Modelling clinical outcomes and cost-effectiveness of primary care interventions for osteoarthritis using prediction and decision models

The overall aim of this thesis is to develop prediction models to identify key predictors of poor outcome in people with osteoarthritis (OA) and examine the cost effectiveness of two approaches to delivering primary care interventions for OA compared to current primary care. This thesis is comprised of two parts – the first part concerns the development of prediction models to identify the combination of factors that predicts poor outcome of OA in relation to pain and functional limitation at three year follow up for participants aged 50 years or more. The strongest baseline predictors of pain and functional disability were having pain in the previous year and poor physical function at baseline respectively. The models developed showed good internal validity and hence may be further tested for external validity in community-based adults with similar characteristics as those in this study. The second part involves a summary of evidence on the effectiveness of four primary care interventions (information and advice, simple analgesia, topical NSAIDs and exercise) in reducing pain and improving function at one or more joint sites among osteoarthritis patients in primary care. The results showed significant small to moderate improvements in pain and functional disability for advice/information, topical NSAIDs and exercise interventions compared to their controls, whilst simple analgesia failed to demonstrate significant improvements in either measures. This evidence was used to populate the economic (decision) model developed in this thesis. The decision model examined the cost effectiveness of two approaches to delivering primary care interventions for OA - stepped care and one-stop-shop care were compared with current primary care. The primary results were robust to changes in the input v variables with stepped care emerging as the most cost-effective option ahead of one-stop-shop care and current care in that order. These findings need to be confirmed in samples of primary care consulters

Interventions to reduce mortality from in-hospital cardiac arrest: a mixed-methods study

BackgroundUnchecked patient deterioration can lead to in-hospital cardiac arrest (IHCA) and avoidable death. The National Cardiac Arrest Audit (NCAA) has found fourfold variation in IHCA rates and survival between English hospitals. Key to reducing IHCA is both the identification of patients at risk of deterioration and prompt response. A range of targeted interventions have been introduced but implementation varies between hospitals. These differences are likely to contribute to the observed variation between and within hospitals over time.ObjectiveTo determine how interventions aimed at identification and management of deteriorating patients are associated with IHCA rates and outcomes.DesignA mixed-methods study involving a systematic literature review, semistructured interviews with 60 NHS staff, an organisational survey in 171 hospitals and interrupted time series and difference-in-difference analyses (106 hospitals).SettingEnglish hospitals participating in the NCAA audit.ParticipantsNHS staff (approximately 300) and patients (13 million).InterventionsEducation, track-and-trigger systems (TTSs), standardised handover tools and outreach teams.Main outcome measuresIHCA rates, survival and hospital-wide mortality.Data sourcesNCAA, Hospital Episode Statistics, Office for National Statistics Mortality Statistics.MethodsA literature review and qualitative interviews were used to design an organisational survey that determined how interventions have been implemented in practice and across time. Associations between variations in services and IHCA rates and survival were determined using cross-sectional, interrupted time series and difference-in-difference analyses over the index study period (2009/10 to 2014/15).ResultsAcross NCAA hospitals, IHCAs fell by 6.4% per year and survival increased by 5% per year, with hospital mortality decreasing by a similar amount. A national, standard TTS [the National Early Warning Score (NEWS)], introduced in 2012, was adopted by 70% of hospitals by 2015. By 2015, one-third of hospitals had converted from paper-based TTSs to electronic TTSs, and there had been an increase in the number of hospitals with an outreach team and an increase in the number with a team available at all times. The extent of variation in the uses of educational courses and structured handover tools was limited, with 90% of hospitals reporting use of standardised communication tools, such as situation, background, assessment and recommendation, in 2015. Introduction of the NEWS was associated with an additional 8.4% decrease in IHCA rates and, separately, a conversion from paper to electronic TTS use was associated with an additional 7.6% decrease. However, there was no associated change in IHCA survival or hospital mortality. Outreach teams were not associated with a change in IHCA rates, survival or hospital mortality. A sensitivity analysis restricted to ward-based IHCAs did not alter the findings but did identify an association between increased outreach team intensity in 2015 and IHCA survival.LimitationsThe organisational survey was not able to explore all aspects of the interventions and the contextual factors that influenced them. Changes over time were dependent on respondents’ recall.ConclusionsStandardisation of TTSs and introduction of electronic TTSs are associated with a reduction in IHCAs. The apparent lack of impact of outreach teams may reflect their mode of introduction, that their effect is through providing support for implementation of TTS or that the organisation of the response to deterioration is not critical, as long as it is timely. Their role in end-of-life decision-making may account for the observed association with IHCA survival.Future workTo assess the potential impact of outreach teams at hospital level and patient level, and to establish which component of the TTS has the greatest effect on outcomes.FundingThe National Institute for Health Research Health Services and Delivery Research programme.</jats:sec

Type of Track and Trigger system and incidence of in-hospital cardiac arrest: an observational registry-based study.

BACKGROUND: Failure to recognise and respond to patient deterioration on hospital wards is a common cause of healthcare-related harm. If patients are not rescued and suffer a cardiac arrest as a result then only around 15% will survive. Track and Trigger systems have been introduced into the NHS to improve both identification and response to such patients. This study examines the association between the type of Track & Trigger System (TTS) (National Early Warning Score (NEWS) versus non-NEWS) and the mode of TTS (paper TTS versus electronic TTS) and incidence of in-hospital ward-based cardiac arrests (IHCA) attended by a resuscitation team. METHODS: TTS type and mode was retrospectively collected at hospital level from 106 NHS acute hospitals in England between 2009 to 2015 via an organisational survey. Poisson regression and logistic regression models, adjusted for case-mix, temporal trends and seasonality were used to determine the association between TTS and hospital-level ward-based IHCA and survival rates. RESULTS: The NEWS was introduced in England in 2012 and by 2015, three-fifths of hospitals had adopted it. One fifth of hospitals had instituted an electronic TTS by 2015. Between 2009 and 2015 the incidence of IHCA fell. Introduction or use of NEWS in a hospital was associated with a reduction of 9.4% in the rate of ward-based IHCA compared to non-NEWS systems (incidence rate ratio 0.906, p < 0.001). The use of an electronic TTS was also associated with a reduction of 9.8% in the rate of IHCA compared with paper-based TTS (incidence rate ratio 0.902, p = 0.009). There was no change in hospital survival. CONCLUSIONS: The introduction of standardised TTS and electronic TTS have the potential to reduce ward-based IHCA. This is likely to be via a range of mechanisms from early intervention to institution of treatment limits. The lack of association with survival may reflect the complexity of response to triggering of the afferent arm of the rapid response system

Removal of GABA(A) Receptor gamma 2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations

Peer reviewe

Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: A multicentre randomized clinical pilot trial

Background: Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. Methods: An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. Results: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. Conclusion: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. Trial registration: ISRCTN16022198. Registered on 14 August 2017

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

A Feasibility Study of the Therapeutic Response and Durability of Short-term Androgen-targeted Therapy in Early Prostate Cancer Managed with Surveillance: The Therapeutics in Active Prostate Surveillance (TAPS01) Study.

BACKGROUND: Active surveillance (AS) is a preferred management option for men with prostate cancer with favourable prognosis. However, nearly half of men on AS switch to treatment within 5 years, so therapeutic strategies to prevent or delay disease progression could be considered. The androgen receptor is the pre-eminent oncogenic driver in prostate cancer. OBJECTIVE: To explore image-based tumour responses and the patient impact of short-duration androgen-targeted therapy (ATT) to abrogate disease progression during AS. DESIGN SETTING AND PARTICIPANTS: Men on AS with Cambridge Prognostic Group 1 & 2 (low and favourable intermediate risk) prostate cancer and lesions visible on magnetic resonance imaging (MRI) were recruited to an open-label, single-centre, phase 2 feasibility study of short-term ATT (the TAPS01 study). INTERVENTION: Apalutamide 240 mg was administered for 90 days. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MRI-measured tumour volume (TV), gland volume (GV), and the TV/GV ratio were calculated at baseline, at day 90 (end of treatment), and at 6- and 18-month follow-up. Quality of life metrics were measured at day 0, day 90, and 6 weeks after ATT. RESULTS AND LIMITATIONS: Eleven patients (40% of eligible men approached) agreed to participate, of whom nine completed treatment. At day 90, the median percentage reduction was -38.2% (range -51.8% to -23.5%) for GV, -54.2% (range -74.1% to -13.8%) for TV, and -27.2% (range -61.5% to -7.5%) for TV/GV (all p < 0.0001). At 6 mo, while GV had returned to baseline (p = 0.95) both TV (-31.9%; p = 0.0007) and TV/GV (-28.7%; p = 0.0009) remained significantly reduced. This reduction was sustained at 18 months (TV -18%, TV/GV -23.8%; p = 0.01). European Organization for Research and Treatment of Cancer QoL core 30-item questionnaire scores for global, physical, role, and social functioning decreased during treatment, but all were recovering by 6 weeks. EQ-VAS scores were unchanged compared to baseline. CONCLUSIONS: TAPS01 has demonstrated feasibility and patient tolerability for short-term ATT in men on AS. Our data suggest a selective and durable antitumour effect in the short term and support a larger-scale randomised trial. PATIENT SUMMARY: We investigated the feasibility of short-term treatment with an androgen inhibitor to prevent or delay disease progression for men on active surveillance for prostate cancer. Results for a small group of patients show that 90-day treatment led to a sustained decrease in tumour volume over 18 months. The findings warrant a larger clinical trial for this approach, which could allow patients to delay or even avoid longer-term active treatments.Janssen unrestricted education gran