Surrogate Outcome Measures Research Articles

Combined Traumatic Brain Injury and Hemorrhagic Shock in Ferrets Leads to Structural, Neurochemical, and Functional Impairments.

Aeromedical evacuation-relevant hypobaria after traumatic brain injury (TBI) leads to increased neurological injury and death in rats relative to those maintained under normobaria. Applicability of rodent brain injury research to humans may be limited, however, by differences in neuroanatomy. Therefore, we developed a model in which ferrets are exposed to polytrauma consisting of controlled cortical impact TBI and hemorrhagic shock subjected 24 h later to 6 h of hypobaria or normobaria. Our objective was to determine whether the deleterious effects of hypobaria observed in rats, with lissencephalic brains, are also present in a species with a human-like gyrencephalic brain. While no deaths were observed, magnetic resonance spectroscopy (MRS) results obtained two days post-injury indicated reduced cortical creatine, N-acetylaspartate, gamma-aminobutyric acid, myo-inositol, and glutamate that were not affected by hypobaria. T2-weighted magnetic resonance imaging quantification revealed increased hyperintensity volume representing cortical edema at the site of impact after polytrauma. Hypobaria did not exacerbate this focal edema but did lead to overall reductions in total cortical volume. Both normobaric and hypobaric ferrets exhibited impaired spatial memory six days post-injury on the Object Location Test, but no differences were noted between groups. Finally, cortical lesion volume was not exacerbated by hypobaria exposure on day 7 post-injury. Results suggest that air travel 24 h after polytrauma is associated with structural changes in the ferret brain. Future studies should investigate secondary injury from hypobaria after polytrauma in greater detail including alternative outcome measures, time points, and exposure to multiple flights.

Full-field sensitivity threshold and the relation to the oxygen metabolic retinal function in retinitis pigmentosa.

The aim of our study was to evaluate retinal function with white light dark-adapted full-field sensitivity threshold (FST) and find possible correlations with metabolic function measured with retinal oximetry (RO) in patients with retinitis pigmentosa (RP). In this prospective observational study (BASEC 2020-00,122), FST and RO measurements were performed on 66 RP eyes (33 subjects, 12♀ 21♂) aged between 18 and 80years (mean 43.2years); all eyes were graded for disease severity. Main outcome parameters were white FST thresholds using the Diagnosys Espion system with the ColorDomeTM LED full-field stimulator (Diagnosys LLC, Lowell, MA) as well as the main RO parameters: the mean arterial (A-SO2; %), venular (V-SO2; %) oxygen saturation, their difference (A-V SO2; %), and the corresponding mean diameters of the peripapillary retinal arterioles (D-A; μm) and venules (D-V; μm) recorded with the oxygen saturation tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). In addition, semi-automated kinetic perimetry (V4e, III4e, I4e, III3e isopters, Octopus 900®, Haag-Streit AG Bern, Switzerland) was performed and included in the linear mixed-effects models analysis calculated with SPSS®. Neither the oxygen saturation parameters (p > 0.21) nor the D-A and D-V (p > 0.13) showed significant correlations with the FST. However, when compared systematically with the visual field (VF) areas of the different isopters, RO parameters V-SO2 (p = 0.024) and A-V SO2 (p < 0.02) showed significant correlations. Furthermore, both V-SO2 and A-V SO2 showed gradual changes with more pronounced impairment in oxygen metabolic function in advanced stages of RP when analyzed in subgroups of disease severity grades. In contrast to standardized VF parameters, white dark-adapted FST appears not to correlate with retinal oxygen metabolic function measured with RO in patients with RP, suggesting that the two examinations may capture unrelated aspects of the retinal pathological process. However, RO showed a significant association with standardized VF testing parameters and may, therefore, offer an alternative outcome measure for interventional trials.

Reliability and Validity of the Student Version of the Oldenburg Burnout Inventory in Physical Therapist Students

Introduction. Limited research exists on burnout in physical therapists (PTs) and PT students. The prevalence of PT student burnout is unknown and few outcome measures exist to study burnout in students. The purpose of this study was to assess the test–retest reliability and internal consistency of the Oldenburg Burnout Inventory for Students (OLBI-S) and convergent validity of the OLBI-S with the Maslach Burnout Inventory General Survey for Students (MBI-GSS) in Doctor of Physical Therapy (DPT) students. Review of Literature. Most authors studying burnout have used the MBI, which has been criticized in recent years. The OLBI was developed in response to the criticisms and psychometric limitations of the MBI. The OLBI-S has not yet been validated in PT students. Subjects. Participants included a convenience sample of DPT students attending Texas Woman's University in Houston during the fall semester of 2020. Methods. Students completed the OLBI-S and MBI-GSS and completed the OLBI-S a second time 1 week later. Intraclass correlation coefficients (ICCs) were calculated to examine test–retest reliability, Cronbach's α was calculated to assess internal consistency, and convergent validity was assessed by calculating Pearson's correlations comparing corresponding subscales for the OLBI-S and MBI-GSS. Results. Test–retest reliability was excellent for both the OLBI-S exhaustion subscale (ICC = .916, P &lt; .001) and the OLBI-S disengagement subscale (ICC = .955, P &lt; .001). Internal consistency was good for both the exhaustion subscale (Cronbach's α = .833) and the disengagement subscale (Cronbach's α = .784). Convergent validity was found to be good between the OLBI-S and MBI-GSS exhaustion subscales (r = .741, P &lt; .001) as well as the disengagement subscale of the OLBI-S and cynicism subscale of the MBI-GSS (r = .766, P &lt; .001). Discussion and Conclusion. The OLBI-S has excellent reliability, good validity, and is a free alternative outcome measure to the MBI-GSS to measure burnout in DPT students.

Circulating Collagen Metabolites and the Enhanced Liver Fibrosis (ELF) Score as Fibrosis Markers in Systemic Sclerosis.

Background: Serum fibrosis markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score is a collagen marker set consisting of procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). This longitudinal study aimed to examine the performance of the ELF score and its single analytes as surrogate outcome measures of fibrosis in SSc. Methods: Eighty-five SSc patients fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, HA, and the ELF score were measured and correlated with clinical variables including the modified Rodnan skin score (mRSS) and interstitial lung disease (ILD). Twenty SSc patients underwent a follow-up serological testing and mRSS evaluation during treatment with immunosuppressants and/or anti-fibrotic drugs. Results: Serum PIIINP, TIMP-1, and ELF score were significantly higher in patients with SSc than in healthy controls [PIIINP: 10.31 (7.83–14.10) vs. 5.61 (4.69–6.30), p < .001; TIMP-1: 110.73 (66.21–192.45) vs. 61.81 (48.86–85.24), p < .001; ELF: 10.34 (9.91–10.86) vs. 9.68 (9.38–9.99), p < .001]. Even higher levels of PIIINP, TIMP-1, and ELF score were found in patients with diffuse cutaneous SSc than those with limited cutaneous SSc. At baseline, both PIIINP and ELF score showed good correlation with mRSS (PIIINP: r = .586, p < .001; ELF: r = .482, p < .001). Longitudinal analysis showed that change in PIIINP positively correlated with change in mRSS (r = 0.701, p = .001), while change in ELF score were not related, in a statistical context, to the change in mRSS (ELF: r = .140, p = .555). Serum TIMP-1 was significantly higher in SSc patients with ILD, compared to the matched group of patients without ILD [109.45 (93.05–200.09) vs. 65.50 (40.57–110.73), p = 0.007]. Conclusion: In patients with SSc, the ELF score well correlates with the extent of skin fibrosis, while serum PIIINP is a sensitive marker for longitudinal changes of skin fibrosis. In the future, circulating collagen metabolites may potentially be used to evaluate therapeutic effects of anti-fibrotic treatments in the disease.

Five-year follow-up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE-AMI trial.

AimsThe long‐term outcomes of the intracoronary delivery of autologous bone marrow‐derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE‐AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo.Methods and resultsA 5 year follow‐up of major adverse cardiac events (defined as the composite of all‐cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC‐treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non‐cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group.ConclusionThis 5 year follow‐up analysis of the REGENERATE‐AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.

Development, implementation and evaluation of an evidence-based paediatric early warning system improvement programme: the PUMA mixed methods study

BackgroundPaediatric mortality rates in the United Kingdom are amongst the highest in Europe. Clinically missed deterioration is a contributory factor. Evidence to support any single intervention to address this problem is limited, but a cumulative body of research highlights the need for a systems approach.MethodsAn evidence-based, theoretically informed, paediatric early warning system improvement programme (PUMA Programme) was developed and implemented in two general hospitals (no onsite Paediatric Intensive Care Unit) and two tertiary hospitals (with onsite Paediatric Intensive Care Unit) in the United Kingdom. Designed to harness local expertise to implement contextually appropriate improvement initiatives, the PUMA Programme includes a propositional model of a paediatric early warning system, system assessment tools, guidance to support improvement initiatives and structured facilitation and support.Each hospital was evaluated using interrupted time series and qualitative case studies. The primary quantitative outcome was a composite metric (adverse events), representing the number of children monthly that experienced one of the following: mortality, cardiac arrest, respiratory arrest, unplanned admission to Paediatric Intensive Care Unit, or unplanned admission to Higher Dependency Unit. System changes were assessed qualitatively through observations of clinical practice and interviews with staff and parents. A qualitative evaluation of implementation processes was undertaken.ResultsAll sites assessed their paediatric early warning systems and identified areas for improvement. All made contextually appropriate system changes, despite implementation challenges. There was a decline in the adverse event rate trend in three sites; in one site where system wide changes were organisationally supported, the decline was significant (ß = -0.09 (95% CI: − 0.15, − 0.05); p = < 0.001). Changes in trends coincided with implementation of site-specific changes.ConclusionsSystem level change to improve paediatric early warning systems can bring about positive impacts on clinical outcomes, but in paediatric practice, where the patient population is smaller and clinical outcomes event rates are low, alternative outcome measures are required to support research and quality improvement beyond large specialist centres, and methodological work on rare events is indicated. With investment in the development of alternative outcome measures and methodologies, programmes like PUMA could improve mortality and morbidity in paediatrics and other patient populations.

Development, implementation and evaluation of an early warning system improvement programme for children in hospital: the PUMA mixed-methods study

Background The Paediatric early warning system Utilisation and Morbidity Avoidance (PUMA) study was commissioned to develop, implement and evaluate a paediatric track-and-trigger tool for widespread adoption. Following findings from three systematic reviews, revised aims focused on implementation of a whole-systems improvement programme. Objectives (1) Identify, through systematic review, the following: evidence for core components of effective paediatric track-and-trigger tools and paediatric early warning systems, and contextual factors consequential for paediatric track-and-trigger tool and early warning system effectiveness. (2) Develop and implement an evidence-based paediatric early warning system improvement programme (i.e. the PUMA programme). (3) Evaluate the effectiveness of the PUMA programme by examining clinical practice and core outcomes trends. (4) Identify ingredients of successful implementation of the PUMA programme. Review methods The quantitative reviews addressed the following two questions: how well validated are existing paediatric track-and-trigger tools and their component parts for predicting inpatient deterioration? How effective are paediatric early warning systems (with or without a tool) at reducing mortality and critical events? The qualitative review addressed the following question: what sociomaterial and contextual factors are associated with successful or unsuccessful paediatric early warning systems (with or without tools)? Design Interrupted time series and ethnographic case studies were used to evaluate the PUMA programme. Qualitative methods were deployed in a process evaluation. Setting The study was set in two district general and two tertiary children’s hospitals. Intervention The PUMA programme is a paediatric early warning system improvement programme designed to harness local expertise to implement contextually appropriate interventions. Main outcome measures The primary outcome was a composite metric, representing children who experienced one of the following in 1 month: mortality, cardiac arrest, respiratory arrest, unplanned admission to a paediatric intensive care unit or unplanned admission to a high-dependency unit. Paediatric early warning system changes were assessed through ethnographic ward case studies. Results The reviews showed limited effectiveness of paediatric track-and-trigger tools in isolation, and multiple failure points in paediatric early warning systems. All sites made paediatric early warning system changes; some of the clearer quantitative findings appeared to relate to qualitative observations. Systems changed in response to wider contextual factors. Limitations Low event rates made quantitative outcome measures challenging. Implementation was not a one-shot event, creating challenges for the interrupted time series in conceptualising ‘implementation’ and ‘post-intervention’ periods. Conclusions Detecting and acting on deterioration in the acute hospital setting requires a whole-systems approach. The PUMA programme offers a framework to support ongoing system-improvement work; the approach could be used more widely. Organisational-level system change can affect clinical outcomes positively. Alternative outcome measures are required for research and quality improvement. Future work The following further research is recommended: a consensus study to identify upstream indicators of paediatric early warning system performance; an evaluation of OUTCOME approach in other clinical areas; an evaluation of supernumerary nurse co-ordinator role; and an evaluation of mandated system improvement. Study registration This study is registered as PROSPERO CRD42015015326. Funding This project was funded by the National Institute for Health Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 1. See the NIHR Journals Library website for further project information.

UK Trainee Cardiothoracic Surgeons' Perceptions of Public Outcome Reporting in Surgery: A Mixed-Methods Study.

BackgroundSince 2004, the Society for Cardiothoracic Surgery in Great Britain and Ireland has reported outcomes of named surgeons. In 2013, the National Health Service England published outcome data for 10 specialties, including cardiothoracic surgery. Before this, no consistent and major stakeholder feedback had occurred. This is the first study to assess UK trainee cardiothoracic surgeons’ perceptions of public outcome reporting (POR) in surgery.MethodologyIn this study, first, an online survey was sent to all trainee cardiothoracic surgeons (n = 257) in the UK. The survey had a response rate of 17%. Second, 10 semi-structured, one-to-one interviews were conducted with trainee cardiothoracic surgeons who had completed the survey.ResultsThe majority of respondents opposed the public release of surgeon-specific mortality data in adult cardiac surgery. It is believed to be associated with several consequences, including risk aversion, ‘gaming’, and detriments to the training and development of surgeons. Despite this, the majority of respondents favoured the POR of alternative outcome measures, including unit mortality, which provides a better indicator for the overall quality of care provided to patients.ConclusionsTrainee cardiothoracic surgeons accept and approve of POR. However, policymakers should refine the current strategy if they are to receive full support from the future of the specialty.

Long-Term Cognitive Outcome following Aneurysmal Subarachnoid Haemorrhage

ObjectivesSurvivors of aneurysmal subarachnoid haemorrhage (aSAH) frequently suffer from cognitive dysfunction. The aim of this study was to assess, in a large sample size with long term follow-up, the characteristics of cognitive dysfunction following aSAH and explore whether cognitive deficits mediate employment outcome. Materials and methodsIn this retrospective case-controlled study, aSAH survivors (n = 884) were identified from the UK Biobank and compared to matched controls (n = 3536). Controls were propensity score matched according to age, sex, Townsend deprivation score, educational status and relevant medications known to influence cognition. Cognitive outcomes and employment status were compared between cases and controls using group comparison and cross-tabulation tests. A regression-based mediation analysis was performed to assess whether cognitive deficits mediate employment status following aSAH. ResultsPsychomotor reaction time and employment status significantly differed between aSAH cases and controls with slower reaction times (p < 0.001) and more unemployment or inability to work due to illness (p < 0.001) in the aSAH cohort at a mean follow-up of 125 months. Psychomotor slowing was estimated to mediate a significant proportion (6.59%) of the effect of aSAH on employment status. ConclusionsPsychomotor reaction time and employment status differed significantly between aSAH cases and control matched individuals in the UK Biobank. Psychomotor slowing following aSAH had a discernible impact on employment status. Psychomotor reaction time and employment status are practical to acquire and can be used as surrogate measures of outcome in future studies of aSAH survivors.

A randomised controlled trial evaluating two universal prevention programs for children: Building resilience to manage worry

BackgroundChildhood anxiety and depression lead to great distress and impairment. Preventing them simultaneously in early life is critically important. We evaluated the long-term efficacy of an emotion regulation-based (ER) and a behavioural activation-based (BA) program. Both aimed to build resilience to prevent worry, a transdiagnostic feature across anxiety and depression. MethodsParticipants were 316 students (52.2% female; 8–13 years) from six South Australian primary schools. Schools were randomised to the ER, BA or a control condition. Measures of resilience, worry, anxiety, and depression were taken at pre- and post- program, and at 6- and 12-month follow-up. In addition, levels of emotion regulation, behavioural activation and resilience were measured as potential mediators of changes in anxiety and depression. ResultsNo significant condition × time interactions were observed. However, the percentage of children who met the clinical cut-offs for generalised anxiety disorder and major depressive disorder decreased significantly in the BA condition at 12-month follow-up, as well as the percentage of children who met the clinical cut-off for obsessive compulsive disorder in the ER condition. Furthermore, emotion regulation mediated the relationship between condition and worry at post-program in the ER condition. LimitationsThe sample size is relatively small. Reliance on child self-report may have resulted in inaccurate responses. ConclusionThe ER and BA transdiagnostic prevention programs for childhood anxiety and depression showed promising results for certain anxiety disorders not otherwise observed in universal school-based studies. Future research should consider evaluating the programs with a larger sample using alternative outcome measures.

Role of S100B Serum Concentration as a Surrogate Outcome Parameter After Mechanical Thrombectomy.

Background and ObjectivesTo establish serum concentration of protein S100B as an objective biomarker surrogate for astroglial tissue damage after mechanical thrombectomy in patients with acute ischemic stroke.MethodsThis prospective 2-center study recruited patients with acute middle cerebral artery infarctions caused by large vessel occlusion treated with mechanical thrombectomy. Blood samples were collected at day 2 after intervention and analyzed for S100B serum concentrations using ELISA techniques. Infarct size was determined on follow-up brain imaging and functional outcome according to modified Rankin Scale (mRS) was assessed at 90 days.ResultsA total of 171 patients were included (mean age ± SD: 70 ± 14 years, 42% female). S100B levels correlated with infarct size. Median S100B concentrations at day 2 after intervention were lower in patients with favorable outcome (mRS score 0–1) at 90 days compared to patients with unfavorable outcome (mRS score 2–6) (median 0.10 µg/L [interquartile range 0.07–0.14] vs 0.20 µg/L [0.11–0.48], p < 0.001). Younger age (odds ratio [OR] 1.120 [confidence interval (CI) 1.068–1.174]; p < 0.001), lower National Institutes of Health Stroke Scale score 24 hours after symptom onset (OR 1.232 [CI 1.106–1.372]; p < 0.001), and lower S100B serum concentrations (OR 1.364 [CI 1.105–1.683]; p = 0.004) were independently associated with a favorable outcome. S100B was able to eliminate the lateralization bias associated with the use of mRS for functional outcome assessment at 90 days after stroke.DiscussionS100B serum concentrations after mechanical thrombectomy indicate the extent of ischemic tissue damage. This can be assessed rapidly, independent of brain imaging and clinical outcome scales. Following prospective validation in further studies, this may provide an objective surrogate outcome measure both in clinical routine and interventional trials.Classification of EvidenceThis study provides Class I evidence that S100B 2 days following mechanical thrombectomy for acute ischemic stroke accurately distinguishes favorable from unfavorable functional outcome.

Time in remission as an alternative outcome measure for rheumatoid arthritis: a 10-year prospective study of 2618 new users of anti-TNF.

Achieving targeted disease activity (DA) is the primary therapeutic strategy in RA. Point measurements of DA are done at out-patient visits, however true DA between visits remains unobserved. This study sought to describe and validate a new outcome measure, i.e. time in remission (TIR). Patients were enrolled in the Czech ATTRA-RA registry. TIR was calculated using linear interpolation of the DAS28-ESR determined at outpatient visits. Correlation coefficients were computed between TIR and DAS28-CRP, HAQ, Simple Disease Activity Index (SDAI), patient global assessment (PGA) and physician global assessment (PhGA). Using logistic regression, TIR was used as a predictor of remission (SDAI ≤3.3) and non-disability (HAQ <0.5). The predictive value of TIR was compared with point and sustained remission using the cross-validated area under receiver-operating curves. Since 2010, 2618 RA patients started anti-TNF therapy and were followed until 2020 or until treatment discontinuation. During the first 6 months of therapy, 56% of patients had no remission (TIR = 0), and 22% of patients reached sustained remission (TIR = 1), while 22% of patients had point remissions with 0 < TIR < 1. EULAR good responders and moderate/non-responders spent 64 ± 42% and 6 ± 18% of time in remission, respectively. The mean TIR grew during the follow-up and was correlated with DAS28-CRP, SDAI, HAQ, PGA, and PhGA (P < 0.0001). TIR at 3 and 6 months predicted remission (SDAI ≤3.3) and non-disability (HAQ <0.5) at 13 and 19 months better than point or sustained remission. TIR is an intuitive way of estimating unobserved DA between scheduled visits; its calculation only requires two consecutive DA values (https://www.medevio.cz/tir-calculator/). TIR is a valid predictor of RA outcomes.

A Systematic Review and Quantitative Analysis of Interteaching.

Interteaching is a behavioral teaching method that departs from the traditional lecture format (Boyce & Hineline in BA 25:215–226, 2002). We updated and expanded previous interteaching reviews and conducted a meta-analysis on its effectiveness. Systematic searches identified 38 relevant studies spanning the years 2005–2018. The majority of these studies were conducted in undergraduate face-to-face courses. The most common independent variables were manipulations of the configuration of interteaching or comparisons to traditional-lecture format. The most common dependent variables were quiz or examination scores. Only 24% of all studies implemented at least five of the seven components of interteaching. Prep guides, discussions, record sheets, and frequent assessments were the most commonly implemented. Meta-analyses indicated that interteaching is more effective than traditional lecture or other control conditions, with an overall large effect size. Furthermore, variations in the configuration of the interteaching components do not seem to substantially limit its effectiveness, as long as the discussion component is included. Future research informed by the present review includes: (a) investigating the efficacy of interteaching in additional academic areas, online environments, workplace training, and continuing education, (b) testing alternative outcome measures, generalization, and procedural integrity, (c) conducting systematic component analyses, and (d) measuring social validity from the instructor’s perspective.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10864-021-09452-3.

Merkel Cell Carcinoma: Changing Practice Patterns and Impact on Recurrence-Free and Overall Survival at a Single Institution and Nationally

BackgroundMerkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Our report describes the evolution of management and characteristics associated with recurrence, disease-specific survival (DSS) and overall survival (OS) in the treatment of MCC.MethodsA single institution retrospective review of MCC and SEER data to determine factors associated with RFS, DSS, and OS using a multivariable Cox regression on inverse-probability weighted cohorts.ResultsOne hundred fifty-nine patients were identified with a median age of 75. Of these, 96% were Caucasian and 60% male. Fifty-eight out of 159 (36%) of all patients were deceased with 21/58 (36%) dead from MCC with a median follow-up of 3.1 years. Institutionally, trends over time demonstrated an increased use of immunotherapy with a concomitant decrease in chemotherapy and decreased use of radiotherapy alone. Institutionally and nationally, there has been increased surgical nodal staging. Institutionally, factors associated with shorter DSS included advanced age, active cigarette smoker (p = 0.002), cT2 disease (p = 0.007), and MCC with unknown primary (p < 0.001). Institutionally, factors associated with shorter OS included ages ≥ 75 years (p < 0.001), an immunocompromised state (p < 0.001), truncal primary site (p = 0.002), and cT2 disease (HR 9.59, p < 0.001).ConclusionChanging practice patterns in MCC management have been driven by the adoption of immunotherapy. Our study highlights that competing risks of mortality in MCC patients likely prevents OS from being an accurate surrogate outcome measure to understand factors associated with DSS.

Automated Final Lesion Segmentation in Posterior Circulation Acute Ischemic Stroke Using Deep Learning.

Final lesion volume (FLV) is a surrogate outcome measure in anterior circulation stroke (ACS). In posterior circulation stroke (PCS), this relation is plausibly understudied due to a lack of methods that automatically quantify FLV. The applicability of deep learning approaches to PCS is limited due to its lower incidence compared to ACS. We evaluated strategies to develop a convolutional neural network (CNN) for PCS lesion segmentation by using image data from both ACS and PCS patients. We included follow-up non-contrast computed tomography scans of 1018 patients with ACS and 107 patients with PCS. To assess whether an ACS lesion segmentation generalizes to PCS, a CNN was trained on ACS data (ACS-CNN). Second, to evaluate the performance of only including PCS patients, a CNN was trained on PCS data. Third, to evaluate the performance when combining the datasets, a CNN was trained on both datasets. Finally, to evaluate the performance of transfer learning, the ACS-CNN was fine-tuned using PCS patients. The transfer learning strategy outperformed the other strategies in volume agreement with an intra-class correlation of 0.88 (95% CI: 0.83–0.92) vs. 0.55 to 0.83 and a lesion detection rate of 87% vs. 41–77 for the other strategies. Hence, transfer learning improved the FLV quantification and detection rate of PCS lesions compared to the other strategies.

Lee Silverman Voice Treatment versus standard speech and language therapy versus control in Parkinson\u2019s disease: preliminary cost-consequence analysis of the PD COMM pilot randomised controlled trial

BackgroundThe PD COMM pilot randomised controlled trial compared Lee Silverman Voice Treatment (LSVT® LOUD) with standard NHS speech and language therapy (SLT) and a control arm in people with Parkinson’s disease (PwPD) with self-reported problems with voice or speech. This analysis compares costs and quality of life outcomes between the trial arms, and considers the validity of the alternative outcome measures for economic evaluations.MethodsA comparison of costs and outcomes was undertaken alongside the PD COMM pilot trial involving three arms: LSVT® LOUD treatment (n = 30); standard NHS SLT (n = 30); and a control arm (n = 29) excluded from receiving therapy for at least 6 months after randomisation unless deemed medically necessary. For all trial arms, resource use and NHS, social care and patient costs and quality of life were collected prospectively at baseline, 3, 6, and 12 months. Total economic costs and outcomes (EQ-5D-3L, ICECAP-O) were considered over the 12-month follow-up period from an NHS payer perspective. Quality of life measures for economic evaluation of SLT for people with Parkinson’s disease were compared.ResultsWhilst there was no difference between arms in voice or quality of life outcomes at 12 months, there were indications of differences at 3 months in favour of SLT, which need to be confirmed in the main trial. The estimated mean cost of NHS care was £3288 per patient per year for the LSVT® LOUD arm, £2033 for NHS SLT, and £1788 for the control arm. EQ-5D-3L was more strongly correlated to voice impairment than ICECAP-O, and was sensitive to differences in voice impairment between arms.ConclusionsThe pilot did not identify an effect of SLT on disease-specific or economic outcomes for PwPD at 12 months; however, there appeared to be improvements at 3 months. In addition to the sample size not powered to detect difference in cost-consequence analysis, many patients in the control arm started SLT during the 12-month period used for economic analysis, in line with the study protocol. The LSVT® LOUD intervention was more intense and therefore more costly. Early indications suggest that the preferred economic outcome measure for the full trial is EQ-5D-3L; however, the ICECAP-O should still be included to capture a broader measure of wellbeing.Trial registrationInternational Standard Randomised Controlled Trial Number Register: ISRCTN75223808. Registered 22 March 2012.

Imaging in X-Linked Adrenoleukodystrophy

Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques-including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging-used in ALD and their role in clinical practice and research opportunities for the future.

Can UN Peacekeeping Promote Environmental Quality?

AbstractThis research focuses on a positive, and previously largely unknown, implication of United Nations (UN) peacekeeping: better environmental quality. While maintaining international peace and security remains the main goal of peacekeeping operations, we contend that they can also be linked to environmentally friendly outcomes. Mission mandates and UN policies increasingly comprise actions that potentially promote environmental quality. At the same time, positive side effects on the environment materialize due to the cooperation with and activities of other UN bodies. The empirical analyses, also correcting for the likely non-random assignment of peace missions and employing several alternative outcome measures, suggest that UN peace missions are indeed substantively associated with better environmental quality. This research has important implications for our understanding of peacekeeping operations, and it contributes to the literatures on the (unintended) consequences of peacekeeping as well as environmental politics.

Validating the clinical relevance of alternative stimulant use treatment outcome measures by examining their association with 3-month follow-up outcomes.

The lack of a consensus on empirically supported and clinically meaningful outcome measures for stimulant use disorders (SUDs) continues to undermine the development and evaluation of effective behavioral and pharmacological treatment options. The aim of this study was to evaluate the clinical relevance of four stimulant use treatment outcome measures (longest duration of abstinence [LDA], percent of negative urinalysis submitted, abstinent in the last 2 weeks of treatment, and three or more weeks of continuous abstinence) by exploring their utility via association with stimulant and alcohol use, employment and legal problems, and severity of psychiatric symptomatology collected at follow-up. Data used in these secondary analyses came from a multisite randomized contingency management treatment trial for SUDs (n = 441) conducted through the NIDA Clinical Trials Network. Multiple regression analyses were conducted to explore the association of four stimulant use treatment outcome measures and eight 3-month follow-up outcomes. The percent of negative urinalysis outcomes showed the most consistent performance compared to alternative outcomes, being significantly associated with better responses in all eight 3-month follow-up outcomes (β range: -169 to -241, p < .01). Both dichotomous outcome measures showed similar performances being significantly associated with four follow-up outcomes (β range: -159 to -203, p < .01). All outcome measures were consistently associated with better outcome responses at the 3-month follow-up, adding support to their clinical relevance and their adoption in SUD treatment trials. The two dichotomous outcome measures are reliable candidates to be used as endpoint outcomes, as recommended by the U.S. Food and Drug Administration (FDA). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Tampon Test as a Primary Outcome Measure in Provoked Vestibulodynia: A Mixed Methods Study

Provoked vestibulodynia (PVD) is characterized by severe pain, often induced by penetrative sex. This may lead to women abstaining from sexual intercourse, hence the recording of pain intensity levels in PVD research is often challenging. The standardized tampon test was designed as an alternative outcome measure to sexual intercourse pain and has frequently been used in clinical studies. The aim of this mixed methods study is to evaluate the tampon test as a primary outcome measure for an upcoming randomized clinical trial for women with PVD. An explanatory sequential design was applied, integrating quantitative and qualitative methods. In phase one, pain intensity levels were evaluated with the tampon test amongst 10 women, aged 18-33, with PVD. The test was repeated on day 1, 7 and 14. Pain intensity was rated on the Numerical Rating Scale (NRS), (0-10), 10 being worst possible pain. In phase two, the participants' experiences with the test were explored with semi-structured interviews using a descriptive and inductive qualitative design. All participants were recruited from the Vulva Clinic, Oslo University Hospital, Norway. The tampon test data and interviews were brought together to see how the interviews could refine and help to explain the quantitative findings. The tampon test data demonstrated large intra- and inter-individual variability. Median tampon pain intensity was 4.5 (min=1.7; max=10; Q1=2.5; Q3=6). Many experienced the test as an inadequate representation of pain during intercourse as it was less painful, different in nature and conducted in an entirely different context. Four participants had a mean score of four or lower on the NRS, whilst concurrently reporting high levels of pain during sexual intercourse. The findings indicate that the tampon test may underestimate severity of pain among some women with PVD. Participants with low pain scores would be excluded from studies where the tampon test is part of the trial eligibility criteria, even though severe pain was experienced during sexual intercourse. Large intra-individual variability in pain scores also reduces the test's ability to register clinical meaningful changes and hence necessitates repeated measurements per assessment time point. Although the tampon test has many advantages, this study indicates several potential problems with the application of the test as a primary outcome measure in PVD. In our opinion the test is most useful as a secondary outcome, preferably undertaken repeatedly in order to increase precision of the pain estimation.