Efficient Synthesis of DNA Duplexes Containing Reduced Acetaldehyde Interstrand Cross-Links.

DNA interstrand cross-links (ICLs) prevent DNA replication and transcription and can lead to potentially lethal events, such as cancer or bone marrow failure. ICLs are typically repaired by proteins within the Fanconi Anemia (FA) pathway, although the details of the pathway are not fully established. Methods to generate DNA containing ICLs are key to furthering the understanding of DNA cross-link repair. A major route to ICL formation in vivo involves reaction of DNA with acetaldehyde, derived from ethanol metabolism. This reaction forms a three-carbon bridged ICL involving the amino groups of adjacent guanines in opposite strands of a duplex resulting in amino and imino functionalities. A stable reduced form of the ICL has applications in understanding the recognition and repair of these types of adducts. Previous routes to creating DNA duplexes containing these adducts have involved lengthy post-DNA synthesis chemistry followed by reduction of the imine. Here, an efficient and high-yielding approach to the reduced ICL using a novel N2-((R)-4-trifluoroacetamidobutan-2-yl)-2'-deoxyguanosine phosphoramidite is described. Following standard automated DNA synthesis and deprotection, the ICL is formed overnight in over 90% yield upon incubation at room temperature with a complementary oligodeoxyribonucleotide containing 2-fluoro-2'-deoxyinosine. The cross-linked duplex displayed a melting transition 25 °C higher than control sequences. Importantly, we show using the Xenopus egg extract system that an ICL synthesized by this method is repaired by the FA pathway. The simplicity and efficiency of this methodology for preparing reduced acetaldehyde ICLs will facilitate access to these DNA architectures for future studies on cross-link repair.

Factors associated with increased suicidality risk following referral for isotretinoin commencement.

OBJECTIVE: To establish whether there is a significant change in suicidality risk following psychiatric assessment for commencement of isotretinoin and identify factors that underpin any potential risk change. METHOD: Retrospective cohort study. Suicidality risk was defined as a combination of the following: (i) actual/intended self-harm and/or attempted/completed suicide, and (ii) increased service utilisation associated with suicidal ideation/behaviour. All patients referred to Psychiatry for assessment prior to commencement of isotretinoin between 2014 and 2019 were examined. Inclusion criteria: >16 years of age, assessed for commencement of isotretinoin, complete clinical records. Data were collected by reviewing the Electronic Patient Records. Fifty-seven patients were eligible. We employed descriptive statistics, parametric/non-parametric/normality tests and logistic regression analysis, using socio-demographic and clinical characteristics as independent parameters, and suicidality risk as the dependent parameter. RESULTS: Actual/intended self-harm/attempted suicide decreased significantly following assessment without significant change in service utilisation. Female gender, absence of protective factors and assessment by Consultation-Liaison Psychiatry were linked to increased suicidality risk, after controlling for age, ethnicity, recommendation for isotretinoin, and substance misuse. CONCLUSIONS: Psychiatric assessment is helpful before commencing isotretinoin. Female gender, and absence of ongoing psychopharmacological and/or psychological intervention and/or regular psychiatric follow-up predict increased suicidality risk among patients assessed for prescription of isotretinoin.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

Engaging Patients and Other Non-Researchers in Health Research: Defining Research Engagement.

With the increase in patient and consumer activism through the late twentieth century and into this century, patient roles in research evolved into a new model of research engagement, with patients serving as active advisors and co-leading or leading clinical research. By requiring active engagement of patients and other stakeholders, several government research funders have advanced this model, particularly in Canada, the United States (US), United Kingdom (UK), and Australia. A consortium of individuals from these countries formed a Multi-Stakeholder Engagement (MuSE) consortium to examine critical issues in engaged research, establish consensus on definitions, and provide guidance for the field, beginning with an overview of how to involve stakeholders in health research (Concannon et al. J Gen Intern Med. 2019;34(3):458-463) and continuing here with an examination of definitions of research engagement. The political and advocacy roots of engaged research are reflected in definitions. Engagement is conceptualized with reference to research project goals, from informing specific clinical decisions to informing health-system level decisions. Political and cultural differences across countries are evident. Some of these government funders focus on empirical rather than ethical rationales. In countries with centralized health technology assessment, the link between societal values and engaged research is explicit. Ethical rationales for engagement are explicit in most of the published literature on research engagement. Harmonization of definitions is recommended so that research engagement elements, methods, and outcomes and impacts can be clearly examined and understood, and so that the field of research engagement can proceed from a clear conceptual foundation. Specific recommendations for terminology definitions are provided. Placing engaged research on a continuum from specific clinical decisions to more global public and social justice concerns clarifies the type of engaged research, supports appropriate comparisons, and improves the rigor of engaged research methods. The results help identify knowledge gaps in this growing field.

Testing small study effects in multivariate meta-analysis.

Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias, and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection processes can be involved in the reporting of multivariate outcomes. For example, some studies may be completely unpublished while others may selectively report multiple outcomes. In this paper, we propose a score test as an overall test of small study effects in multivariate meta-analysis. Two detailed case studies are given to demonstrate the advantage of the proposed test over various naive applications of univariate tests in practice. Through simulation studies, the proposed test is found to retain nominal Type I error rates with considerable power in moderate sample size settings. Finally, we also evaluate the concordance between the proposed tests with the naive application of univariate tests by evaluating 44 systematic reviews with multiple outcomes from the Cochrane Database.

A diagnostic solution for haemostasis laboratories for patients taking direct oral anticoagulants using DOAC-Remove.

This study describes the use of a simple charcoal product (DOAC-RemoveTM ) to allow haemostasis assays on patients taking direct oral anticoagulants (DOAC). In the proposed algorithm, patients taking DOAC are screened using the dilute thrombin time (dTT) and anti-Xa assay. If either are positive then DOAC-Remove is utilised. In a validation, DOAC-Remove did not interfere with coagulation testing in normal plasma or in patients on DOAC with a known lupus anticoagulant (LA). Of 1566 routine patient samples tested, 125 (8%) had evidence of anti-Xa activity (>0·1 iu/ml) or prolonged dTT suggestive of either a direct/indirect Xa inhibitor or direct thrombin inhibitor. All of these 125 patients had a prolonged dilute Russell viper venom time (dRVVT) screening test and 106 had a LA detected by dRVVT after phospholipid correction. After DOAC-Remove, 91 patients (73%) had a negative dRVVT screen. After further investigation only 9 (7%) had a positive LA. DOAC-Remove prevented 5% of patients having a LA inappropriately detected. DOAC did not significantly affect the LA activated partial thromboplastin time (aPTT) ratio, protein S antigen or protein C activity. DOAC cause low intrinsic factor assays, high prothrombin time/aPTT and high activated protein C sensitivity ratio, which DOAC-Remove reversed (P < 0·05). Despite recommendations, haemostasis testing for patients on DOAC continues; this algorithm aids diagnostic accuracy. Further validation and research are warranted.

27 years of prenatal diagnosis for Huntington disease in the United Kingdom.

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Challenges encountered in the conduct of Optimal Health: A patient-centered comparative effectiveness study of interventions for adults with serious mental illness.

BACKGROUND: The aim of patient-centered comparative effectiveness research is to conduct stakeholder-driven investigations that identify which interventions are most effective for which patients under specific circumstances. Conducting this research in real-world settings comes with unique experiences and challenges. We provide the study design, challenges confronted, and the solutions we devised for Optimal Health, a stakeholder-informed patient-centered comparative effectiveness study focused on the needs of seriously mentally ill individuals receiving case management services in community mental health centers across Pennsylvania. METHODS: Optimal Health, supported by the Patient-Centered Outcomes Research Institute, is a cluster-randomized trial of two evidence-based interventions for improving health and wellness across 11 provider sites. Participants were followed for 18-24 months, with repeated measurements of self-reported health status and activation in care and administrative measurements of primary and specialty health service utilization. Health-related quality of life, engagement in care, and service utilization are to be compared via random effects mixed models. Stakeholders were, and continue to be, engaged via focus groups, interviews, and stakeholder advisory board meetings. A learning collaborative model was used to support shared learning and implementation fidelity across provider sites. RESULTS: From 1 November 2013 through 15 July 2014, we recruited 1229 adults with serious mental illness, representing 85.1% of those eligible for study participation. Of these, 713 are in the Provider-Supported arm of the study and 516 in Patient Self-Directed Care. Across five data collection time points, we retained 86% and 83% of the participants in the Provider-Supported and Self-Directed arms, respectively. LESSONS LEARNED: Lessons learned relate to estimation of the size of our study population, the value of multiple data sources, and intervention training and implementation. The use of historical claims data can lead to an overestimation of eligible participants and, subsequently, a reduced study sample and an imbalance between intervention arms. Disruptions in continuity of care in real-world settings can pose challenges to on-site self-report data collection, although the inclusion of multiple data sources in study design can improve data completeness. Geographic dispersion of rural provider sites and staff turnover can lead to training and intervention fidelity challenges that can be overcome with the use of a "train-the-trainer" model, "wellness champions," and the use of a Learning Collaborative approach. Stakeholder engagement in mitigating these challenges proved to be critical to study progress. CONCLUSION: Conducting real-world patient-centered comparative effectiveness research in healthcare systems that care for seriously mentally ill persons is an important yet challenging undertaking, one which requires flexibility in identifying potential adaptations within all major study phases. Advice from a wide range of stakeholders is critical in development of successful strategies.

Association of Spinal Manipulative Therapy With Clinical Benefit and Harm for Acute Low Back Pain: Systematic Review and Meta-analysis.

IMPORTANCE: Acute low back pain is common and spinal manipulative therapy (SMT) is a treatment option. Randomized clinical trials (RCTs) and meta-analyses have reported different conclusions about the effectiveness of SMT. OBJECTIVE: To systematically review studies of the effectiveness and harms of SMT for acute (≤6 weeks) low back pain. DATA SOURCES: Search of MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, and Current Nursing and Allied Health Literature from January 1, 2011, through February 6, 2017, as well as identified systematic reviews and RCTs, for RCTs of adults with low back pain treated in ambulatory settings with SMT compared with sham or alternative treatments, and that measured pain or function outcomes for up to 6 weeks. Observational studies were included to assess harms. DATA EXTRACTION AND SYNTHESIS: Data extraction was done in duplicate. Study quality was assessed using the Cochrane Back and Neck (CBN) Risk of Bias tool. This tool has 11 items in the following domains: randomization, concealment, baseline differences, blinding (patient), blinding (care provider [care provider is a specific quality metric used by the CBN Risk of Bias tool]), blinding (outcome), co-interventions, compliance, dropouts, timing, and intention to treat. Prior research has shown the CBN Risk of Bias tool identifies studies at an increased risk of bias using a threshold of 5 or 6 as a summary score. The evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. MAIN OUTCOMES AND MEASURES: Pain (measured by either the 100-mm visual analog scale, 11-point numeric rating scale, or other numeric pain scale), function (measured by the 24-point Roland Morris Disability Questionnaire or Oswestry Disability Index [range, 0-100]), or any harms measured within 6 weeks. FINDINGS: Of 26 eligible RCTs identified, 15 RCTs (1711 patients) provided moderate-quality evidence that SMT has a statistically significant association with improvements in pain (pooled mean improvement in the 100-mm visual analog pain scale, -9.95 [95% CI, -15.6 to -4.3]). Twelve RCTs (1381 patients) produced moderate-quality evidence that SMT has a statistically significant association with improvements in function (pooled mean effect size, -0.39 [95% CI, -0.71 to -0.07]). Heterogeneity was not explained by type of clinician performing SMT, type of manipulation, study quality, or whether SMT was given alone or as part of a package of therapies. No RCT reported any serious adverse event. Minor transient adverse events such as increased pain, muscle stiffness, and headache were reported 50% to 67% of the time in large case series of patients treated with SMT. CONCLUSIONS AND RELEVANCE: Among patients with acute low back pain, spinal manipulative therapy was associated with modest improvements in pain and function at up to 6 weeks, with transient minor musculoskeletal harms. However, heterogeneity in study results was large.

Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis.

Importance: The use of palliative care programs and the number of trials assessing their effectiveness have increased. Objective: To determine the association of palliative care with quality of life (QOL), symptom burden, survival, and other outcomes for people with life-limiting illness and for their caregivers. Data Sources: MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL to July 2016. Study Selection: Randomized clinical trials of palliative care interventions in adults with life-limiting illness. Data Extraction and Synthesis: Two reviewers independently extracted data. Narrative synthesis was conducted for all trials. Quality of life, symptom burden, and survival were analyzed using random-effects meta-analysis, with estimates of QOL translated to units of the Functional Assessment of Chronic Illness Therapy-palliative care scale (FACIT-Pal) instrument (range, 0-184 [worst-best]; minimal clinically important difference [MCID], 9 points); and symptom burden translated to the Edmonton Symptom Assessment Scale (ESAS) (range, 0-90 [best-worst]; MCID, 5.7 points). Main Outcomes and Measures: Quality of life, symptom burden, survival, mood, advance care planning, site of death, health care satisfaction, resource utilization, and health care expenditures. Results: Forty-three RCTs provided data on 12 731 patients (mean age, 67 years) and 2479 caregivers. Thirty-five trials used usual care as the control, and 14 took place in the ambulatory setting. In the meta-analysis, palliative care was associated with statistically and clinically significant improvements in patient QOL at the 1- to 3-month follow-up (standardized mean difference, 0.46; 95% CI, 0.08 to 0.83; FACIT-Pal mean difference, 11.36] and symptom burden at the 1- to 3-month follow-up (standardized mean difference, -0.66; 95% CI, -1.25 to -0.07; ESAS mean difference, -10.30). When analyses were limited to trials at low risk of bias (n = 5), the association between palliative care and QOL was attenuated but remained statistically significant (standardized mean difference, 0.20; 95% CI, 0.06 to 0.34; FACIT-Pal mean difference, 4.94), whereas the association with symptom burden was not statistically significant (standardized mean difference, -0.21; 95% CI, -0.42 to 0.00; ESAS mean difference, -3.28). There was no association between palliative care and survival (hazard ratio, 0.90; 95% CI, 0.69 to 1.17). Palliative care was associated consistently with improvements in advance care planning, patient and caregiver satisfaction, and lower health care utilization. Evidence of associations with other outcomes was mixed. Conclusions and Relevance: In this meta-analysis, palliative care interventions were associated with improvements in patient QOL and symptom burden. Findings for caregiver outcomes were inconsistent. However, many associations were no longer significant when limited to trials at low risk of bias, and there was no significant association between palliative care and survival.

Evaluating site-of-care-related racial disparities in kidney graft failure using a novel federated learning framework.

OBJECTIVES: Racial disparities in kidney transplant access and posttransplant outcomes exist between non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients in the United States, with the site of care being a key contributor. Using multi-site data to examine the effect of site of care on racial disparities, the key challenge is the dilemma in sharing patient-level data due to regulations for protecting patients' privacy. MATERIALS AND METHODS: We developed a federated learning framework, named dGEM-disparity (decentralized algorithm for Generalized linear mixed Effect Model for disparity quantification). Consisting of 2 modules, dGEM-disparity first provides accurately estimated common effects and calibrated hospital-specific effects by requiring only aggregated data from each center and then adopts a counterfactual modeling approach to assess whether the graft failure rates differ if NHB patients had been admitted at transplant centers in the same distribution as NHW patients were admitted. RESULTS: Utilizing United States Renal Data System data from 39 043 adult patients across 73 transplant centers over 10 years, we found that if NHB patients had followed the distribution of NHW patients in admissions, there would be 38 fewer deaths or graft failures per 10 000 NHB patients (95% CI, 35-40) within 1 year of receiving a kidney transplant on average. DISCUSSION: The proposed framework facilitates efficient collaborations in clinical research networks. Additionally, the framework, by using counterfactual modeling to calculate the event rate, allows us to investigate contributions to racial disparities that may occur at the level of site of care. CONCLUSIONS: Our framework is broadly applicable to other decentralized datasets and disparities research related to differential access to care. Ultimately, our proposed framework will advance equity in human health by identifying and addressing hospital-level racial disparities.

WITHDRAWN: Spinal manipulative therapy for low-back pain.

BACKGROUND: Low-back pain is a costly illness for which spinal manipulative therapy is commonly recommended. Previous systematic reviews and practice guidelines have reached discordant results on the effectiveness of this therapy for low-back pain. OBJECTIVES: To resolve the discrepancies related to the use of spinal manipulative therapy and to update previous estimates of effectiveness, by comparing spinal manipulative therapy with other therapies and then incorporating data from recent high-quality randomized, controlled trials (RCTs) into the analysis. SEARCH METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and CINAHL were electronically searched from their respective beginning to January 2000, using the Back Group search strategy; references from previous systematic reviews were also screened. SELECTION CRITERIA: Randomized, controlled trials (RCT) that evaluated spinal manipulative therapy for patients with low-back pain, with at least one day of follow-up, and at least one clinically-relevant outcome measure. DATA COLLECTION AND ANALYSIS: Two authors, who served as the authors for all stages of the meta-analysis, independently extracted data from unmasked articles. Comparison treatments were classified into the following seven categories: sham, conventional general practitioner care, analgesics, physical therapy, exercises, back school, or a collection of therapies judged to be ineffective or even harmful (traction, corset, bed rest, home care, topical gel, no treatment, diathermy, and minimal massage). MAIN RESULTS: Thirty-nine RCTs were identified. Meta-regression models were developed for acute or chronic pain and short-term and long-term pain and function. For patients with acute low-back pain, spinal manipulative therapy was superior only to sham therapy (10-mm difference [95% CI, 2 to 17 mm] on a 100-mm visual analogue scale) or therapies judged to be ineffective or even harmful. Spinal manipulative therapy had no statistically or clinically significant advantage over general practitioner care, analgesics, physical therapy, exercises, or back school. Results for patients with chronic low-back pain were similar. Radiation of pain, study quality, profession of manipulator, and use of manipulation alone or in combination with other therapies did not affect these results. AUTHORS' CONCLUSIONS: There is no evidence that spinal manipulative therapy is superior to other standard treatments for patients with acute or chronic low-back pain.

Infusion of statistical science in comparative effectiveness research.

PURPOSE: We present a general introduction to comparative effectiveness research (CER) from a statistician's viewpoint and focus on how statisticians can contribute to the methodology of CER. CONCLUSIONS: The statistical science community needs to determine the priorities for methodological research in CER, in collaboration with our colleagues in the aligned medical fields. CER requires that we apply a new paradigm - a focus on the patient. The emphasis on the patient is driven by patients themselves, the federal government, and private payers, in addition to the fact that there is a rising chronic disease burden that is making patient populations more heterogeneous. The availability of new technology and data sources introduces not only complexity but also opportunity. Statistical scientists should rise to meet these new demands and develop optimal, statistically valid approaches to CER, just as they have in agriculture and clinical trials.

Economic evaluation of quality improvement interventions to prevent catheter-associated urinary tract infections in the hospital setting: a systematic review.

BACKGROUND: Hospitals have implemented diverse quality improvement (QI) interventions to reduce rates of catheter-associated urinary tract infections (CAUTIs). The economic value of these QI interventions is uncertain. OBJECTIVE: To systematically review economic evaluations of QI interventions designed to prevent CAUTI in acute care hospitals. METHODS: A search of Ovid MEDLINE, Econlit, Centre for Reviews & Dissemination, New York Academy of Medicine's Grey Literature Report, WorldCat, IDWeek conference abstracts and prior systematic reviews was conducted from January 2000 to October 2020.We included English-language studies of any design that evaluated organisational or structural changes to prevent CAUTI in acute care hospitals, and reported programme and infection-related costs.Dual reviewers assessed study design, effectiveness, costs and study quality. For each eligible study, we performed a cost-consequences analysis from the hospital perspective, estimating the incidence rate ratio (IRR) and incremental net cost/savings per hospital over 3 years. Unadjusted weighted regression analyses tested predictors of these measures, weighted by catheter days per study. RESULTS: Fifteen unique economic evaluations were eligible, encompassing 74 hospitals. Across 12 studies amenable to standardisation, QI interventions were associated with a 43% decline in infections (mean IRR 0.57, 95% CI 0.44 to 0.70) and wide ranges of net costs (mean US$52 000, 95% CI -$288 000 to $392 000), relative to usual care. CONCLUSIONS: QI interventions were associated with large declines in infection rates and net costs to hospitals that varied greatly but that, on average, were not significantly different from zero over 3 years. Future research should examine specific practices associated with cost-savings and clinical effectiveness, and examine whether or not more comprehensive interventions offer hospitals and patients the best value.

Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.

INTRODUCTION: Patients with COVID-19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID-19. METHODS: Platelet poor plasma of 34 patients with noncritical COVID-19 was compared with 75 patients with critical COVID-19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender. RESULTS: Critical patients had significantly increased fibrinogen, CRP, interleukin-6 and D-dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low-molecular weight heparin. CONCLUSION: These results confirm increased fibrinogen and D-dimer in critical COVID-19-infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin-antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter-intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).

Learning from local to global: An efficient distributed algorithm for modeling time-to-event data.

OBJECTIVE: We developed and evaluated a privacy-preserving One-shot Distributed Algorithm to fit a multicenter Cox proportional hazards model (ODAC) without sharing patient-level information across sites. MATERIALS AND METHODS: Using patient-level data from a single site combined with only aggregated information from other sites, we constructed a surrogate likelihood function, approximating the Cox partial likelihood function obtained using patient-level data from all sites. By maximizing the surrogate likelihood function, each site obtained a local estimate of the model parameter, and the ODAC estimator was constructed as a weighted average of all the local estimates. We evaluated the performance of ODAC with (1) a simulation study and (2) a real-world use case study using 4 datasets from the Observational Health Data Sciences and Informatics network. RESULTS: On the one hand, our simulation study showed that ODAC provided estimates nearly the same as the estimator obtained by analyzing, in a single dataset, the combined patient-level data from all sites (ie, the pooled estimator). The relative bias was <0.1% across all scenarios. The accuracy of ODAC remained high across different sample sizes and event rates. On the other hand, the meta-analysis estimator, which was obtained by the inverse variance weighted average of the site-specific estimates, had substantial bias when the event rate is <5%, with the relative bias reaching 20% when the event rate is 1%. In the Observational Health Data Sciences and Informatics network application, the ODAC estimates have a relative bias <5% for 15 out of 16 log hazard ratios, whereas the meta-analysis estimates had substantially higher bias than ODAC. CONCLUSIONS: ODAC is a privacy-preserving and noniterative method for implementing time-to-event analyses across multiple sites. It provides estimates on par with the pooled estimator and substantially outperforms the meta-analysis estimator when the event is uncommon, making it extremely suitable for studying rare events and diseases in a distributed manner.

Evidence for improving palliative care at the end of life: a systematic review.

BACKGROUND: Many persons and their families are burdened by serious chronic illness in late life. How to best support quality of life is an important consideration for care. PURPOSE: To assess evidence about interventions to improve palliative and end-of-life care. DATA SOURCES: English-language citations (January 1990 to November 2005) from MEDLINE, the Database of Abstracts of Reviews of Effects, the National Consensus Project for Quality Palliative Care bibliography, and November 2005 to January 2007 updates from expert reviews and literature surveillance. STUDY SELECTION: Systematic reviews that addressed "end of life," including terminal illness (for example, advanced cancer) and chronic, eventually fatal illness with ambiguous prognosis (for example, advanced dementia), and intervention studies (randomized and nonrandomized designs) that addressed pain, dyspnea, depression, advance care planning, continuity, and caregiving. DATA EXTRACTION: Single reviewers screened 24,423 titles to find 6381 relevant abstracts and reviewed 1274 articles in detail to identify 33 high-quality systematic reviews and 89 relevant intervention studies. They synthesized the evidence by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) classification. DATA SYNTHESIS: Strong evidence supports treating cancer pain with opioids, nonsteroidals, radionuclides, and radiotherapy; dyspnea from chronic lung disease with short-term opioids; and cancer-associated depression with psychotherapy, tricyclics, and selective serotonin reuptake inhibitors. Strong evidence supports multi component interventions to improve continuity in heart failure. Moderate evidence supports advance care planning led by skilled facilitators who engage key decision makers and interventions to alleviate caregiver burden. Weak evidence addresses cancer-related dyspnea management, and no evidence addresses noncancer pain, symptomatic dyspnea management in advanced heart failure, or short-acting antidepressants in terminal illness. No direct evidence addresses improving continuity for patients with dementia. Evidence was weak for improving caregiver burdens in cancer and was absent for heart failure. LIMITATIONS: Variable literature indexing for advanced chronic illness and end of life limited the comprehensiveness of searches, and heterogeneity was too great to do meta-analysis. CONCLUSION: Strong to moderate evidence supports interventions to improve important aspects of end-of-life care. Future research should quantify these effects and address the generalizability of insights across the conditions and settings of the last part of life. Many critical issues lack high-quality evidence.

Comparative Clinical Effectiveness of Nonsurgical Treatment Methods in Patients With Lumbar Spinal Stenosis: A Randomized Clinical Trial.

Importance: Lumbar spinal stenosis (LSS) is the most common reason for spine surgery in older US adults. There is an evidence gap about nonsurgical LSS treatment options. Objective: To explore the comparative clinical effectiveness of 3 nonsurgical interventions for patients with LSS. Design, Setting, and Participants: Three-arm randomized clinical trial of 3 years' duration (November 2013 to June 2016). Analysis began in August 2016. All interventions were delivered during 6 weeks with follow-up at 2 months and 6 months at an outpatient research clinic. Patients older than 60 years with LSS were recruited from the general public. Eligibility required anatomical evidence of central canal and/or lateral recess stenosis (magnetic resonance imaging/computed tomography) and clinical symptoms associated with LSS (neurogenic claudication; less symptoms with flexion). Analysis was intention to treat. Interventions: Medical care, group exercise, and manual therapy/individualized exercise. Medical care consisted of medications and/or epidural injections provided by a physiatrist. Group exercise classes were supervised by fitness instructors in senior community centers. Manual therapy/individualized exercise consisted of spinal mobilization, stretches, and strength training provided by chiropractors and physical therapists. Main Outcomes and Measures: Primary outcomes were between-group differences at 2 months in self-reported symptoms and physical function measured by the Swiss Spinal Stenosis questionnaire (score range, 12-55) and a measure of walking capacity using the self-paced walking test (meters walked for 0 to 30 minutes). Results: A total of 259 participants (mean [SD] age, 72.4 [7.8] years; 137 women [52.9%]) were allocated to medical care (88 [34.0%]), group exercise (84 [32.4%]), or manual therapy/individualized exercise (87 [33.6%]). Adjusted between-group analyses at 2 months showed manual therapy/individualized exercise had greater improvement of symptoms and physical function compared with medical care (-2.0; 95% CI, -3.6 to -0.4) or group exercise (-2.4; 95% CI, -4.1 to -0.8). Manual therapy/individualized exercise had a greater proportion of responders (≥30% improvement) in symptoms and physical function (20%) and walking capacity (65.3%) at 2 months compared with medical care (7.6% and 48.7%, respectively) or group exercise (3.0% and 46.2%, respectively). At 6 months, there were no between-group differences in mean outcome scores or responder rates. Conclusions and Relevance: A combination of manual therapy/individualized exercise provides greater short-term improvement in symptoms and physical function and walking capacity than medical care or group exercises, although all 3 interventions were associated with improvements in long-term walking capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT01943435.