homes were randomised on a 1 : 1 basis to the GtACH programme or usual care using a secure web-based randomisation service. Research assistants, participating residents and staff informants were blind to allocation at recruitment; research assistants were blind to allocation at follow-up. NHS Digital data were extracted blindly.SettingOlder people’s care homes from 10 UK sites.ParticipantsOlder care home residents.InterventionThe GtACH programme, which includes care home staff training, systematic use of a multidomain decision support tool and implementation of falls prevention actions, compared to usual falls prevention care.OutcomesThe primary trial outcome was the rate of falls per participating resident occurring during the 90-day period between 91 and 180 days post randomisation. The primary outcome for the cost-effectiveness analysis was the cost per fall averted, and the primary outcome for the cost–utility analysis was the incremental cost per quality adjusted life-year. Secondary outcomes included the rate of falls over days 0–90 and 181–360 post randomisation, activity levels, dependency and fractures. The number of falls per resident was compared between arms using a negative binomial regression model (generalised estimating equation).ResultsA total of 84 care homes were randomised: 39 to the GtACH arm and 45 to the control arm. A total of 1657 residents consented and provided baseline measures (mean age 85 years, 32% men). GtACH programme training was delivered to 1051 staff (71% of eligible staff) over 146 group sessions. Primary outcome data were available for 630 GtACH participants and 712 control participants. The primary outcome result showed an unadjusted incidence rate ratio of 0.57 (95% CI 0.45 to 0.71; p < 0.01) in favour of the GtACH programme. Falls rates were lower in the GtACH arm in the period 0–90 days. There were no other differences between arms in the secondary outcomes. Care home staff valued the training, systematic strategies and specialist peer support, but the incorporation of the GtACH programme documentation into routine care home practice was limited. No adverse events were recorded. The incremental cost was £20,889.42 per Dementia Specific Quality of Life-based quality-adjusted life-year and £4543.69 per quality-adjusted life-year based on the EuroQol-5 dimensions, five-level version. The mean number of falls was 1.889 (standard deviation 3.662) in the GtACH arm and 2.747 (standard deviation 7.414) in the control arm. Therefore, 0.858 falls were averted. The base-case incremental cost per fall averted was £190.62.ConclusionThe GtACH programme significantly reduced the falls rate in the study care homes without restricting residents’ activity levels or increasing their dependency, and was cost-effective at current thresholds in the NHS.Future workFuture work should include a broad implementation programme, focusing on scale and sustainability of the GtACH programme.LimitationsA key limitation was the fact that care home staff were not blinded, although risk was small because of the UK statutory requirement to record falls in care homes.Trial registrationThis trial is registered as ISRCTN34353836.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 9. See the NIHR Journals Library website for further project information

Skin Lesions on Common Bottlenose Dolphins (Tursiops truncatus) from Three Sites in the Northwest Atlantic, USA

Skin disease occurs frequently in many cetacean species across the globe; methods to categorize lesions have relied on photo-identification (photo-id), stranding, and by-catch data. The current study used photo-id data from four sampling months during 2009 to estimate skin lesion prevalence and type occurring on bottlenose dolphins (Tursiops truncatus) from three sites along the southeast United States coast [Sarasota Bay, FL (SSB); near Brunswick and Sapelo Island, GA (BSG); and near Charleston, SC (CHS)]. The prevalence of lesions was highest among BSG dolphins (P = 0.587) and lowest in SSB (P = 0.380), and the overall prevalence was significantly different among all sites (p<0.0167). Logistic regression modeling revealed a significant reduction in the odds of lesion occurrence for increasing water temperatures (OR = 0.92; 95%CI:0.906–0.938) and a significantly increased odds of lesion occurrence for BSG dolphins (OR = 1.39; 95%CI:1.203–1.614). Approximately one-third of the lesioned dolphins from each site presented with multiple types, and population differences in lesion type occurrence were observed (p<0.05). Lesions on stranded dolphins were sampled to determine the etiology of different lesion types, which included three visually distinct samples positive for herpesvirus. Although generally considered non-fatal, skin disease may be indicative of animal health or exposure to anthropogenic or environmental threats, and photo-id data provide an efficient and cost-effective approach to document the occurrence of skin lesions in free-ranging populations