Low-Cost, Compact Quadrupole Mass Filters with Unity Mass Resolution via Ceramic Resin Vat Photopolymerization.

This study reports novel, compact, and additively manufactured quadrupole mass filters (QMFs) with adequate filtering performance for practical mass spectrometry applications. The QMFs are monolithically fabricated via vat photopolymerization of glass-ceramic resin using 57 µm × 57 µm × 100 µm voxels, and selective electroless plating of nickel-boron. Experimental characterization of QMF prototypes at 1.74 MHz using FC-43 yields 131 Da peaks with 0.50 Da full width at half maximum (260 resolution), surpassing the resolution of reported miniaturized counterparts under similar conditions, and being on par with commercial, non-miniaturized, heavier devices. The sensitivity of the 3D-printed devices is estimated at 0.13 mA Torr-1 (comparable to that of optimized, commercial counterparts), while the devices attained up to 250 Da of mass range (limited by the driving electronics). The work is of interest to low-cost, capable mass spectrometry, 3D-printed instruments, and in-space manufacturing of complex instrumentation.

Racial, Ethnic, and Language-Based Inequities in Inpatient Opioid Prescribing by Diagnosis from Internal Medicine Services, a Retrospective Cohort Study.

Introduction: Opioid administration is extremely common in the inpatient setting, yet we do not know how the administration of opioids varies across different medical conditions and patient characteristics on internal medicine services. Our goal was to assess racial, ethnic, and language-based inequities in opioid prescribing practices for patients admitted to internal medicine services. Methods: We conducted a retrospective cohort study of all adult patients admitted to internal medicine services from 2013 to 2021 and identified subcohorts of patients treated for the six most frequent primary hospital conditions (pneumonia, sepsis, cellulitis, gastrointestinal bleed, pyelonephritis/urinary tract infection, and respiratory disease) and three select conditions typically associated with pain (abdominal pain, acute back pain, and pancreatitis). We conducted a negative binomial regression analysis to determine how average administered daily opioids, measured as morphine milligram equivalents (MMEs), were associated with race, ethnicity, and language, while adjusting for additional patient demographics, hospitalization characteristics, medical comorbidities, prior opioid therapy, and substance use disorders. Results: The study cohort included 61,831 patient hospitalizations. In adjusted models, we found that patients with limited English proficiency received significantly fewer opioids (66 MMEs, 95% CI: 52, 80) compared to English-speaking patients (101 MMEs, 95% CI: 91, 111). Asian (59 MMEs, 95% CI: 51, 66), Latinx (89 MMEs, 95% CI: 79, 100), and multi-race/ethnicity patients (81 MMEs, 95% CI: 65, 97) received significantly fewer opioids compared to white patients (103 MMEs, 95% CI: 94, 112). American Indian/Alaska Native (227 MMEs, 95% CI: 110, 344) patients received significantly more opioids. Significant inequities were also identified across race, ethnicity, and language groups when analyses were conducted within the subcohorts. Most notably, Asian and Latinx patients received significantly fewer MMEs and American Indian/Alaska Native patients received significantly more MMEs compared to white patients for the top six most frequent conditions. Most patients from minority groups also received fewer MMEs compared to white patients for three select pain conditions. Discussion. There are notable inequities in opioid prescribing based on patient race, ethnicity, and language status for those admitted to inpatient internal medicine services across all conditions and in the subcohorts of the six most frequent hospital conditions and three pain-associated conditions. This represents an institutional and societal opportunity for quality improvement initiatives to promote equitable pain management.

Opioid and High-Risk Prescribing Among Racial and Ethnic Minority Veterans.

INTRODUCTION: The purpose of this study is to compare opioid prescribing and high-risk prescribing by race and ethnicity in a national cohort of U.S. veterans. METHODS: A cross-sectional analysis of veteran characteristics and healthcare use was performed on electronic health record data for 2018 Veterans Health Administration users and enrollees in 2022. RESULTS: Overall, 14.8% received an opioid prescription. The adjusted odds of being prescribed an opioid were lower for all race/ethnicity groups than for non-Hispanic White veterans, except for non-Hispanic multiracial (AOR=1.03; 95% CI=0.999, 1.05) and non-Hispanic American Indian/Alaska Native (AOR=1.06; 95% CI=1.03, 1.09) veterans. The odds of any day of overlapping opioid prescriptions (i.e., opioid overlap) were lower for all race/ethnicity groups than for the non-Hispanic White group, except for the non-Hispanic American Indian/Alaska Native group (AOR=1.01; 95% CI=0.96, 1.07). Similarly, all race/ethnicity groups had lower odds of any day of daily dose >120 morphine milligram equivalents than the non-Hispanic White group, except for the non-Hispanic multiracial (AOR=0.96; 95% CI=0.87, 1.07) and non-Hispanic American Indian/Alaska Native (AOR=1.06; 95% CI=0.96, 1.17) groups. Non-Hispanic Asian veterans had the lowest odds for any day of opioid overlap (AOR=0.54; 95% CI=0.50, 0.57) and daily dose >120 morphine milligram equivalents (AOR=0.43; 95% CI=0.36, 0.52). For any day of opioid-benzodiazepine overlap, all races/ethnicities had lower odds than non-Hispanic White. Non-Hispanic Black/African American (AOR=0.71; 95% CI=0.70, 0.72) and non-Hispanic Asian (AOR=0.73; 95% CI=0.68, 0.77) veterans had the lowest odds of any day of opioid-benzodiazepine overlap. CONCLUSIONS: Non-Hispanic White and non-Hispanic American Indian/Alaska Native veterans had the greatest likelihood to receive an opioid prescription. When an opioid was prescribed, high-risk prescribing was more common in White and American Indian/Alaska Native veterans than in all other racial/ethnic groups. As the nation's largest integrated healthcare system, the Veterans Health Administration can develop and test interventions to achieve health equity for patients experiencing pain.

Comprehensive assessment of anaplastic lymphoma kinase in localized and metastatic prostate cancer reveals targetable alterations.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is first line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by immunohistochemistry and RNA-Seq, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacological ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5/52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacological ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Further, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.

The Companion Pandemic to COVID-19: The Use of Informal Practices to Access Public Healthcare Services in the European Union.

Objectives: The objective of this paper is to evaluate the use of informal payments and personal connections to gain preferential access to public health services during the COVID-19 pandemic and to propose effective policy measures for tackling this phenomenon. Methods: Using data from 25,744 patients in the European Union, six different scenarios are analyzed in relation to making informal payments and/or relying on personal connections to access public healthcare services. To evaluate the propensity to engage in informal practices in healthcare, probit regressions with sample selection and predicted probabilities are used. Robustness checks are also performed to test the reliability of the findings. Results: For each scenario, a statistically significant association is revealed between the propensity to make informal payments and/or rely on personal connections and the asymmetry between the formal rules and the patients' personal norms and trust in public authorities. Conclusion: To tackle informal practices in healthcare, policy measures are required to reduce the asymmetry between the formal rules and personal norms by raising trust in public authorities.

Who Purchases From the Informal Economy and Why?

In recent decades scholars have acknowledged that transactions in the informal economy have not vanished with modernization and industrialization as expected but rather remain an important contemporary aspect of overall production and consumption across the world, in both developing and developed countries. Yet little is known about the profile of the consumers in this realm or what drives them to purchase from the informal economy. A systematic review of the literature investigating consumption in the informal economy reveals a severely underdeveloped area of consumer studies with significant gaps in terms of its theoretical approaches, methods and regional coverage. The findings of the existing literature is that multiple motives are used by consumers for justifying their purchases in the informal economy beyond the dominant simplistic view that they do simply for financial gain or for a lower price (namely, it identifies social ends and failures in formal market provision in terms of availability, speed of provision and quality). The outcome is a recognition that responsibility to reducing this phenomenon with negative effects on governments, businesses, workers and consumers lies not just with public authorities but also practitioners who need to correct the failures in formal market provision. The significant gaps identified in the literature are then used to highlight a comprehensive future research agenda, which includes the need for the development of an institutionalist theoretical perspective when explaining consumers' participation in the informal economy and social marketing interventions.

The association between physical health-related quality of life, physical functioning, and risk of contralateral breast cancer among older women.

BACKGROUND: Physical limitations prior to cancer diagnosis may lead to suboptimal health outcomes. Our objective was to evaluate the impacts of poor physical health-related quality of life (HRQOL) and physical functioning (PF) on the risk of contralateral breast cancer (CBC). METHODS: We performed a nested case-control study of women with invasive unilateral breast cancer (UBC) who did not receive prophylactic contralateral mastectomy using the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey data resource. Among 2938 women aged ≥ 65 years diagnosed with first stage I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 matched controls without CBC using incidence density sampling without replacement. Pre-diagnosis physical HRQOL and PF were determined using Medical Outcomes Trust Short Form-36 (SF-36)/Veterans Rand 12-Item Health Survey (VR-12) responses within 2 years prior to first UBC diagnosis. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. RESULTS: Cases and controls were similar with respect to comorbidities, stage, surgery, and radiation treatments, but differed by hormone receptor status (ER/PR-negative, 23% and 11%, respectively) of first UBC. Cases had modestly lower mean pre-diagnosis physical HRQOL (- 1.8) and PF (- 2.2) scores. In multivariable models, we observed an increased CBC risk associated with low physical HRQOL (lowest vs. highest quartile, OR = 1.8; 95% CI 0.8-4.3), but CIs included 1.0. Low PF was associated with a 2.7-fold (95% CI 1.1-6.7) increased CBC risk. CONCLUSIONS: Findings indicate that low physical HRQOL, specifically poor PF, is associated with CBC risk. Efforts to understand and minimize declines in PF post-breast cancer are well motivated.

Institutional Determinants of Informal Payments for Health Services: An Exploratory Analysis across 117 Countries.

Healthcare accessibility and equity remain important issues, as corruption in the form of informal payments is still prevalent in many countries across the world. This study employs a panel data analysis over the 2006-2013 period to explore the role of different institutional factors in explaining the prevalence of informal payments. Covering 117 countries, our findings confirm the significant role of both formal and informal institutions. Good governance, a higher trust among individuals, and a higher commitment to tackling corruption are associated with diminishing informal payments. In addition, higher shares of private finance, such as out-of-pocket and domestic private health expenditure, are also correlated with a lower prevalence of informal payments. In policy terms, this displays how correcting institutional imperfections may be among the most efficient ways to tackle informal payments in healthcare.

Informal Payments by Patients in Central and Eastern Europe during the COVID-19 Pandemic: An Institutional Perspective.

Confronted with a global pandemic, public healthcare systems are under pressure, making access to healthcare services difficult for patients. This provides fertile ground for using illegal practices such as informal payments to gain access. This paper aims to evaluate the use of informal payments by patients during the COVID-19 pandemic and the institutions that affect the prevalence of this practice. Various measurements of formal and informal institutions are here investigated, namely the acceptability of corruption, the level of trust, transparency, and performance of the healthcare system. To do so, a logistic regression of 10,859 interviews with patients conducted across 11 Central and Eastern Europe countries in October-December 2020 is employed. The finding is that there are large disparities between countries in the prevalence of informal payments, and that the practice is more likely to occur where there are poorer formal and informal institutions, namely higher acceptability of corruption, lower trust in authorities, lower perceived transparency in handling the COVID-19 pandemic, difficult access to, and poor quality of, healthcare services, and higher mortality rates due to the COVID-19 pandemic. These findings suggest that policy measures for tackling informal payments need to address the current state of the institutional environment.

Population-based recurrence rates among older women with HR-positive, HER2-negative early breast cancer: Clinical risk factors, frailty status, and differences by race.

BACKGROUND: Multiple independent risk factors are associated with the prognosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), the most common BC subtype. This study describes U.S. population-based recurrence rates among older, resected women with HR+/HER2- early BC. METHODS: We conducted a retrospective cohort study of older women diagnosed with incident, invasive stages I-III HR+/HER2- BC who underwent surgery to remove the primary tumor using the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked Database (2007-2015). SEER records and administrative health claims data were used to ascertain patient and tumor-specific characteristics, treatment, and frailty status. Cumulative incidences of BC recurrence were estimated using a validated algorithm for administrative claims data. Multivariable Fine-Gray competing risk models estimated adjusted subdistribution hazards ratios and 95 % confidence intervals for associations with BC recurrence risk. RESULTS: Overall, 46,027 women age ≥65 years were included in our analysis. Over a median follow up of 7 years, 6531 women experienced BC recurrence with an estimated 3 and 5-year cumulative incidence rates of 10 % and 16 %, respectively. Higher 3- and 5-year cumulative incidences were observed in women with larger tumor size (5+ cm, 21 % and 28 %), lymph node involvement (4+ nodes, 27 % and 37 %), and with frail health status at diagnosis (13 % and 20 %). Independent of these clinical risk factors, Black, Hispanic and American Indian/Alaskan Native women had significantly increased BC recurrence risks. CONCLUSIONS: Rates of recurrence in HR+/HER2- early BC differs by several patient and clinical factors, including high-risk tumor characteristics. Racial differences in BC outcomes deserve continued attention from clinicians and policymakers.

Echocardiographic assessment of left ventricular size and systolic function in Warmblood horses using linear measurements, area-based indices, and volume estimates: A retrospective database analysis.

BACKGROUND: Echocardiographic assessment of left ventricular (LV) size and function using area-based indices and volumetric estimates is not well established in horses. OBJECTIVE: To report reference intervals and measurement variability for uni-, 2-, and 3-dimensional echocardiographic indices of LV size and systolic function in Warmblood horses and to provide proof of concept for allometric scaling of variables to body weight. Unidimensional indices were to be compared to area-based indices and LV volume estimates to establish their clinical use. ANIMALS: Thirty healthy Warmblood horses and 70 Warmblood horses with a primary diagnosis of mitral regurgitation or aortic regurgitation. METHODS: Echocardiographic indices of LV size and systolic function were measured using an existing echocardiography database. Weight-related variables were scaled to body weight (BWT). Reference intervals and measurement variability were calculated, the influence of valvular regurgitation on LV size and function was investigated and agreement between different variables for detection of reduced, normal, and increased LV size and systolic function was assessed. RESULTS: Reference values for healthy Warmblood horses were reported. Measurement variability was sufficiently low for clinical use of all variables. Allometric scaling was effective to correct diastolic LV dimensions and cardiac output for differences in BWT. Various echocardiographic indices resulted in different conclusions regarding identification of LV enlargement and systolic dysfunction in healthy horses and horses with valvular regurgitation. CONCLUSIONS AND CLINICAL IMPORTANCE: Echocardiographic assessment of LV size and systolic function should include joint assessment of multiple uni- and multidimensional indices. Area-based or volumetric indices that reflect LV long-axis motion should be included.

Patients' productivity losses and informal care costs related to ischemic stroke: a French population-based study.

BACKGROUND AND PURPOSE: Large societal costs of stroke should not be ignored. We aimed to estimate patients' productivity losses and informal care costs during the first year after ischemic stroke. METHODS: A cross-sectional survey was performed within the STROKE69 regional population-based cohort study. At 1 year post-stroke, each patient and the corresponding main informal caregiver received questionnaires followed by a telephone interview if necessary. Time losses were valued using the human capital approach and proxy good method for patients with and without a professional activity, respectively. RESULTS: Among the 222 patients with ischemic stroke (58% men; mean age 68 years; and 86% with a modified Rankin Scale (mRS) score of <3 at 3 months), 54%, 32%, and 25% received informal, formal, and both cares, respectively. Among the 108 main informal caregivers, 63% were women, 74% lived with the patient, and 57% were retired or unemployed. The mean cost of productivity losses was estimated at €7589 ± €12 305 per patient in the first post-stroke year with 5.4%, 71.2%, and 23.4% of these being attributed to presenteeism, absenteeism, and leisure time, respectively. Informal care was given at an average of 25 h/week. The annual mean estimated total cost of informal care was €10 635 per caregiver. CONCLUSIONS: Informal care and productivity losses of patients with ischemic stroke during the first post-stroke year represent a significant economic burden for society comparable to direct costs. These costs should be included in economic evaluations with the adoption of a societal perspective to avoid underestimating the societal stroke economic burden.

Assessment of active tubulointerstitial nephritis in non-scarred renal cortex improves prediction of renal outcomes in patients with IgA nephropathy.

BACKGROUND: The addition of tubulointerstitial inflammation to the existing pathological classification of IgA nephropathy (IgAN) is appealing but was previously precluded due to reportedly wide inter-observer variability. We report a novel method to score percentage of non-atrophic renal cortex containing active tubulointerstitial inflammation (ATIN) in patients with IgAN and assess its utility to predict clinical outcomes. METHODS: All adult patients with a native renal biopsy diagnosis of IgAN between 2010 and 2015 in a unit serving 1.5 million people were identified. Baseline characteristics, biopsy reports and outcome data were collected. ATIN was calculated by subtracting the percentage of atrophic cortex from the percentage of total cortex with tubulointerstitial inflammation, with ≥10% representing significant ATIN. The primary outcome was a composite of requiring renal replacement therapy or doubling of serum creatinine. RESULTS: In total 153 new cases of IgAN were identified, of which 111 were eligible for inclusion. Of these, 76 (68%) were male and 54 (49%) had ATIN on biopsy. During a median follow-up of 2.3 years, 34 (31%) reached the primary outcome. On univariable Cox regression analysis, ATIN was associated with a five-fold increase in the primary outcome [hazard ratio (HR) (95% confidence interval) 4.9 (95% confidence interval (CI) 2.1-11.3)]. On multivariable analysis, mesangial hypercellularity, tubular atrophy and interstitial fibrosis and ATIN independently associated with renal outcome (P = 0.02 for ATIN). Inter-observer reproducibility revealed fair agreement in the diagnosis of ATIN (κ=0.43, P = 0.05). CONCLUSIONS: Within our centre, ATIN was significantly associated with renal outcome in patients with IgAN, independently of established histological features and baseline clinical characteristics.

Clinical determinants for successful circulating tumor DNA analysis in prostate cancer.

BACKGROUND: Plasma-based cell-free DNA is an attractive biospecimen for assessing somatic mutations due to minimally-invasive real-time sampling. However, next generation sequencing (NGS) of cell-free DNA (cfDNA) may not be appropriate for all patients with advanced prostate cancer (PC). METHODS: Blood was obtained from advanced PC patients for plasma-based sequencing. UW-OncoPlex, a ∼2 Mb multi-gene NGS panel performed in the CLIA/CAP environment, was optimized for detecting cfDNA mutations. Tumor tissue and germline samples were sequenced for comparative analyses. Multivariate logistic regression was performed to determine the clinical characteristic associated with the successful detection of somatic cfDNA alterations (ie detection of at least one clearly somatic PC mutation). RESULTS: Plasma for cfDNA sequencing was obtained from 93 PC patients along with tumor tissue (N = 67) and germline (N = 93) controls. We included data from 76 patients (72 prostate adenocarcinoma; 4 variant histology PC) in the analysis. Somatic DNA aberrations were detected in 34 cfDNA samples from patients with prostate adenocarcinoma. High PSA level, high tumor volume, and castration-resistance were significantly associated with successful detection of somatic cfDNA alterations. Among samples with somatic mutations detected, the cfDNA assay detected 93/102 (91%) alterations found in tumor tissue, yielding a clustering-corrected sensitivity of 92% (95% confidence interval 88-97%). All germline pathogenic variants present in lymphocyte DNA were also detected in cfDNA (N = 12). Somatic mutations from cfDNA were detected in 30/33 (93%) instances when PSA was >10 ng/mL. CONCLUSIONS: Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens.

Health policy for telestroke in France: A retrospective description from 2003 to 2016.

INTRODUCTION: Stroke is a public health priority in France. The use of telemedicine for stroke known as telestroke, is a safe and effective practice improving access to acute stroke care including thrombolysis. Telestroke is currently being implemented in France. The objective was to describe the public health policy supporting telestroke implementation in France. METHODS: An external ex-post evaluation of telestroke policy in France was conducted through a retrospective descriptive study from 2003 to 31st December 2016. Process, content, and actors of the health policy were described at a national level. The logical framework of the telestroke policy was described. The stages model of public policy from the 'Institut National de Santé Publique du Quebec' was used. RESULTS: Agenda setting was produced from 2003 to 2007. Policy formulation lasted from 2008 to 2009 with official reports on telemedicine, telehealth and stroke. The decision-making stage included the national stroke plan, the national telemedicine implementation strategy and an administrative document in 2012 that described the organization of telestroke implementation. Implementation in 2011 was initiated with dedicated funding and methodological resources. No dedicated evaluation of policy for telestroke was defined. CONCLUSIONS: Using a health policy model allowed to describe the policies supporting telestroke implementation in France and to highlight the need for better evaluation.

Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT.

BACKGROUND: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. OBJECTIVES: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. DESIGN: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. SETTING: UK outpatient rheumatology departments. PARTICIPANTS: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. INTERVENTIONS: Alternative TNFi, abatacept or rituximab (and continued background MTX). MAIN OUTCOME MEASURES: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. LIMITATIONS: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. RESULTS: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. FUTURE WORK: The results will add to the randomised evidence base and could be included in future meta-analyses. CONCLUSIONS: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. 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. 22, No. 34. See the NIHR Journals Library website for further project information.

Amaze: a randomized controlled trial of adjunct surgery for atrial fibrillation.

OBJECTIVES: Atrial fibrillation (AF) reduces survival and quality of life (QoL). It can be treated at the time of major cardiac surgery using ablation procedures ranging from simple pulmonary vein isolation to a full maze procedure. The aim of this study is to evaluate the impact of adjunct AF surgery as currently performed on sinus rhythm (SR) restoration, survival, QoL and cost-effectiveness. METHODS: In a multicentre, Phase III, pragmatic, double-blinded, parallel-armed randomized controlled trial, 352 cardiac surgery patients with >3 months of documented AF were randomized to surgery with or without adjunct maze or similar AF ablation between 2009 and 2014. Primary outcomes were SR restoration at 1 year and quality-adjusted life years at 2 years. Secondary outcomes included SR at 2 years, overall and stroke-free survival, medication, QoL, cost-effectiveness and safety. RESULTS: More ablation patients were in SR at 1 year [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.20-3.54; P = 0.009]. At 2 years, the OR increased to 3.24 (95% CI 1.76-5.96). Quality-adjusted life years were similar at 2 years (ablation - control -0.025, P = 0.6319). Significantly fewer ablation patients were anticoagulated from 6 months postoperatively. Stroke rates were 5.7% (ablation) and 9.1% (control) (P = 0.3083). There was no significant difference in stroke-free survival [hazard ratio (HR) = 0.99, 95% CI 0.64-1.53; P = 0.949] nor in serious adverse events, operative or overall survival, cardioversion, pacemaker implantation, New York Heart Association, EQ-5D-3L and SF-36. The mean additional ablation cost per patient was £3533 (95% CI £1321-£5746). Cost-effectiveness was not demonstrated at 2 years. CONCLUSIONS: Adjunct AF surgery is safe and increases SR restoration and costs but not survival or QoL up to 2 years. A continued follow-up will provide information on these outcomes in the longer term. Study registration: ISRCTN82731440 (project number 07/01/34).

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer.

Importance: Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. Objective: To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS. Design, Setting, and Participants: Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS. Main Outcomes and Measures: Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS. Results: In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection. Conclusions and Relevance: Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

Rethinking informal payments by patients in Europe: An institutional approach.

The aim of this paper is to explain informal payments by patients to healthcare professionals for the first time through the lens of institutional theory as arising when there are formal institutional imperfections and asymmetry between norms, values and practices and the codified formal laws and regulations. Reporting a 2013 Eurobarometer survey of the prevalence of informal payments by patients in 28 European countries, a strong association is revealed between the degree to which formal and informal institutions are unaligned and the propensity to make informal payments. The association between informal payments and formal institutional imperfections is then explored to evaluate which structural conditions might reduce this institutional asymmetry, and thus the propensity to make informal payments. The paper concludes by exploring the implications for tackling such informal practices.