Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

INTRODUCTION: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. AIM: To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. METHODS: A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. RESULTS: Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained. CONCLUSION: This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Treatment switch to nonacog beta pegol factor IX in hemophilia B: A Canadian cost-consequence analysis based on real-world factor IX consumption and clinical outcomes.

Background: The Canadian Bleeding Disorders Registry (CBDR) is a source of real-world data for Canadian patients with hemophilia B. Nonacog beta pegol (N9-GP), an extended half-life (EHL) recombinant factor IX (FIX) concentrate, was awarded a Canadian Blood Services contract in 2018 and subsequently made available across Canada (except Québec) to adult patients. For most patients already on another EHL FIX treatment, a switch to N9-GP occurred. Objectives: This study estimates the impact on treatment costs of a switch from a prior FIX to N9-GP based on annualized bleed rates and FIX consumption volumes before and after N9-GP switch from the CBDR. Methods: Real-world data from the CBDR for total FIX consumption and annualized bleed rates were used to inform a deterministic 1-year cost-consequence model. The model considered that the EHL to N9-GP switches were from eftrenonacog alfa and the standard half-life switches were from nonacog alfa. Because FIX prices are confidential in Canada, the model assumed cost parity for annual prophylaxis with each FIX based on the product monograph recommended dosing regimen to calculate an estimated price per international unit for each product. Results: The switch to N9-GP resulted in improvements in real-world annualized bleed rates and therefore reductions in annual breakthrough bleed treatment costs. Switching to N9-GP also resulted in reduced real-world annual FIX consumption for prophylaxis. Overall, annual treatment costs were 9.4% and 10.5% lower after the switch to N9-GP from nonacog alfa and eftrenonacog alfa, respectively. Conclusion: N9-GP improves clinical outcomes and may be cost-saving vs nonacog alfa and eftrenonacog alfa.

Cost-utility analysis of emicizumab for the treatment of severe hemophilia A patients in Canada.

INTRODUCTION: EHL FVIII products and emicizumab provide clinicians with other prophylactic options for treating hemophilia A, however, it is unclear if emicizumab is a cost-saving option. The objective of this study is to estimate the health and economic effects of using prophylactic EHL FVIII, SHL FVIII, and emicizumab in severe haemophilia A patients. MATERIALS AND METHODS: A state-transition Markov model evaluated the cost-effectiveness of prophylactic SHL FVIII, EHL FVIII, and emicizumab in a cohort of 2-year-old male patients over a lifetime horizon in the form of a cost-utility analysis using a Canadian provincial ministry of health payer perspective. The transition probabilities, costs, and utilities were obtained from literature and the Canadian Bleeding Disorders Registry. Probabilistic sensitivity and scenario analyses were performed to test the robustness of the model. RESULTS: The base-case analysis, over a lifetime horizon, resulted in a total cost and utilities per person for SHL FVIII, EHL FVIII, and emicizumab of $27.2 million (M), $36.7 M, and $26.2 M, respectively, and 31.30, 31.16, and 31.61 quality-adjusted life years, respectively. Emicizumab treatment resulted in 29 and 16 less bleeds in a lifetime compared to SHL FVIII and EHL FVIII, respectively. Probabilistic sensitivity analysis showed that emicizumab was cost-saving 100% of the time compared to SHL FVIII and EHL FVIII. CONCLUSION: The cost-utility analysis showed that emicizumab is more effective and may be less costly than FVIII for Canadian haemophilia A patients, conditional on drug cost assumptions. Our model indicates that emicizumab may be a potentially favourable treatment option for minimising healthcare costs and providing higher effectiveness.

Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis.

BACKGROUND: Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). METHODS: Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. RESULTS: Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4-24%). There were 22 maternal deaths (0%, 95% CI 0-1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9-20%), and endoscopic interventions were performed in 12% (95% CI 8-17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3-12%). Thrombocytopenia was the most common complication (41%, 95% CI 23-60%). Miscarriages occurred in 14% (95% CI 8-20%), preterm birth in 27% (95% CI 19-37%), and low birth weights in 22% (95% CI 15-30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84-14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30-0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. CONCLUSION: One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.

Risk factors for bleeding in people living with hemophilia A and B treated with regular prophylaxis: A systematic review of the literature.

BACKGROUND: Knowledge about the risk for bleeding in patients with hemophilia (PWH) would be relevant for patients, stakeholders, and policy makers. OBJECTIVES: To perform a systematic review of the literature on risk assessment models (RAMs) and risk factors for bleeding in PWH on regular prophylaxis. METHODS: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from inception through August 2019. In duplicate, reviewers screened the articles for inclusion, extracted data, and assessed the risk for bias using the Quality in Prognostic Studies (QUIPS) tool. A qualitative synthesis of the results was not performed due to high heterogeneity in risk factors, outcomes definition and measurement, and statistical analysis of the results. RESULTS: From 1843 search results, 10 studies met the inclusion criteria. No RAM for the risk for bleeding in PWH was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact. CONCLUSIONS: Our findings suggest that plasma factor levels, history of bleeds, and physical activity should be considered for the derivation analysis when building a RAM for bleeding in PWH, and the role of other risk factors, including antithrombotic treatment and obesity, should be explored.

Switching to nonacog beta pegol in hemophilia B: Outcomes from a Canadian real-world, multicenter, retrospective study.

Background: The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9-GP) was approved in Canada in 2018. Objectives: To assess treatment outcomes following switching to N9-GP in a real-world setting. Methods: CBDR data for Canadian male patients (aged 7-72 years) with hemophilia B receiving prophylactic N9-GP for ≥6 months as of March 31, 2021, were included. To allow comparison with the previously used products, only patients for whom data were available in the CBDR for at least 6 months before the switch to N9-GP were included in this retrospective analysis. Results: Forty-two patients were included in the analysis (total observation period: 148.0 patient-years). The distribution of disease severity was 62% severe, 36% moderate, 2% mild, with 62% of patients previously receiving recombinant factor IX-Fc-fusion protein (rFIXFc) and 38% previously receiving standard half-life (SHL) recombinant factor IX (rFIX). During a median follow-up period of 2.3 years on N9-GP prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9-GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9-GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278). Conclusions: Results from this first real-world study of N9-GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9-GP, irrespective of the previous product.

Managing pregnancy in women with Sturge-Weber syndrome: case report and review of the literature.

Sturge-Weber syndrome (SWS) is a sporadic congenital neuro-cutaneous anomaly with capillary-venous malformation involving the brain, eye, and the ophthalmic division of the trigeminal nerve. In these cases, physiological changes in pregnancy, including hormonal and hemodynamic changes, may predispose to increased seizure frequency and even a life-threatening intracranial haemorrhage. There are only few case reports available about the management of women with pregnancy and SWS. We report two patients with SWS diagnosed in childhood and managed during pregnancy and reviewed the outcomes and complications during pregnancy in women with this disorder.

Accuracy and Acceptability of Wrist-Wearable Activity-Tracking Devices: Systematic Review of the Literature.

BACKGROUND: Numerous wrist-wearable devices to measure physical activity are currently available, but there is a need to unify the evidence on how they compare in terms of acceptability and accuracy. OBJECTIVE: The aim of this study is to perform a systematic review of the literature to assess the accuracy and acceptability (willingness to use the device for the task it is designed to support) of wrist-wearable activity trackers. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and SPORTDiscus for studies measuring physical activity in the general population using wrist-wearable activity trackers. We screened articles for inclusion and, for the included studies, reported data on the studies' setting and population, outcome measured, and risk of bias. RESULTS: A total of 65 articles were included in our review. Accuracy was assessed for 14 different outcomes, which can be classified in the following categories: count of specific activities (including step counts), time spent being active, intensity of physical activity (including energy expenditure), heart rate, distance, and speed. Substantial clinical heterogeneity did not allow us to perform a meta-analysis of the results. The outcomes assessed most frequently were step counts, heart rate, and energy expenditure. For step counts, the Fitbit Charge (or the Fitbit Charge HR) had a mean absolute percentage error (MAPE) <25% across 20 studies. For heart rate, the Apple Watch had a MAPE <10% in 2 studies. For energy expenditure, the MAPE was >30% for all the brands, showing poor accuracy across devices. Acceptability was most frequently measured through data availability and wearing time. Data availability was ≥75% for the Fitbit Charge HR, Fitbit Flex 2, and Garmin Vivofit. The wearing time was 89% for both the GENEActiv and Nike FuelBand. CONCLUSIONS: The Fitbit Charge and Fitbit Charge HR were consistently shown to have a good accuracy for step counts and the Apple Watch for measuring heart rate. None of the tested devices proved to be accurate in measuring energy expenditure. Efforts should be made to reduce the heterogeneity among studies.

Percutaneous balloon mitral valvotomy during pregnancy: A systematic review and meta-analysis.

INTRODUCTION: The objective of this study was to systematically review the maternal and fetal outcomes in pregnant women who underwent percutaneous balloon mitral valvuloplasty (PBMV) during pregnancy. MATERIAL AND METHODS: A search was conducted on MEDLINE and Embase databases to identify studies published between 2000 and 2018 that reported on maternal and fetal outcomes following PBMV performed in pregnancy. Randomized controlled trials, cohort studies, case-control studies, cross-sectional studies and case series with four or more pregnancies in which PBMV was performed during pregnancy were included. Reference lists from relevant articles were also hand-searched for relevant citations. A successful procedure was defined as one where there was a reported improvement in the valve area or reduction in the mitral valve gradient. A random effects model was used to derive pooled estimates of various outcomes and the final estimates were reported as percentages with a 95% confidence interval (95% CI). RESULTS: Twenty-one observational studies reporting 745 pregnancies were included in the review, all of them having reported outcomes without a comparison group. Most of the studies fell into the low-risk category as determined using the Joanna Briggs Institute (JBI) critical appraisal checklist for case series. Most of the studies (86%) were reported from low- to middle-income countries and PBMV was mostly performed during the second trimester of pregnancy. Forty-three procedures (5.7%) were unsuccessful, nearly half (n = 19) of them reported among women with the severe subvalve disease (Wilkins subvalve score 3 or more). There were 11 maternal deaths among those with suboptimal valve anatomy (severe subvalve disease or Wilkin score >8). Mitral regurgitation was the most common cardiac complication (12.7%; 95% CI 7.3%-19.1%), followed by restenosis (2.4%; 95% CI 0.02%-7.2%). Pooled incidence of cesarean section was 12.1% (95% CI 3.6%-23.8%), preterm delivery 3.9% (95% CI 0.6%-9.0%), stillbirth 0.9% (95%CI 0.2%-2.2%) and low birthweight 5.4% (95% CI 0.2%-14.7%). CONCLUSIONS: PBMV may be an effective and safe procedure for optimizing outcomes in pregnant women with mitral stenosis in the absence of severe subvalve disease.

Biomimetic Properties of Engineered Periodontal Ligament/Cementum in Dental Implants.

The conventional concept of osseointegrated dental implants based on direct connection to alveolar bone lacks a structured periodontal ligament (PDL) as in natural tooth. This limits the physiologic and functional efficiency of the implant in cushioning occlusal overload, orthodontic tooth movement, and proprioception. Development of bio-mimetic implants that can satisfy the bio-functional requirements of the natural tooth will be an innovative approach and preliminary researches in this area has been reported. This review includes in vivo studies which reported structural features and functional efficiency of an artificial PDL or cementum developed around dental implants. The electronic search identified 12 animal studies and one human trial which utilized retained or adjacent natural tooth roots, exogenous scaffold materials, dental progenitor cells derived from PDL of extracted tooth root as PDL substitutes. The result of the review is dominated by bio-hybrid implants that used dental follicles separated on the particular embryonic day and cell sheets from immortalized human cells. A summary of the currently available research on artificial PDL/cementum around dental implants highlights the potential need of autologous cell-derived tissues to bioengineer a fully functional implant design.

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization.

Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.

Pregnancy in women with Klippel-Trenaunay syndrome: Report of three pregnancies in a single patient and review of literature.

Klippel-Trenaunay syndrome is characterised by vascular abnormality which increases the risk of thromboembolism and haemorrhage. Physiological changes in pregnancy pose an increased risk to these complications. Being an uncommon disorder, there is limited literature about the management of women with pregnancy and Klippel-Trenaunay syndrome. We report in detail two of three pregnancies in a woman with Klippel-Trenaunay syndrome who had repeated episodes of haematochezia leading to anaemia, managed with Argon laser Photo-Coagulation in pregnancy and also reviewed the complications and the management of pregnant women with Klippel-Trenaunay syndrome.

Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol.

BACKGROUND: Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. OBJECTIVE: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. METHODS: Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. RESULTS: The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (available at www.wapps-hemo.org, version 2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. CONCLUSIONS: The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRK9bKP6).

Interventions for Enhancing Adherence to Antiretroviral Therapy (ART): A Systematic Review of High Quality Studies.

We sought to review the effectiveness of interventions designed to improve adherence to antiretroviral therapy (ART) from studies included in a recent Cochrane review that reported a clinical and an adherence outcome, with at least 80% follow-up for 6 months or more. Data were extracted independently and in duplicate, with an adjudicator for disagreements. Risk of bias was assessed using the Cochrane Risk of Bias tool. Of 182 relevant studies in the Cochrane review, 49 were related to ART. Statistical pooling was not warranted due to heterogeneity in interventions, participants, treatments, adherence measures and outcomes. Many studies had high risk of bias in elements of design and outcome ascertainment. Only 10 studies improved both adherence and clinical outcomes. These used the following interventions: adherence counselling (two studies); a once-daily regimen (compared to twice daily); text messaging; web-based cognitive behavioral intervention; face-to-face multi-session intensive behavioral interventions (two studies); contingency management; modified directly observed therapy; and nurse-delivered home visits combined with telephone calls. Patient-related adherence interventions were the most frequently tested. Uniform adherence measures and higher quality studies of younger populations are encouraged.

Technology-mediated interventions for enhancing medication adherence.

BACKGROUND: Despite effective therapies for many conditions, patients find it difficult to adhere to prescribed treatments. Technology-mediated interventions (TMIs) are increasingly being used with the hope of improving adherence. OBJECTIVE: To assess the effects of TMI, intended to enhance patient adherence to prescribed medications, on both medication adherence and clinical outcomes. METHODS: A secondary in-depth analysis was conducted of the subset of studies that utilized technology in at least one component of the intervention from an updated Cochrane review on all interventions for enhancing medication adherence. We included studies that clearly described an information and communication technology or medical device as the sole or major component of the adherence intervention. RESULTS: Thirty-eight studies were eligible for in-depth review. Only seven had a low risk of bias for study design features, primary adherence, and clinical outcomes. Eighteen studies used a TMI for education and/or counseling, 11 studies used a TMI for self-monitoring and/or feedback, and nine studies used electronic reminders. Studies used a variety of TMIs, with telephone the most common technology in use. Studies targeted a wide distribution of diseases and used a variety of adherence and clinical outcome measures. A minority targeted children and adolescents. Fourteen studies reported significant effects in both adherence and clinical outcome measures. CONCLUSIONS: This review provides evidence for the inconsistent effectiveness of TMI for medication adherence and clinical outcomes. These results must be interpreted with caution due to a lack of high-quality studies.

Interventions for enhancing medication adherence.

BACKGROUND: People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications. OBJECTIVES: The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes. SEARCH METHODS: We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles. SELECTION CRITERIA: We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive findings at earlier time points. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta-analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome. MAIN RESULTS: The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub-analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes. AUTHORS' CONCLUSIONS: Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements in patient-important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.

PubMed alternatives to search MEDLINE: an environmental scan.

The prime objective of this article is to introduce the newer methods to access, search and process MEDLINE citations. It also aims to provide a brief overview of each service's salient features. A targeted search was conducted in MEDLINE through the OVID gateway. This was followed with a search in Google Scholar as well as Google and Bing. Ninety-two web-based services that can be used to search MEDLINE were identified. The list was shortened to 24 by applying a set of relevancy criteria to select those services more relevant to general medical and dental users. Salient features of the selected services are outlined and a use case based classification of the system has been proposed to help dental practitioners and researchers select the appropriate service for a given purpose.

Adherence measurement and patient recruitment methods are poor in intervention trials to improve patient adherence.

OBJECTIVES: To develop a scale and survey the measurement of patient adherence and patient recruitment, and to explore how these methods impact the results in randomized controlled trials of interventions to improve patient adherence to medications. STUDY DESIGN: Analytic survey of a purposively selected sample of patient adherence intervention trials from a systematic review, assessing the quality of adherence measurement and patient recruitment methods. RESULTS: We identified 44 different measures of adherence, with qualities ranging from valid and objective to unreliable and subjective. The median overall quality of measures of adherence was 5 (interquartile range [IQR], 3; range, 0-9, 9 is high quality). The quality of the measures was associated with variation in the estimate of adherence (Spearman r = 0.66; 95% confidence interval: 0.39, 0.83). The median overall quality of patient recruitment methods was 2 (IQR, 1; maximum score 6, higher is better). There was no significant correlation between the power of the trial to detect an effect and the quality of the patient recruitment methods. CONCLUSION: Measurement and recruitment methods in adherence trials varied considerably, and most methods were of low quality. Adherence research could be advanced by using higher quality measures of adherence and better selection and baseline assessment of study participants.

Net improvement of correct answers to therapy questions after pubmed searches: pre/post comparison.

BACKGROUND: Clinicians search PubMed for answers to clinical questions although it is time consuming and not always successful. OBJECTIVE: To determine if PubMed used with its Clinical Queries feature to filter results based on study quality would improve search success (more correct answers to clinical questions related to therapy). METHODS: We invited 528 primary care physicians to participate, 143 (27.1%) consented, and 111 (21.0% of the total and 77.6% of those who consented) completed the study. Participants answered 14 yes/no therapy questions and were given 4 of these (2 originally answered correctly and 2 originally answered incorrectly) to search using either the PubMed main screen or PubMed Clinical Queries narrow therapy filter via a purpose-built system with identical search screens. Participants also picked 3 of the first 20 retrieved citations that best addressed each question. They were then asked to re-answer the original 14 questions. RESULTS: We found no statistically significant differences in the rates of correct or incorrect answers using the PubMed main screen or PubMed Clinical Queries. The rate of correct answers increased from 50.0% to 61.4% (95% CI 55.0%-67.8%) for the PubMed main screen searches and from 50.0% to 59.1% (95% CI 52.6%-65.6%) for Clinical Queries searches. These net absolute increases of 11.4% and 9.1%, respectively, included previously correct answers changing to incorrect at a rate of 9.5% (95% CI 5.6%-13.4%) for PubMed main screen searches and 9.1% (95% CI 5.3%-12.9%) for Clinical Queries searches, combined with increases in the rate of being correct of 20.5% (95% CI 15.2%-25.8%) for PubMed main screen searches and 17.7% (95% CI 12.7%-22.7%) for Clinical Queries searches. CONCLUSIONS: PubMed can assist clinicians answering clinical questions with an approximately 10% absolute rate of improvement in correct answers. This small increase includes more correct answers partially offset by a decrease in previously correct answers.