The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix: the STOPPIT 2 RCT.

BACKGROUND: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. OBJECTIVE: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. DESIGN: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group - the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. SETTING: Antenatal clinics in the UK and elsewhere in Europe. PARTICIPANTS: Women with twin pregnancy at < 21 weeks' gestation with known chorionicity and gestation established by scan at ≤ 16 weeks' gestation. INTERVENTIONS: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0-20+ 6 weeks' gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. MAIN OUTCOME MEASURES: Obstetric - all births before 34+ 0 weeks' gestation following the spontaneous onset of labour; and neonatal - composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. RESULTS: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal 'easy' or 'fairly easy' in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. LIMITATIONS: There was the possibility of a type II error around smaller than anticipated benefit. CONCLUSIONS: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. FUTURE WORK: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. FUNDING: This 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. 25, No. 44. See the NIHR Journals Library website for further project information.

Women who are pregnant with twins have a much higher risk of going into labour early and having an early (preterm) birth than women who are pregnant with only one baby. For this reason, babies who are twins are much more likely to die or to have serious health complications in the first months of life. Although we know that women with twin pregnancy are at risk, there are no treatments that are recommended to prevent early births. Some studies have suggested that the Arabin pessary can help. The Arabin pessary is a silicone ring that fits around the cervix (neck of the womb). The pessary can be put in place in a clinic without any need for an anaesthetic. Some studies have suggested that the Arabin pessary helps and others have suggested that it does not. It appears to be most helpful when the cervix (neck of the womb) is already shortening. Shortening of the neck of the womb is a sign that early birth is even more likely. We asked women with twin pregnancy to take part in STOPPIT 2. Women who agreed had an ultrasound scan of the neck of the womb, which measured its length. Those with a short cervix were randomised to be offered the Arabin pessary (in addition to standard care) or standard care alone. This allocation was carried out 'at random' by a computer. We followed women up until the end of their pregnancy and collected information on the babies' health after birth. We found that the Arabin pessary did not reduce the risk of an early birth; nor did it reduce the risk of health complications for the baby. We conclude that the Arabin pessary should not be used for this purpose.

Improving reduced complexity model assessment and usability.

Reduced complexity climate models are useful tools with practical policy applications, yet evaluation of their performance and application is nascent. We call for stakeholder-driven development and assessment to address user needs, including provision of open-source code and guidance to inform model selection and application.

Systematic Review: Monoclonal Antibody-Induced Subacute Cutaneous Lupus Erythematosus.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) lacks consensus diagnostic criteria and the pathogenesis is poorly understood. There are increasing reports of SCLE induced by monoclonal antibodies (mAbs), but there are limited data on the aetiology, clinical characteristics and natural course of this disease. METHODS: We devised a set of diagnostic criteria for SCLE in collaboration with a multinational, multispecialty panel. This systematic review employed a two-layered search strategy of five databases for cases of mAb-induced SCLE (PROSPERO registered protocol CRD42019116521). To explore the relationship between relative mAb use and the number of SCLE cases reported, the estimated number of mAb users was modelled from 2013 to 2018 global commercial data and estimated annual therapy costs. RESULTS: From 40 papers, we identified 52 cases of mAb-induced SCLE, occurring in a cohort that was 73% female and with a median age of 61 years. Fifty percent of cases were induced by anti-tumour necrosis factor (TNF)-ɑ agents. A median of three drug doses preceded SCLE onset and the lesions lasted a median of 7 weeks after drug cessation. Oral and topical corticosteroids were most frequently used. Of the licensed mAbs, adalimumab, denosumab, rituximab, etanercept and infliximab were calculated to have the highest relative number of yearly users based on global sales data. Comparing the number of mAb-induced SCLE cases with estimated yearly users, the checkpoint inhibitors pembrolizumab and nivolumab showed strikingly high rates of SCLE relative to their global use, but ipilimumab did not. CONCLUSION: We present the first systematic review characterising mAb-induced SCLE with respect to triggers, clinical signs, laboratory findings, prognosis and treatment approaches. We identify elevated rates associated with the use of checkpoint inhibitors and anti-TNFɑ agents.

A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality.

BACKGROUND AND PURPOSE: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area. MATERIALS AND METHODS: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. RESULTS: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. CONCLUSION: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.

Correction: A macroeconomic assessment of the impact of medical research expenditure: A case study of NIHR Biomedical Research Centres.

[This corrects the article DOI: 10.1371/journal.pone.0214361.].

A macroeconomic assessment of the impact of medical research expenditure: A case study of NIHR Biomedical Research Centres.

Quantifying the value of investment in medical research can inform decision-making on the prioritisation of research programmes. Existing methodologies to estimate the rate of return of medical research are inappropriate for early-phase translational research due to censoring of health benefits and time lags. A strategy to improve the process of translational research for patient benefit has been initiated as part of the UK National Institute for Health Research (NIHR) investment in Biomedical Research Centres (BRCs) in England. By providing a platform for partnership between universities, NHS trusts and industry, successful BRCs should reduce time lags within translational research whilst also providing an impetus for local economic growth through industry collaboration. We present a novel contribution in the assessment of early-phase biomedical research by estimating the impact of the Oxford Biomedical Research Centre (OxBRC) on income and job creation following the initial NIHR investment. We adopt a macroeconomic assessment approach using Input-Output Analysis to estimate the value of medical research in terms of income and job creation during the early pathway towards translational biomedical research. Inter-industry linkages are assessed by building a model economy for the South East England region to estimate the return on investment of the OxBRC. The results from the input-output model estimate that the return on investment in biomedical research within the OxBRC is 46%. Each £1 invested in the OxBRC generates an additional £0.46 through income and job creation alone. Multiplicative employment effects following a marginal investment in the OxBRC of £98m during the period 2007-2017 result in an estimated additional 196 full time equivalent positions being created within the local economy on top of direct employment within OxBRC. Results from input-output analyses can be used to inform the prioritisation of biomedical research programmes when compared against national minimum thresholds of investment.

Open randomised trial of the (Arabin) pessary to prevent preterm birth in twin pregnancy with health economics and acceptability: STOPPIT-2-a study protocol.

INTRODUCTION: The STOPPIT-2 study aims to determine the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix, about which there is current uncertainty. STOPPIT-2 will resolve uncertainty around effectiveness for women with a twin pregnancy and a cervical length of 35 mm or less, define adverse effects, ascertain acceptability and estimate National Health Service costs and savings. METHODS: STOPPIT-2 is a pragmatic multicentre open-label randomised controlled trial. Consenting women with twin pregnancy will have an transvaginal ultrasound scan of their cervical length performed between 18+0 and 20+6 weeks' gestation by an accredited practitioner: women with a cervical length of ≤35 mm will be eligible for inclusion in the treatment phase of the study. The intervention by the insertion of the Arabin cervical pessary will be compared with standard treatment (no pessary).The primary outcomes are (obstetric) spontaneous onset of labour for the mother leading to delivery before 34 weeks' gestation and (neonatal) a composite of specific adverse outcomes or death occurring up to the end of the first 4 weeks after the estimated date of delivery to either or both babies.We plan to recruit 500 women in the treatment phase of the study. Assuming a treatment effect of 0.6, and background rates of 35% and 18%, respectively, for each of the primary outcomes, our study has 85% power to detect a difference between the intervention and the control groups. ANALYSIS: Data will be analysed on the intention-to-treat principle. ETHICS: STOPPIT-2 was approved by the South East Scotland Ethics Committee 02 on 29 August 2014, reference number 14/SS/1031 IRAS ID 159610. DISSEMINATION: Peer reviewed journals, presentations at national and international scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN98835694 and NCT02235181.

Use of Coronary Computed Tomographic Angiography to Guide Management of Patients With Coronary Disease.

BACKGROUND: In a prospective, multicenter, randomized controlled trial, 4,146 patients were randomized to receive standard care or standard care plus coronary computed tomography angiography (CCTA). OBJECTIVES: The purpose of this study was to explore the consequences of CCTA-assisted diagnosis on invasive coronary angiography, preventive treatments, and clinical outcomes. METHODS: In post hoc analyses, we assessed changes in invasive coronary angiography, preventive treatments, and clinical outcomes using national electronic health records. RESULTS: Despite similar overall rates (409 vs. 401; p = 0.451), invasive angiography was less likely to demonstrate normal coronary arteries (20 vs. 56; hazard ratios [HRs]: 0.39 [95% confidence interval (CI): 0.23 to 0.68]; p < 0.001) but more likely to show obstructive coronary artery disease (283 vs. 230; HR: 1.29 [95% CI: 1.08 to 1.55]; p = 0.005) in those allocated to CCTA. More preventive therapies (283 vs. 74; HR: 4.03 [95% CI: 3.12 to 5.20]; p < 0.001) were initiated after CCTA, with each drug commencing at a median of 48 to 52 days after clinic attendance. From the median time for preventive therapy initiation (50 days), fatal and nonfatal myocardial infarction was halved in patients allocated to CCTA compared with those assigned to standard care (17 vs. 34; HR: 0.50 [95% CI: 0.28 to 0.88]; p = 0.020). Cumulative 6-month costs were slightly higher with CCTA: difference $462 (95% CI: $303 to $621). CONCLUSIONS: In patients with suspected angina due to coronary heart disease, CCTA leads to more appropriate use of invasive angiography and alterations in preventive therapies that were associated with a halving of fatal and non-fatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

Parameter Heterogeneity In Breast Cancer Cost Regressions - Evidence From Five European Countries.

We investigate parameter heterogeneity in breast cancer 1-year cumulative hospital costs across five European countries as part of the EuroHOPE project. The paper aims to explore whether conditional mean effects provide a suitable representation of the national variation in hospital costs. A cohort of patients with a primary diagnosis of invasive breast cancer (ICD-9 codes 174 and ICD-10 C50 codes) is derived using routinely collected individual breast cancer data from Finland, the metropolitan area of Turin (Italy), Norway, Scotland and Sweden. Conditional mean effects are estimated by ordinary least squares for each country, and quantile regressions are used to explore heterogeneity across the conditional quantile distribution. Point estimates based on conditional mean effects provide a good approximation of treatment response for some key demographic and diagnostic specific variables (e.g. age and ICD-10 diagnosis) across the conditional quantile distribution. For many policy variables of interest, however, there is considerable evidence of parameter heterogeneity that is concealed if decisions are based solely on conditional mean results. The use of quantile regression methods reinforce the need to consider beyond an average effect given the greater recognition that breast cancer is a complex disease reflecting patient heterogeneity.

Which stroke patients gain most from intermittent pneumatic compression: further analyses of the CLOTS 3 trial.

BACKGROUND: The CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of DVT and improved survival after stroke. AIMS: To provide additional information which may help clinicians target IPC on the most appropriate patients by exploring the variation in its effects on subgroups defined by predicted prognosis. METHODS: A multicentre, parallel group, randomized trial enrolled immobile acute stroke patients and allocated them to IPC or no IPC. The primary outcome was proximal DVT at 30 days. Secondary outcomes at six-months included survival, disability, quality of life, and hospital costs. We stratified patients into quintiles according to their predicted prognosis at randomization, based on the Six Simple Variable model. RESULTS: Between December 2008 and September 2012, we enrolled 2876 patients in 94 UK hospitals. Patients with the best predicted outcome had the lowest absolute risk of proximal DVT (6·7%) and death by six-months (9·3%). Allocation to IPC had little effect on DVT, survival, disability, quality of life, hospital length of stay, or costs. In patients with the worst predicted outcomes, the overall risk of DVT and death was 16·0% and 51·3%, respectively. IPC reduced DVT (odds reduction 34%) and improved survival 17% and significantly increased length of stay and hospital costs. In the three intermediate quintiles, IPC reduced the odds of DVT (35-43%) and improved survival (11-13%). Disability and quality of life at six-months depended on baseline severity but was not influenced significantly by IPC. CONCLUSIONS: IPC appears to reduce the risk of DVT and probably improves survival in all immobile stroke patients, other than the fifth with the best prognosis. It therefore seems reasonable to recommend that IPC should be considered in all immobile stroke patients, but that the final decision should be based on a judgment about the individual's prognosis. In some, their prognosis for survival with an acceptable quality of life will be so poor that use of IPC might be considered futile, while at the other end of the spectrum, patients' risk of DVT, and of dying from VTE, may not be high enough to justify the modest cost and inconvenience of IPC use.

Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial.

IMPORTANCE: Critical illness results in disability and reduced health-related quality of life (HRQOL), but the optimum timing and components of rehabilitation are uncertain. OBJECTIVE: To evaluate the effect of increasing physical and nutritional rehabilitation plus information delivered during the post-intensive care unit (ICU) acute hospital stay by dedicated rehabilitation assistants on subsequent mobility, HRQOL, and prevalent disabilities. DESIGN, SETTING, AND PARTICIPANTS: A parallel group, randomized clinical trial with blinded outcome assessment at 2 hospitals in Edinburgh, Scotland, of 240 patients discharged from the ICU between December 1, 2010, and January 31, 2013, who required at least 48 hours of mechanical ventilation. Analysis for the primary outcome and other 3-month outcomes was performed between June and August 2013; for the 6- and 12-month outcomes and the health economic evaluation, between March and April 2014. INTERVENTIONS: During the post-ICU hospital stay, both groups received physiotherapy and dietetic, occupational, and speech/language therapy, but patients in the intervention group received rehabilitation that typically increased the frequency of mobility and exercise therapies 2- to 3-fold, increased dietetic assessment and treatment, used individualized goal setting, and provided greater illness-specific information. Intervention group therapy was coordinated and delivered by a dedicated rehabilitation practitioner. MAIN OUTCOMES AND MEASURES: The Rivermead Mobility Index (RMI) (range 0-15) at 3 months; higher scores indicate greater mobility. Secondary outcomes included HRQOL, psychological outcomes, self-reported symptoms, patient experience, and cost-effectiveness during a 12-month follow-up (completed in February 2014). RESULTS: Median RMI at randomization was 3 (interquartile range [IQR], 1-6) and at 3 months was 13 (IQR, 10-14) for the intervention and usual care groups (mean difference, -0.2 [95% CI, -1.3 to 0.9; P = .71]). The HRQOL scores were unchanged by the intervention (mean difference in the Physical Component Summary score, -0.1 [95% CI, -3.3 to 3.1; P = .96]; and in the Mental Component Summary score, 0.2 [95% CI, -3.4 to 3.8; P = .91]). No differences were found for self-reported symptoms of fatigue, pain, appetite, joint stiffness, or breathlessness. Levels of anxiety, depression, and posttraumatic stress were similar, as were hand grip strength and the timed Up & Go test. No differences were found at the 6- or 12-month follow-up for any outcome measures. However, patients in the intervention group reported greater satisfaction with physiotherapy, nutritional support, coordination of care, and information provision. CONCLUSIONS AND RELEVANCE: Post-ICU hospital-based rehabilitation, including increased physical and nutritional therapy plus information provision, did not improve physical recovery or HRQOL, but improved patient satisfaction with many aspects of recovery. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN09412438.

Movement variability in stroke patients and controls performing two upper limb functional tasks: a new assessment methodology.

BACKGROUND: In the evaluation of upper limb impairment post stroke there remains a gap between detailed kinematic analyses with expensive motion capturing systems and common clinical assessment tests. In particular, although many clinical tests evaluate the performance of functional tasks, metrics to characterise upper limb kinematics are generally not applicable to such tasks and very limited in scope. This paper reports on a novel, user-friendly methodology that allows for the assessment of both signal magnitude and timing variability in upper limb movement trajectories during functional task performance. In order to demonstrate the technique, we report on a study in which the variability in timing and signal magnitude of data collected during the performance of two functional tasks is compared between a group of subjects with stroke and a group of individually matched control subjects. METHODS: We employ dynamic time warping for curve registration to quantify two aspects of movement variability: 1) variability of the timing of the accelerometer signals' characteristics and 2) variability of the signals' magnitude. Six stroke patients and six matched controls performed several trials of a unilateral ('drinking') and a bilateral ('moving a plate') functional task on two different days, approximately 1 month apart. Group differences for the two variability metrics were investigated on both days. RESULTS: For 'drinking from a glass' significant group differences were obtained on both days for the timing variability of the acceleration signals' characteristics (p = 0.002 and p = 0.008 for test and retest, respectively); all stroke patients showed increased signal timing variability as compared to their corresponding control subject. 'Moving a plate' provided less distinct group differences. CONCLUSION: This initial application establishes that movement variability metrics, as determined by our methodology, appear different in stroke patients as compared to matched controls during unilateral task performance ('drinking'). Use of a user-friendly, inexpensive accelerometer makes this methodology feasible for routine clinical evaluations. We are encouraged to perform larger studies to further investigate the metrics' usefulness when quantifying levels of impairment.

Amino acid profiling in plant cell cultures: an inter-laboratory comparison of CE-MS and GC-MS.

A CE-MS method for metabolic profiling of amino acids was developed and used in an integrated functional genomics project to study the response of Medicago truncatula liquid suspension cell cultures to stress. This project required the analysis of more than 500 root cell culture extracts. The CE-MS method profiled 20 biologically important amino acids. The CE-MS method required no sample derivatization prior to injection and used minimal sample preparation. The method is described in terms of CE and MS operational parameters, reproducibility of migration times and response ratios, sample preparation, sample throughput, and reliability. This method was then compared with a previously published report that used GC-MS metabolic profiling for the same tissues. The data reveal a high level of similarity between the CE-MS and GC-MS amino acid profiling methods, thus supporting these as complementary technologies for metabolomics. We conclude that CE-MS is a valid alternative to GC-MS for targeted profiling of metabolites, such as amino acids, and possesses some significant advantages over GC-MS.

Climate change and human health impacts in the United States: an update on the results of the U.S. national assessment.

The health sector component of the first U.S. National Assessment, published in 2000, synthesized the anticipated health impacts of climate variability and change for five categories of health outcomes: impacts attributable to temperature, extreme weather events (e.g., storms and floods) , air pollution, water- and food-borne diseases, and vector- and rodent-borne diseases. The Health Sector Assessment (HSA) concluded that climate variability and change are likely to increase morbidity and mortality risks for several climate-sensitive health outcomes, with the net impact uncertain. The objective of this study was to update the first HSA based on recent publications that address the potential impacts of climate variability and change in the United States for the five health outcome categories. The literature published since the first HSA supports the initial conclusions, with new data refining quantitative exposure-response relationships for several health end points, particularly for extreme heat events and air pollution. The United States continues to have a very high capacity to plan for and respond to climate change, although relatively little progress has been noted in the literature on implementing adaptive strategies and measures. Large knowledge gaps remain, resulting in a substantial need for additional research to improve our understanding of how weather and climate, both directly and indirectly, can influence human health. Filling these knowledge gaps will help better define the potential health impacts of climate change and identify specific public health adaptations to increase resilience.