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Abstract: Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.

Abstract Background There is a worldwide shortage of organs available for transplant, leading to preventable mortality associated with end-stage organ disease. While most citizens in many countries with an intent-to-donate “opt-in” system support organ donation, registration rates remain low. In Canada, most Canadians support organ donation but less than 25% in most provinces have registered their desire to donate their organs when they die. The family physician office is a promising yet underused setting in which to promote organ donor registration and address known barriers and enablers to registering for deceased organ and tissue donation. We developed a protocol to evaluate an intervention to promote registration for organ and tissue donation in family physician waiting rooms. Methods/design This protocol describes a planned, stepped-wedge, cluster randomized registry trial in six family physician offices in Ontario, Canada to evaluate the effectiveness of reception staff providing patients with a pamphlet that addresses barriers and enablers to registration including a description of how to register for organ donation. An Internet-enabled tablet will also be provided in waiting rooms so that interested patients can register while waiting for their appointments. Family physicians and reception staff will be provided with training and/or materials to support any conversations about organ donation with their patients. Following a 2-week control period, the six offices will cross sequentially into the intervention arm in randomized sequence at 2-week intervals until all offices deliver the intervention. The primary outcome will be the proportion of patients visiting the office who are registered organ donors 7 days following their office visit. We will evaluate this outcome using routinely collected registry data from provincial administrative databases. A post-trial qualitative evaluation process will assess the experiences of reception staff and family physicians with the intervention and the stepped-wedge trial design. Discussion Promoting registration for organ donation in family physician offices is a potentially useful strategy for increasing registration for organ donation. Increased registration may ultimately help to increase the number of organs available for transplant. The results of this trial will provide important preliminary data on the effectiveness of using family physician offices to promote registration for organ donation. Trial registration ClinicalTrials.gov, ID: NCT03213171 . Registered on 11 July 2017.

Background: Associations between long-term exposure to air pollution and road traffic noise have been established for ischemic heart disease, but findings have been mixed for atrial fibrillation (AF). Objectives: The goal of the study was to examine associations of long-term exposure to road traffic noise and air pollution with AF. Methods: Time-varying Cox regression models were used to estimate associations of 1-, 3-, and 23-y mean road traffic noise and air pollution exposures with AF incidence in 23,528 women enrolled in the Danish Nurse Cohort (age >44 y at baseline in 1993 or 1999). AF diagnoses were ascertained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels ([L.sub.den]) at the nurses' residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter Results: Of 23,528 nurses with no prior AF diagnosis at the cohort baseline, 1,522 developed AF during follow-up. In a fully adjusted model (including [PM.sub.2.5]), the estimated risk of AF was 18% higher [hazard ratio (HR); 95% confidence interval (CI): 1.18; 1.02, 1.36] in nurses with residential 3-y mean [L.sub.den] levels >58dB vs. Conclusion: Our analysis of prospective data from a cohort of Danish female nurses followed for up to 14 y provided suggestive evidence of independent associations between incident AF and 1- and 3-y exposures to road traffic noise and [PM.sub.2.5]. https://doi.org/10.1289/EHP8090, Introduction Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, characterized by abnormal electrophysiology of the heart's atria (Kirchhof et al. 2016). AF increases the risk of stroke, [...]

Abstract Background A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an ‘ultra-low’ dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions. Methods/Design REDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 × 500 or 1 × 200 mg) compared to standard low dose (1 × 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP

Abstract Background Guidelines for assessing methodological and reporting quality of systematic reviews (SRs) were developed to contribute to implementing evidence-based health care and the reduction of research waste. As SRs assessing a cohort of SRs is becoming more prevalent in the literature and with the increased uptake of SR evidence for decision-making, methodological quality and standard of reporting of SRs is of interest. The objective of this study is to evaluate SR adherence to the Quality of Reporting of Meta-analyses (QUOROM) and PRISMA reporting guidelines and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Overview Quality Assessment Questionnaire (OQAQ) quality assessment tools as evaluated in methodological overviews. Methods The Cochrane Library, MEDLINE®, and EMBASE® databases were searched from January 1990 to October 2014. Title and abstract screening and full-text screening were conducted independently by two reviewers. Reports assessing the quality or reporting of a cohort of SRs of interventions using PRISMA, QUOROM, OQAQ, or AMSTAR were included. All results are reported as frequencies and percentages of reports and SRs respectively. Results Of the 20,765 independent records retrieved from electronic searching, 1189 reports were reviewed for eligibility at full text, of which 56 reports (5371 SRs in total) evaluating the PRISMA, QUOROM, AMSTAR, and/or OQAQ tools were included. Notable items include the following: of the SRs using PRISMA, over 85% (1532/1741) provided a rationale for the review and less than 6% (102/1741) provided protocol information. For reports using QUOROM, only 9% (40/449) of SRs provided a trial flow diagram. However, 90% (402/449) described the explicit clinical problem and review rationale in the introduction section. Of reports using AMSTAR, 30% (534/1794) used duplicate study selection and data extraction. Conversely, 80% (1439/1794) of SRs provided study characteristics of included studies. In terms of OQAQ, 37% (499/1367) of the SRs assessed risk of bias (validity) in the included studies, while 80% (1112/1387) reported the criteria for study selection. Conclusions Although reporting guidelines and quality assessment tools exist, reporting and methodological quality of SRs are inconsistent. Mechanisms to improve adherence to established reporting guidelines and methodological assessment tools are needed to improve the quality of SRs.

Abstract Background The methodological quality and completeness of reporting of the systematic reviews (SRs) is fundamental to optimal implementation of evidence-based health care and the reduction of research waste. Methods exist to appraise SRs yet little is known about how they are used in SRs or where there are potential gaps in research best-practice guidance materials. The aims of this study are to identify reports assessing the methodological quality (MQ) and/or reporting quality (RQ) of a cohort of SRs and to assess their number, general characteristics, and approaches to ‘quality’ assessment over time. Methods The Cochrane Library, MEDLINE®, and EMBASE® were searched from January 1990 to October 16, 2014, for reports assessing MQ and/or RQ of SRs. Title, abstract, and full-text screening of all reports were conducted independently by two reviewers. Reports assessing the MQ and/or RQ of a cohort of ten or more SRs of interventions were included. All results are reported as frequencies and percentages of reports. Results Of 20,765 unique records retrieved, 1189 of them were reviewed for full-text review, of which 76 reports were included. Eight previously published approaches to assessing MQ or reporting guidelines used as proxy to assess RQ were used in 80% (61/76) of identified reports. These included two reporting guidelines (PRISMA and QUOROM) and five quality assessment tools (AMSTAR, R-AMSTAR, OQAQ, Mulrow, Sacks) and GRADE criteria. The remaining 24% (18/76) of reports developed their own criteria. PRISMA, OQAQ, and AMSTAR were the most commonly used published tools to assess MQ or RQ. In conjunction with other approaches, published tools were used in 29% (22/76) of reports, with 36% (8/22) assessing adherence to both PRISMA and AMSTAR criteria and 26% (6/22) using QUOROM and OQAQ. Conclusions The methods used to assess quality of SRs are diverse, and none has become universally accepted. The most commonly used quality assessment tools are AMSTAR, OQAQ, and PRISMA. As new tools and guidelines are developed to improve both the MQ and RQ of SRs, authors of methodological studies are encouraged to put thoughtful consideration into the use of appropriate tools to assess quality and reporting.

Abstract Background Accessibility and availability are important characteristics of efficient and effective primary healthcare systems. Currently, timely access to a family physician is a concern in Canada. Adverse outcomes are associated with longer wait times for primary care appointments and often leave individuals to rely on urgent care. When wait times for appointments are too long patients may experience worse health outcomes and are often left to use emergency department resources. The primary objective of our study was to systematically review the literature to identify interventions designed to reduce wait times for primary care appointments. Secondary objectives were to assess patient satisfaction and reduction of no-show rates. Methods We searched multiple databases, including: Medline via Ovid SP (1947 to present), Embase (from 1980 to present), PsychINFO (from 1806 to present), Cochrane Central Register of Controlled Trials (CENTRAL; all dates), Cumulative Index to Nursing and Allied Health (CINAHL; 1937 to present), and Pubmed (all dates) to identify studies that reported outcomes associated with interventions designed to reduce wait times for primary care appointments. Two independent reviewers assessed all identified studies for inclusion using pre-defined inclusion/exclusion criteria and a multi-level screening approach. Our study methods were guided by the Cochrane Handbook for Systematic Reviews of Interventions. Results Our search identified 3,960 articles that were eligible for inclusion, eleven of which satisfied all inclusion/exclusion criteria. Data abstraction of included studies revealed that open access scheduling is the most commonly used intervention to reduce wait times for primary care appointments. Additionally, included studies demonstrated that dedicated telephone calls for follow-up consultation, presence of nurse practitioners on staff, nurse and general practitioner triage, and email consultations were effective at reducing wait times. Conclusions To our knowledge, this is the first study to systematically review and identify interventions designed to reduce wait times for primary care appointments. Our findings suggest that open access scheduling and other patient-centred interventions may reduce wait times for primary care appointments. Our review may inform policy makers and family healthcare providers about interventions that are effective in offering timely access to primary healthcare.

Introduction: Injuries account for 10% of the global burden of disease, resulting in approximately 5.8 million deaths annually. Trauma registries are an important tool in the development of a trauma system; however, limited resources in low- and middle-income countries (LMIC) make the development of high-quality trauma registries challenging. We describe the development of a LMIC trauma registry based on a robust retrospective chart review, which included data derived from prehospital, emergency centre and inpatient records. Methods: This paper outlines our methods for identifying and locating patients and their medical records using pragmatic and locally appropriate record linkage techniques. A prehospital database was queried to identify patients transported to University Teaching Hospital – Kigali, Rwanda from December 2012 through February 2015. Demographic information was recorded and used to create a five-factor identification index, which was then used to search OpenClinic GA, an online open source hospital information system. The medical record number and archive number obtained from OpenClinic GA were then used to locate the physical medical record for data extraction. Results: A total of 1668 trauma patients were transported during the study period. 66.7% were successfully linked to their medical record numbers and archive codes. 94% of these patients were successfully linked to their medical record numbers and archive codes were linked by four or five of the five pre-set identifiers. 945 charts were successfully located and extracted for inclusion in the trauma registry. Record linkage and chart extraction took approximately 1256 h. Conclusion: The process of record linkage and chart extraction was a resource-intensive process; however, our unique methodology resulted in a high linkage rate. This study suggests that it is feasible to create a retrospective trauma registry in LMICs using pragmatic and locally appropriate record linkage techniques.

Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.

ObjectiveTo develop key performance indicators that evaluate the effectiveness of a prescription medication system.MethodsA modified RAND/UCLA appropriateness method was used to develop key performance indicators (KPIs) for a prescription medication system. A broad list of potential KPIs was compiled. A multidisciplinary group composed of 21 experts rated the potential KPIs. A face-to-face meeting was held following the first rating exercise to discuss each potential KPI individually. The expert panel undertook a final rating of KPIs. The final set of KPIs were those indicators where at least 80 percent of experts rated the indicator highly i.e. rating of ≥ 7 on a scale from 1 to 9.Results292 KPIs were identified from the published literature. After removing duplicates and combining similar indicators 71 KPIs were included. The final ranking resulted in six indicators being ranked 7 or higher by 80% of the respondents and an additional seven indicators being ranked 7 or higher by ≥70 but ≤80% of respondents. The six selected indicators include four specific disease areas, measure structural and process aspects of health service delivery, and assessed three of the domains of healthcare quality: efficiency, effectiveness, and safety.ConclusionsThese indicators are recommended as a starting point to assess the current performance of prescription medication systems. Consideration should be given to developing indicators in additional disease areas as well as indicators that measure the domains of timeliness and patient-centeredness. Future work should focus on the feasibility of measuring these indicators.