Heterologous expression, purification and single step efficient refolding of recombinant tissue plasminogen activator (Reteplase) from E. coli.

Reteplase (recombinant plasminogen activator, rPA) is a mutant non-glycosylated tissue-type plasminogen activator (tPA) containing 355 amino acids with longer half-life and promising thrombolytic activity than its original counterpart, full length tPA. In this study, we aimed to produce and optimize the purification process of recombinant tissue-type plasminogen activator (tPA) known as Reteplase (rPA). Reteplase cDNA synthesized from total mRNA isolated from human placenta was PCR amplified, cloned into a pET-28a(+) E. coli expression vector and expressed in Rosetta-gami 2 E. coli (NovagenⓇ) host. rPA was expressed as an inclusion body in E. coli and its biological activity was achieved after single step solubilization, purification and refolding. We exploited the strategy of Slow Refolding using Gradual Dialysis (SRGD) in which a refolding buffer containing glutathione oxidized (1 mM GSSG) and glutathione reduced (3 mM GSH) and pH 9.0 was used. Using the SRGD method, we were able to successfully obtain the protein in its active form. We obtained 4.26 mg of active refolded protein from a 50 mL culture that was scaled up in a bioreactor. The purity and homogeneity of rPA was evaluated by SDS-PAGE, Western blotting and mass spectrometry. Circular dichroism spectroscopy was conducted to evaluate the refolding and stability of the refolded rPA in comparison to reference standard rPA. The thrombolytic potential of rPA was assessed by fibrin plate assay and In Vitro clot lysis assay. The presented protocol offers a viable approach for enhancing both the yield and refolding efficiency of reteplase, potentially resulting in an increase in yield.

Advancing Community Care and Access to Follow-up After Acute Kidney Injury Hospitalization: Design of the AFTER AKI Randomized Controlled Trial.

Background: Acute kidney injury (AKI) is a common complication among hospitalized patients with long-term implications including chronic kidney disease (CKD). Although models are available to predict the risk of advanced CKD after AKI, there is limited evidence regarding follow-up for patients with AKI after hospital discharge, resulting in variable follow-up care. A risk-stratified follow-up approach may improve appropriateness and efficiency of management for CKD among patients at risk of declining kidney function following AKI. Objective: The objective was to compare and evaluate the use of a risk-stratified approach to follow-up care vs usual care for patients with AKI after hospital discharge. Design: This study was a pragmatic randomized controlled trial. Setting: This study was conducted in 2 large urban hospitals in Alberta, Canada. Patients: Hospitalized patients with AKI (KDIGO stage 2 or 3) not previously under the care of a nephrologist, expected to survive greater than 90 days being discharged home. Measurements: We will evaluate whether guideline-recommended CKD care processes are initiated within 90 days, including statin use, angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) use in those with proteinuria or diabetes, and nephrologist follow-up if sustained eGFR <30 mL/min/1.73 m2. We will also assess the feasibility of recruitment and the proportion of patients completing the recommended blood and urine tests at 90 days. Methods: Patients with AKI will be enrolled and randomized near the time of hospital discharge. In the intervention group, low risk patients will receive information regarding AKI, medium risk patients will additionally receive follow-up guidance sent to their primary care physician, and high-risk patients will additionally receive follow-up with a nephrologist. Participants in the intervention and usual care group will receive a requisition for urine testing and bloodwork at 90 days following hospital discharge. Telephone follow-up will be conducted for all study participants at 90 days and 1 year after hospital discharge. Bivariate tests of association will be conducted to evaluate group differences at the follow-up time points. Limitations: We expect there may be challenges with recruitment due to the significant co-existence of comorbidity in this population. Conclusions: If the trial shows a positive effect on these processes for kidney care, it will inform larger-scale trial to determine whether this intervention reduces the incidence of long-term clinical adverse events, including CKD progression, cardiovascular events, and mortality following hospitalization with AKI.

Contexte: L'insuffisance rénale aiguë (IRA) est une complication fréquente chez les patients hospitalisés qui peut avoir des conséquences à long terme, notamment l'insuffisance rénale chronique (IRC). Bien que des modèles de prédiction du risque d'IRC avancée après un épisode d'IRA soient disponibles, peu de données existent sur le suivi des patients atteints d'IRA après leur sortie de l'hôpital, ce qui se traduit par une variabilité dans les soins de suivi. Une approche de suivi stratifiée selon le risque d'IRC peut améliorer la qualité et l'efficacité de la prise en charge de l'IRC chez les patients dont la fonction rénale risque de se détériorer après un épisode d'IRA. Objectifs: Évaluer l'utilisation d'une approche de suivi post-hospitalisation stratifiée selon le risque d'IRC chez les patients atteints d'IRA et la comparer aux soins habituels. Conception: Essai contrôlé randomisé pragmatique. Cadre: Deux grands hôpitaux urbains en Alberta (Canada). Sujets: Patients hospitalisés avec une IRA (stade KDIGO 2 ou 3) qui n'étaient pas suivis auparavant par un néphrologue et dont on prévoyait la survie au-delà de 90 jours après leur sortie de l'hôpital. Mesures: Nous évaluerons si, dans les 90 jours suivant le congé, les soins d'IRC habituels recommandés par les lignes directrices seront amorcés, c'est-à-dire l'utilisation de statines, l'utilisation d'IECA/ARA chez les patients souffrant de protéinurie ou de diabète, et le suivi avec un néphrologue pour les patients avec un DFGe inférieur à 30 ml/min/1,73 m2 de façon soutenue. Nous évaluerons également la faisabilité du recrutement et la proportion de patients qui auront effectué les analyses sanguines et urinaires recommandées à 90 jours. Méthodologie: Les patients atteints d'IRA seront recrutés et randomisés au moment de leur sortie de l'hôpital. Dans le groupe d'intervention, les patients présentant un faible risque d'évolution recevront de l'information sur l'IRA, les patients présentant un risque moyennement élevé recevront en plus des conseils de suivi envoyés à leur médecin de premier recours, et les patients présentant un risque élevé feront également l'objet d'un suivi avec un néphrologue. Les participants des groupes intervention et soins habituels recevront une requête pour des analyses de sang et d'urine 90 jours après la sortie de l'hôpital. Un suivi téléphonique sera effectué auprès de tous les participants à l'étude 90 jours et un an après la sortie de l'hôpital. Des tests d'association bivariés seront effectués pour évaluer les différences entre les groupes aux points temporels de suivi. Limites: Nous nous attendons à ce que le recrutement soit difficile, considérant l'importance des comorbidités dans cette population. Conclusion: Si l'essai montre un effet positif sur ces processus de soins rénaux, il informera un essai à plus grande échelle visant à déterminer si cette intervention réduit l'incidence des événements cliniques indésirables à long terme, notamment la progression de l'IRC, les événements cardiovasculaires et la mortalité après une hospitalisation avec épisode d'IRA.

American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing.

Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

Serious reporting deficiencies exist in minimal important difference studies: current state and suggestions for improvement.

BACKGROUND AND OBJECTIVES: To evaluate reporting of minimal important difference (MID) estimates using anchor-based methods for patient-reported outcome measures (PROMs), and the association with reporting deficiencies on their credibility. METHODS: Systematic survey of primary studies empirically estimating MIDs. We searched Medline, EMBASE, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database until October 2018. We evaluated study reporting, focusing on participants' demographics, intervention(s), characteristics of PROMs and anchors, and MID estimation method(s). We assessed the impact of reporting issues on credibility of MID estimates. RESULTS: In 585 studies reporting on 5,324 MID estimates for 526 distinct PROMs, authors frequently failed to adequately report key characteristics of PROMs and MIDs, including minimum and maximum values of PROM scale, measure of variability accompanying the MID estimate and number of participants included in the MID calculation. Across MID estimates (n = 5,324), the most serious reporting issues impacting credibility included infrequent reporting of the correlation between the anchor and PROM (66%), inadequate details to judge precision of MID point estimate (13%), and insufficient information about the threshold used to ascertain MIDs (16%). CONCLUSION: Serious issues of incomplete reporting in the MID literature threaten the optimal use of MID estimates to inform the magnitude of effects of interventions on PROMs.

Indirectness (transferability) is critical when considering existing economic evaluations for GRADE clinical practice guidelines: a systematic review.

OBJECTIVES: Grading of Recommendations Assessment, Development and Evaluation (GRADE) practice guideline developers often perform systematic reviews of potential economic evaluations to inform recommendation decision-making. We aimed to identify indirectness characteristics of economic evaluations, related to GRADE evidence-to-decision (EtD) theoretical frameworks, that influence selection of these articles. STUDY DESIGN AND SETTING: MEDLINE, EMBASE, CINAHL, and EconLit were systematically searched to May 2020 to identify indirectness characteristics relevant for economic evaluation transferability to GRADE EtD theoretical frameworks. Four reviewers screened citations to identify articles of any type that explored study characteristics most important or relevant to economic evaluation transferability, restricted to English language we generated frequencies of article features, used thematic analysis to summarize study characteristics, and assessed certainty in the evidence using GRADE-CERQual. RESULTS: We included 57 articles, with a dearth of empirical literature-some may have been missed. We identified eight general themes and 28 subthemes most important to transferability from 41% of articles. Moderate-to-high confidence evidence suggested that GRADE EtD domains of population, intervention and comparison research question elements, resource use estimation and methodology, and provider and decision maker acceptability are most important indirectness study characteristics that economists consider when choosing economic evaluation outcomes for use in recommendation decision-making. CONCLUSION: We have identified factors important for guideline developers to consider when selecting economic evaluations as research evidence. An economic competency on the development team facilitates these endeavors. This supports the GRADE Working Group's tenant of transparent reporting or availability of sufficient information elsewhere to assess indirectness.

A systematic survey identified methodological issues in studies estimating anchor-based minimal important differences in patient-reported outcomes.

OBJECTIVE: To systematically survey the literature addressing the reporting of studies estimating anchor-based minimal important differences (MIDs) and choice of optimal MIDs. STUDY DESIGN AND SETTING: We searched Medline, Embase and PsycINFO from 1987 to March 2020. Teams of two reviewers independently identified eligible publications and extracted quotations addressing relevant issues for reporting and/or selecting anchor-based MIDs. Using a coding list, we assigned the same code to quotations capturing similar or related issues. For each code, we generated an 'item', i.e., a specific phrase or sentence capturing the underlying concept. When multiple concepts existed under a single code, the team created multiple items for that code. We clustered codes addressing a broader methodological issue into a 'category' and classified items as relevant for reporting, relevant for selecting an anchor-based MID, or both. RESULTS: We identified 136 eligible publications that provided 6 categories (MID definition, anchors, patient-reported outcome measures, generalizability and statistics) and 24 codes. These codes contained 34 items related to reporting MID studies, of which 29 were also related to selecting MIDs. CONCLUSION: The systematic survey identified items related to reporting of anchor-based MID studies and selecting optimal MIDs. These provide a conceptual framework to inform the design of studies related to MIDs, and a basis for developing a reporting standard and a selection approach for MIDs.

Guidelines that use the GRADE approach often fail to provide complete economic information for recommendations: A systematic survey.

OBJECTIVE: Little is known about how developers and panel members report cost and cost effectiveness considerations in GRADE guideline Evidence-to-Decision (EtD) frameworks. A systematic survey was conducted to explore approaches and factors contributing to variability in economic information reporting. STUDY DESIGN AND SETTING: Guideline organization websites were systematically searched to create a convenience sample of guidelines. Reviewers screened published EtD frameworks and generated frequencies of reporting approaches. We used thematic analysis to summarize factors related to variability of economic information reporting. RESULTS: We included 142 guidelines. The overall rate of reporting economic information was high (91%); however, there was variability across completion of predefined EtD Likert-type judgments (70%), noting information as not identified across EtD framework domains (57%), and providing remarks to justify recommendations (38%). Six themes contributing to variability emerged, related to: intervention, population, payor, provider, healthcare resource use, and economic model building factors. Only 2 guidelines performed a GRADE certainty appraisal of economic outcomes. CONCLUSION: Completing predefined EtD Likert-type judgments, specifically reporting a literature review approach, study selection criteria and economic model building limitations, as well as linking these to recommendation justification remarks are potential areas for improved use, adoption and adaptation of recommendation, and transparency of GRADE EtD frameworks.

Systematic review and meta-analysis of outcomes in patients with suspected pulmonary embolism.

Prompt evaluation and therapeutic intervention of suspected pulmonary embolism (PE) are of paramount importance for improvement in outcomes. We systematically reviewed outcomes in patients with suspected PE, including mortality, incidence of recurrent PE, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included 22 studies with 15 865 patients. Among patients who were diagnosed with PE and discharged with anticoagulation, 3-month follow-up revealed that all-cause mortality was 5.69% (91/1599; 95% confidence interval [CI], 4.56-6.83), mortality from PE was 1.19% (19/1597; 95% CI, 0.66-1.72), recurrent venous thromboembolism (VTE) occurred in 1.38% (22/1597; 95% CI: 0.81-1.95), and major bleeding occurred in 0.90% (2/221%; 95% CI, 0-2.15). In patients with a low pretest probability (PTP) and negative D-dimer, 3-month follow-up revealed mortality from PE was 0% (0/808) and incidence of VTE was 0.37% (4/1094; 95% CI: 0.007-0.72). In patients with intermediate PTP and negative D-dimer, 3-month follow-up revealed that mortality from PE was 0% (0/2747) and incidence of VTE was 0.46% (14/3015; 95% CI: 0.22-0.71). In patients with high PTP and negative computed tomography (CT) scan, 3-month follow-up revealed mortality from PE was 0% (0/651) and incidence of VTE was 0.84% (11/1302; 95% CI: 0.35-1.34). We further summarize outcomes evaluated by various diagnostic tests and diagnostic pathways (ie, D-dimer followed by CT scan).

GRADE notes: How to use GRADE when there is "no" evidence? A case study of the expert evidence approach.

OBJECTIVES: One essential requirement of trustworthy guidelines is that they should be based on systematic reviews of the best available evidence. The GRADE Working Group has provided guidance for evaluating the certainty of evidence based on several domains. However, for many clinical questions, published evidence may be limited, too indirect or simply not exist. In this brief report (GRADE notes), we describe our method of developing evidence-based recommendations when publisheddirect evidence was lacking. STUDY DESIGN AND SETTING: When direct published literature was absent, an expert evidence survey was administered to panel members about their unpublished observations and case series. Focus was on collecting data about cases and outcome, not panel opinions. RESULTS: Out of 26 questions prioritized by the panel for pediatric venous thromboembolism, 12 had no, very limited, or very low certainty of evidence to inform them. The panel survey was administered for these questions. CONCLUSIONS: Areas of sparse evidence often reflect key questions that are critical to address in clinical practice guidelines due to the uncertainty among health care providers. The expert evidence approach used in this study is one method for panels totransparently deal with the lack of published evidence to directly inform recommendations.

Minimal important difference estimates for patient-reported outcomes: A systematic survey.

OBJECTIVES: The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. STUDY DESIGN AND SETTING: We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989-October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. RESULTS: We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). CONCLUSION: A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

Development and initial implementation of electronic clinical decision supports for recognition and management of hospital-acquired acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and is associated with poor patient outcomes and high costs of care. The implementation of clinical decision support tools within electronic medical record (EMR) could improve AKI care and outcomes. While clinical decision support tools have the potential to enhance recognition and management of AKI, there is limited description in the literature of how these tools were developed and whether they meet end-user expectations. METHODS: We developed and evaluated the content, acceptability, and usability of electronic clinical decision support tools for AKI care. Multi-component tools were developed within a hospital EMR (Sunrise Clinical Manager™, Allscripts Healthcare Solutions Inc.) currently deployed in Calgary, Alberta, and included: AKI stage alerts, AKI adverse medication warnings, AKI clinical summary dashboard, and an AKI order set. The clinical decision support was developed for use by multiple healthcare providers at the time and point of care on general medical and surgical units. Functional and usability testing for the alerts and clinical summary dashboard was conducted via in-person evaluation sessions, interviews, and surveys of care providers. Formal user acceptance testing with clinical end-users, including physicians and nursing staff, was conducted to evaluate the AKI order set. RESULTS: Considerations for appropriate deployment of both non-disruptive and interruptive functions was important to gain acceptability by clinicians. Functional testing and usability surveys for the alerts and clinical summary dashboard indicated that the tools were operating as desired and 74% (17/23) of surveyed healthcare providers reported that these tools were easy to use and could be learned quickly. Over three-quarters of providers (18/23) reported that they would utilize the tools in their practice. Three-quarters of the participants (13/17) in user acceptance testing agreed that recommendations within the order set were useful. Overall, 88% (15/17) believed that the order set would improve the care and management of AKI patients. CONCLUSIONS: Development and testing of EMR-based decision support tools for AKI with clinicians led to high acceptance by clinical end-users. Subsequent implementation within clinical environments will require end-user education and engagement in system-level initiatives to use the tools to improve care.

Treatment Outcomes in Patients With Opioid Use Disorder Who Were First Introduced to Opioids by Prescription: A Systematic Review and Meta-Analysis.

OBJECTIVE: Prescription opioid misuse has led to a new cohort of opioid use disorder (OUD) patients who were introduced to opioids through a legitimate prescription. This change has caused a shift in the demographic profile of OUD patients from predominantly young men to middle age and older people. The management of OUD includes medication-assisted treatment (MAT), which produces varying rates of treatment response. In this study, we will examine whether the source of first opioid use has an effect on treatment outcomes in OUD. Using a systematic review of the literature, we will investigate the association between source of first opioid introduction and treatment outcomes defined as continuing illicit opioid use and poly-substance use while in MAT. METHODS: Medline, EMBASE, CINHAL, and PsycInfo were searched from inception to December 31st, 2019 inclusive using a comprehensive search strategy. Five pairs of reviewers conducted screening and data extraction independently in duplicate. The review is conducted and reported according to the PRISMA guidelines. A random-effects model was used for meta analyses assuming heterogeneity among the included studies. RESULTS: The initial search results in 27,345 articles that were screened, and five observational studies were included in the qualitative and quantitative analyses. Our results found that those who were introduced to opioids through a legitimate prescription were significantly less likely to have illicit opioid use (0.70, 95% CI 0.50, 0.99) while on MAT. They were also less likely to use cannabis (0.54, 95% CI 0.32, 0.89), alcohol (0.75, 95% CI 0.59, 0.95), cocaine (0.50, 95% CI 0.29, 0.85), and injection drug use (0.25, 95% CI 0.14, 0.43) than those introduced to opioids through recreational means. CONCLUSION: This study shows that the first exposure to opioids, whether through a prescription or recreationally, influences prognosis and treatment outcomes of opioid use disorder. Although the increased pattern of prescribing opioids may have led to increased OUD in a new cohort of patients, these patients are less likely to continue to use illicit drugs and have a different prognostic and clinical profile that requires a tailored approach to treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017058143.

Systematic review and meta-analysis of test accuracy for the diagnosis of suspected pulmonary embolism.

Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.

Diagnosis of deep vein thrombosis of the upper extremity: a systematic review and meta-analysis of test accuracy.

Upper extremity deep vein thrombosis (UEDVT) accounts for ≤10% of DVT and can be associated with morbidity and mortality. Accurate diagnosis and treatment are necessary for safe and effective patient management. We systematically reviewed the accuracy of D-dimer and duplex ultrasonography (US) for the evaluation of suspected first-episode UEDVT. We searched the Cochrane Central Register, OVID MEDLINE, EMBASE, and PubMed for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included prospective cross-sectional and cohort studies that evaluated test accuracy. Two investigators independently screened and collected data. The risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 9 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.96 (95% confidence interval [CI], 0.87-0.99) and 0.47 (95% CI, 0.43-0.52), respectively. The pooled estimates for duplex US sensitivity and specificity were 0.87 (95% CI, 0.73-0.94) and 0.85 (95% CI, 0.72-0.93), respectively. Certainty of evidence was moderate. In this review, we summarized the test accuracy (sensitivity and specificity) of D-dimer and duplex US for this indication. The sensitivity and specificity of the tests found in the present review should be considered in the context of whether they are used alone or in combination, which is dependent on the prevalence of disease in the population, the clinical setting in which the patient is being evaluated, cost, potential harms, and patient outcomes. This study was registered at PROSPERO as Systematic Review Registration Number CRD42018098488.

Evaluating the credibility of anchor based estimates of minimal important differences for patient reported outcomes: instrument development and reliability study.

OBJECTIVE: To develop an instrument to evaluate the credibility of anchor based minimal important differences (MIDs) for outcome measures reported by patients, and to assess the reliability of the instrument. DESIGN: Instrument development and reliability study. DATA SOURCES: Initial criteria were developed for evaluating the credibility of anchor based MIDs based on a literature review (Medline, Embase, CINAHL, and PsycInfo databases) and the experience of the authors in the methodology for estimation of MIDs. Iterative discussions by the team and pilot testing with experts and potential users facilitated the development of the final instrument. PARTICIPANTS: With the newly developed instrument, pairs of masters, doctoral, or postdoctoral students with a background in health research methodology independently evaluated the credibility of a sample of MID estimates. MAIN OUTCOME MEASURES: Core credibility criteria applicable to all anchor types, additional criteria for transition rating anchors, and inter-rater reliability coefficients were determined. RESULTS: The credibility instrument has five core criteria: the anchor is rated by the patient; the anchor is interpretable and relevant to the patient; the MID estimate is precise; the correlation between the anchor and the outcome measure reported by the patient is satisfactory; and the authors select a threshold on the anchor that reflects a small but important difference. The additional criteria for transition rating anchors are: the time elapsed between baseline and follow-up measurement for estimation of the MID is optimal; and the correlations of the transition rating with the baseline, follow-up, and change score in the patient reported outcome measures are satisfactory. Inter-rater reliability coefficients (ĸ) for the core criteria and for one item from the additional criteria ranged from 0.70 to 0.94. Reporting issues prevented the evaluation of the reliability of the three other additional criteria for the transition rating anchors. CONCLUSIONS: Researchers, clinicians, and healthcare policy decision makers can consider using this instrument to evaluate the design, conduct, and analysis of studies estimating anchor based minimal important differences.

Pharmacologic thromboprophylaxis in adult patients undergoing neurosurgical interventions for preventing venous thromboembolism.

The impact of pharmacologic prophylaxis for venous thromboembolism in patients undergoing neurosurgical intervention remains uncertain. We reviewed the efficacy and safety of pharmacologic compared with nonpharmacologic thromboprophylaxis in neurosurgical patients. Three databases were searched through April 2018, including those for randomized controlled trials (RCTs) and for nonrandomized controlled studies (NRSs). Independent reviewers assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seven RCTs and 3 NRSs proved eligible. No studies reported on symptomatic proximal and distal deep vein thrombosis (DVT). Two RCTs reported on screening-detected proximal and distal DVTs. We used the findings of these 2 RCTs as the closest surrogate outcomes to inform the proximal and distal DVT outcomes. These 2 RCTs suggest that pharmacologic thromboprophylaxis may decrease the risk of developing asymptomatic proximal DVT (relative risk [RR], 0.50; 95% confidence interval [CI], 0.30-0.84; low certainty). Findings were uncertain for mortality (RR, 1.27; 95% CI, 0.57-2.86; low certainty), symptomatic pulmonary embolism (PE) (RR, 0.84; 95% CI, 0.03-27.42; very low certainty), asymptomatic distal DVT (RR, 0.54; 95% CI, 0.27-1.08; very low certainty), and reoperation (RR, 0.43; 95% CI, 0.06-2.84; very low certainty) outcomes. NRSs also reported uncertain findings for whether pharmacologic prophylaxis affects mortality (RR, 0.72; 95% CI, 0.46-1.13; low certainty) and PE (RR, 0.18; 95% CI, 0.01-3.76). For risk of bleeding, findings were uncertain in both RCTs (RR, 1.57; 95% CI, 0.70-3.50; low certainty) and NRSs (RR, 1.45; 95% CI, 0.30-7.12; very low certainty). In patients undergoing neurosurgical procedures, low certainty of evidence suggests that pharmacologic thromboprophylaxis confers benefit for preventing asymptomatic (screening-detected) proximal DVT with very low certainty regarding its impact on patient-important outcomes.

Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis.

After deep vein thrombosis (DVT) is diagnosed, prompt evaluation and therapeutic intervention are of paramount importance for improvement in patient-important outcomes. We systematically reviewed patient-important outcomes in patients with suspected DVT, including mortality, incidence of pulmonary embolism (PE) and DVT, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, Ovid Medline, Embase for eligible studies, references lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Nine studies with 5126 patients were included for lower extremity DVT. Three studies with 500 patients were included for upper extremity DVT. Among patients with lower extremity DVT, 0.85% (95% confidence interval [CI], 0% to 2.10%) and 0% developed recurrent DVT and PE, respectively, at 3 months. Among patients with upper extremity DVT, 0.49% (95% CI, 0% to 1.16%) and 1.98% (95% CI, 0.62% to 3.33%) developed recurrent DVT and PE, respectively, at 3 months. No major bleeding events were reported for those anticoagulated, which is lower than in other systematic reviews. For both upper and lower extremity DVT, low pretest probability patients with a negative D-dimer had a comparable incidence of VTE at 3 months (∼1%) as patients with a negative ultrasound (US). At higher pretest probabilities, negative US testing with or without serial US appears to be the safer option. In this review, we summarized the outcomes of patients evaluated by various diagnostic pathways. In most instances, there was significant limitation due to small population size or lack of direct evidence of effects of using a specific pathway. This systematic review was registered at PROSPERO as CRD42018100502.

Feasibility of behavioral activation group therapy in reducing depressive symptoms and improving quality of life in patients with depression: the BRAVE pilot trial.

BACKGROUND: Depression impacts the lives of millions of people worldwide. Behavioral activation (BA), derived from cognitive behavioral therapy, has the potential for improving depressive symptoms in patients with depression. Studies evaluating the effectiveness of BA specifically in the context of group therapy programs in a hospital setting for patients with depression are limited. In this study, we report findings from a pilot trial evaluating group BA for major depressive disorder. OBJECTIVE: The objectives of this pilot trial are to assess the potential of a full trial of BA group therapy in a large-scale tertiary care setting and to provide preliminary information about possible results regarding mood symptoms and quality of life in adults with depression. METHODS: Using a parallel single-cohort pragmatic pilot randomized controlled trial design, we evaluated the potential of conducting a large trial of BA effectiveness among adults with depression. Participants were randomized to the intervention (BA in addition to usual care) or control (support group in addition to usual care) groups and were assessed weekly for 18 consecutive weeks. Participants randomized to intervention underwent 28 2-h group BA therapy visits administered by trained therapists and completed assessments to examine treatment outcomes. Feasibility was measured in terms of enrollment rates (min. 20%), completion rates of study (min. 80%), and completion rates of weekly measurement scales (min. 80%). The reporting of this pilot trial is in accordance with the CONSORT extension for randomized pilot and feasibility trials. RESULTS: We randomized 20 individuals of mean age of 48.8 years (standard deviation = 9.7) with a DSM-5 diagnosis of major depressive disorder to intervention (n = 10) or control (n = 10) groups. Based on our feasibility criteria, our recruitment rate was excellent (20/27; 74%), study completion was found to be a moderate (80% of the total participants in both arms completed the study; BA = 100%, control = 60%), and completeness of measurements on a weekly basis was adequate overall (82%; BA = 86%, control = 79%). CONCLUSIONS: The study has demonstrated the potential feasibility to perform a larger scale trial upon modifications to the control group to avoid the low rate of study completion (60%) in this group. TRIAL REGISTRATION: ClinicalTrials NCT02045771, Registered January 22, 2014.

Diagnosis of deep vein thrombosis of the lower extremity: a systematic review and meta-analysis of test accuracy.

Deep vein thrombosis (DVT) of the lower extremities can be associated with significant morbidity and may progress to pulmonary embolism and postthrombotic syndrome. Early diagnosis and treatment are important to minimize the risk of these complications. We systematically reviewed the accuracy of diagnostic tests for first-episode and recurrent DVT of the lower extremities, including proximal compression ultrasonography (US), whole leg US, serial US, and high-sensitivity quantitative D-dimer assays. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 43 studies. For any suspected DVT, the pooled estimates for sensitivity and specificity of proximal compression US were 90.1% (95% confidence interval [CI], 86.5-92.8) and 98.5% (95% CI, 97.6-99.1), respectively. For whole-leg US, pooled estimates were 94.0% (95% CI, 91.3-95.9) and 97.3% (95% CI, 94.8-98.6); for serial US pooled estimates were 97.9% (95% CI, 96.0-98.9) and 99.8% (95% CI, 99.3-99.9). For D-dimer, pooled estimates were 96.1% (95% CI, 92.6-98.0) and 35.7% (95% CI, 29.5-42.4). Recurrent DVT studies were not pooled. Certainty of evidence varied from low to high. This systematic review of current diagnostic tests for DVT of the lower extremities provides accuracy estimates. The tests are evaluated when performed in a stand-alone fashion, and in a diagnostic pathway. The pretest probability of DVT often assessed by a clinical decision rule will influence how, together with sensitivity and specificity estimates, patients will be managed.

Long-term outcomes of acute kidney injury and strategies for improved care.

Acute kidney injury (AKI), once viewed predominantly as a self-limited and reversible condition, is now recognized as a growing problem associated with significant risks of adverse long-term health outcomes. Many cohort studies have established important relationships between AKI and subsequent risks of recurrent AKI, hospital re-admission, morbidity and mortality from cardiovascular disease and cancer, as well as the development of chronic kidney disease and end-stage kidney disease. In both high-income countries (HICs) and low-income or middle-income countries (LMICs), several challenges exist in providing high-quality, patient-centered care following AKI. Despite advances in our understanding about the long-term risks following AKI, large gaps in knowledge remain about effective interventions that can improve the outcomes of patients. Therapies for high blood pressure, glycaemic control (for patients with diabetes), renin-angiotensin inhibition and statins might be important in improving long-term cardiovascular and kidney outcomes after AKI. Novel strategies that incorporate risk stratification approaches, educational interventions and new models of ambulatory care following AKI have been described, and some of these are now being implemented and evaluated in clinical studies in HICs. Care for AKI in LMICs must overcome additional barriers due to limited resources for diagnosis and management.