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Background The timing at which venous thromboembolism (VTE) occurs after major surgery has major implications for the optimal duration of thromboprophylaxis. The aim of this study was to perform a systematic review and meta-analysis of the timing of postoperative VTE up to 4 weeks after surgery. Methods A systematic search of MEDLINE, Scopus, and CINAHL databases was performed between 1 January 2009 and 1 April 2022. Prospective studies that recruited patients who underwent a surgical procedure and reported at least 20 symptomatic, postoperative VTE events by time were included. Two reviewers independently selected studies according to the eligibility criteria, extracted data, and evaluated risk of bias. Data were analysed with a Poisson regression model, and the GRADE approach was used to rate the certainty of evidence. Results Some 6258 studies were evaluated, of which 22 (11 general, 5 urological, 4 mixed, and 2 orthopaedic postoperative surgical populations; total 1 864 875 patients and 24 927 VTE events) were eligible. Pooled evidence of moderate certainty showed that 47.1 per cent of the VTE events occurred during the first, 26.9 per cent during the second, 15.8 per cent during the third, and 10.1 per cent during the fourth week after surgery. The timing of VTE was consistent between individual studies. Conclusion Although nearly half of symptomatic VTE events in first 4 weeks occur during the first postoperative week, a substantial number of events occur several weeks after surgery. These data will inform clinicians and guideline developers about the duration of postoperative thromboprophylaxis.

Background Previous studies suggest that haemodiafiltration reduces mortality compared with haemodialysis in patients with end-stage kidney disease (ESKD), but the controversy surrounding its benefits remains and it is unclear to what extent individual patients benefit from haemodiafiltration. This study is aimed to develop and validate a treatment effect prediction model to determine which patients would benefit most from haemodiafiltration compared with haemodialysis in terms of all-cause mortality. Methods Individual participant data from four randomized controlled trials comparing haemodiafiltration with haemodialysis on mortality were used to derive a Royston-Parmar model for the prediction of absolute treatment effect of haemodiafiltration based on pre-specified patient and disease characteristics. Validation of the model was performed using internal-external cross validation. Results The median predicted survival benefit was 44 (Q1–Q3: 44–46) days for every year of treatment with haemodiafiltration compared with haemodialysis. The median survival benefit with haemodiafiltration ranged from 2 to 48 months. Patients who benefitted most from haemodiafiltration were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine and albumin levels. Internal–external cross validation showed adequate discrimination and calibration. Conclusion Although overall mortality is reduced by haemodiafiltration compared with haemodialysis in ESKD patients, the absolute survival benefit can vary greatly between individuals. Our results indicate that the effects of haemodiafiltration on survival can be predicted using a combination of readily available patient and disease characteristics, which could guide shared decision-making.

Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines.To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist.A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group.International collaboration.A total of 119 professionals participated in the development process.Participants' consensus on items in the checklist.The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience.The RIGHT-Ad@pt checklist requires further validation in real-life use.The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations.None.

Background The health effects of dietary fats are a controversial issue on which experts and authoritative organizations have often disagreed. Care providers, guideline developers, policy-makers, and researchers use systematic reviews to advise patients and members of the public on optimal dietary habits, and to formulate public health recommendations and policies. Existing reviews, however, have serious limitations that impede optimal dietary fat recommendations, such as a lack of focus on outcomes important to people, substantial risk of bias (RoB) issues, ignoring absolute estimates of effects together with comprehensive assessments of the certainty of the estimates for all outcomes. Objective We therefore propose a methodologically innovative systematic review using direct and indirect evidence on diet and food-based fats (i.e., reduction or replacement of saturated fat with monounsaturated or polyunsaturated fat, or carbohydrates or protein) and the risk of important health outcomes. Methods We will collaborate with an experienced research librarian to search MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR) for randomized clinical trials (RCTs) addressing saturated fat and our health outcomes of interest. In duplicate, we will screen, extract results from primary studies, assess their RoB, conduct de novo meta-analyses and/or network meta-analysis, assess the impact of missing outcome data on meta-analyses, present absolute effect estimates, and assess the certainty of evidence for each outcome using the GRADE contextualized approach. Our work will inform recommendations on saturated fat based on international standards for reporting systematic reviews and guidelines. Conclusion Our systematic review and meta-analysis will provide the most comprehensive and rigorous summary of the evidence addressing the relationship between saturated fat modification for people-important health outcomes. The evidence from this review will be used to inform public health nutrition guidelines. Trial registration PROSPERO Registration: CRD42023387377.

Background In chronic haemodialysis (HD) patients, the relationship between long-term peridialytic blood pressure (BP) changes and mortality has not been investigated. Methods To evaluate whether long-term changes in peridialytic BP are related to mortality and whether treatment with HD or haemodiafiltration (HDF) differs in this respect, the combined individual participant data of three randomized controlled trials comparing HD with HDF were used. Time-varying Cox regression and joint models were applied. Results During a median follow-up of 2.94 years, 609 of 2011 patients died. As for pre-dialytic systolic BP (pre-SBP), a severe decline (≥21 mmHg) in the preceding 6 months was independently related to increased mortality [hazard ratio (HR) 1.61, P = .01] when compared with a moderate increase. Likewise, a severe decline in post-dialytic diastolic BP (DBP) was associated with increased mortality (adjusted HR 1.96, P Conclusion Severe declines in pre-SBP and post-DBP in the preceding 6 months were independently related to mortality. Therefore peridialytic BP values should be interpreted in the context of their changes and not solely as an absolute value.

Background Patients with chronic kidney disease (CKD) require a personalised strategy for cardiovascular risk management (CVRM) to reduce their high risk of cardiovascular morbidity and mortality. Despite their high risk, patients with CKD appear to be underrepresented in randomised controlled trials (RCTs) for pharmacological CVRM interventions to reduce cardiovascular risk (pharmacological CVRM interventions). As a result, it remains unclear whether the efficacy of these interventions found in patients without CKD is similarly applicable to patients with CKD. This evidence map aims to provide an overview of the availability of the evidence from pharmacological CVRM trials for patients with CKD by assessing how often patients with reduced kidney function are specifically excluded or included from RCTs on pharmacological CVRM interventions and whether studies report efficacy estimates of interventions specifically for kidney patients. Methods We will perform a systematic literature search in ClinicalTrials.gov to identify relevant planned, ongoing, and completed RCTs on a broad range of CVRM medications after which we will retrieve the published protocols and papers via ClinicalTrials.gov itself, Embase, MEDLINE, or Google Scholar. We will include RCTs that investigate the efficacy of platelet inhibitors, anticoagulants, antihypertensives, glucose-lowering medication, and lipid-lowering medication on all-cause mortality, cardiovascular mortality, cardiovascular morbidity, and end-stage kidney disease in patients with a cardiovascular history or a major risk factor for cardiovascular disease. Two reviewers will independently screen trial records and their corresponding full-text publications to determine eligibility and extract data. Outcomes of interest are the exclusion of patients with reduced kidney function from RCTs and whether the study population was restricted to kidney patients or subgroup analyses were performed on kidney function. Results will be visualised in an evidence map. Discussion The availability of evidence on the efficacy and safety of pharmacological CVRM interventions in patients with CKD might be limited. Hence, we will identify knowledge gaps for future research. At the same time, the availability of evidence, or lack thereof, might warrant caution from healthcare decision-makers in making strong recommendations based on the extrapolation of results from studies to patients who were explicitly excluded from participation. Systematic review registration PROSPERO CRD42022296746.

Background Healthcare costs are rising, and a substantial proportion of medical care is of little value. De-implementation of low-value practices is important for improving overall health outcomes and reducing costs. We aimed to identify and synthesize randomized controlled trials (RCTs) on de-implementation interventions and to provide guidance to improve future research. Methods MEDLINE and Scopus up to May 24, 2021, for individual and cluster RCTs comparing de-implementation interventions to usual care, another intervention, or placebo. We applied independent duplicate assessment of eligibility, study characteristics, outcomes, intervention categories, implementation theories, and risk of bias. Results Of the 227 eligible trials, 145 (64%) were cluster randomized trials (median 24 clusters; median follow-up time 305 days), and 82 (36%) were individually randomized trials (median follow-up time 274 days). Of the trials, 118 (52%) were published after 2010, 149 (66%) were conducted in a primary care setting, 163 (72%) aimed to reduce the use of drug treatment, 194 (85%) measured the total volume of care, and 64 (28%) low-value care use as outcomes. Of the trials, 48 (21%) described a theoretical basis for the intervention, and 40 (18%) had the study tailored by context-specific factors. Of the de-implementation interventions, 193 (85%) were targeted at physicians, 115 (51%) tested educational sessions, and 152 (67%) multicomponent interventions. Missing data led to high risk of bias in 137 (60%) trials, followed by baseline imbalances in 99 (44%), and deficiencies in allocation concealment in 56 (25%). Conclusions De-implementation trials were mainly conducted in primary care and typically aimed to reduce low-value drug treatments. Limitations of current de-implementation research may have led to unreliable effect estimates and decreased clinical applicability of studied de-implementation strategies. We identified potential research gaps, including de-implementation in secondary and tertiary care settings, and interventions targeted at other than physicians. Future trials could be improved by favoring simpler intervention designs, better control of potential confounders, larger number of clusters in cluster trials, considering context-specific factors when planning the intervention (tailoring), and using a theoretical basis in intervention design. Registration OSF Open Science Framework hk4b2

ObjectiveTo establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE, PsycINFO and CENTRAL from inception to 1 April 2020.Study selectionNon-randomised studies reporting on harms of medical cannabis or cannabinoids in adults or children living with chronic pain with ≥4 weeks of follow-up.Data extraction and synthesisA parallel guideline panel provided input on the design and interpretation of the systematic review, including selection of adverse events for consideration. Two reviewers, working independently and in duplicate, screened the search results, extracted data and assessed risk of bias. We used random-effects models for all meta-analyses and the Grades of Recommendations, Assessment, Development and Evaluation approach to evaluate the certainty of evidence.ResultsWe identified 39 eligible studies that enrolled 12 143 adult patients with chronic pain. Very low certainty evidence suggests that adverse events are common (prevalence: 26.0%; 95% CI 13.2% to 41.2%) among users of medical cannabis for chronic pain, particularly any psychiatric adverse events (prevalence: 13.5%; 95% CI 2.6% to 30.6%). Very low certainty evidence, however, indicates serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are less common and each typically occur in fewer than 1 in 20 patients. We compared studies with ConclusionsThere is very low certainty evidence that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, but that few patients experience serious adverse events.

Background. Women with lower-extremity arterial disease (LEAD) are often underdiagnosed, present themselves with more advanced disease at diagnosis, and fare worse than men. Objective. To investigate to what extent potential gender differences exist in the frequency and reasons for general practitioner (GP) consultation six months prior to the diagnosis of LEAD, as potential indicators of diagnostic delay. Methods. Individuals older than 18 years diagnosed with LEAD, sampled from the Julius General Practitioner’s Network (JGPN), were included and compared with a reference population, matched (1:2.6 ratio) in terms of age, sex, and general practice. We applied a zero-inflated negative binomial (ZINB) regression model. Results. The study population comprised 4044 patients with LEAD (43.5% women) and 10,486 subjects in the reference population (46.3% women). In the LEAD cohort, the number of GP contacts was 2.70 (95% CI: 2.42, 3.02) in women and 2.54 (2.29, 2.82) in men. In the reference cohort, 1.77 (95% CI: 1.62, 1.94) in women and 1.63 (95% CI: 1.50, 1.78) in men. In the LEAD cohort, 21.9% of GP contacts occurred one month prior to diagnosis. In both cohorts and both sexes, the most common cause of consultation during the last month before the index date was cardiovascular problems. Conclusions. Six months preceding the initial diagnosis of LEAD, patients visit the GP more often than a similar population without LEAD, regardless of gender. Reported gender differences in the severity of LEAD at diagnosis do not seem to be explained by a delay in presentation to the GP.

Hemodiafiltration (HDF), in which both convective and diffusion methods are combined, yields an increased overall solute clearance compared with hemodialysis (HD), specifically for medium and larger molecular weight uremic toxins. Due to uncertainty in the treatment effects, the nephrology community still perceives the implementation of HDF and the achievement of high convective volume as complex. In this article, we review practical aspects of the implementation of HDF that can effectively deliver a high-volume HDF therapy and assure clinical performance to most patients. We also present an overview of the impact of high-volume HDF (compared to HD) on a series of relevant biochemical, patient-reported, and clinical outcomes, including uremic toxin removal, phosphate, Inflammation and oxidative stress, hemodynamic stability, cardiac outcomes, nutritional effects, health-related quality of life, morbidity, and mortality.

Recommendations for preventing and diagnosing recurrent urinary tract infection (UTI) tend to vary between clinical practice guidelines (CPGs) because of low-quality scientific evidence, potentially leading to practice variation and suboptimal care. We assessed the quality of existing CPGs for recurrent UTI.A systematic search was performed from January 2000 to June 2021 in PubMed and EMBASE for CPGs on recurrent UTI prevention or hospital diagnostics in Dutch, English, and Spanish. Each CPG was assessed by four appraisers in a multidisciplinary review team, using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) instrument.We identified and assessed eight CPGs published between 2013 and 2021. The scope and purpose (mean and standard deviation: 67.3 ± 21.8) and clarity of presentation (74.8 ± 17.6) domains scored highly. However, issues with methods, patient participation, conflict of interests, and facilitators and barriers were common and resulted in lower scores for the rigour of development (56.9 ± 25.9), applicability (19.6 ± 23.4), stakeholder involvement (50.4 ± 24.6), and editorial independence (62.1 ± 23.1) domains. Overall, two CPGs were recommended, three were recommended with modifications, and three were not recommended.Significant room for improvement exists in the quality of CPGs for recurrent UTI, with most displaying serious limitations in the stakeholder involvement, rigour of development, and applicability domains. These aspects must be improved to decrease diagnostic and therapeutic uncertainty. Developers could benefit from using checklists and following guidelines when developing de novo CPGs.

Background Despite the clear risks of tobacco use, millions of people continue to smoke. Electronic nicotine delivery systems (ENDS), commonly called e-cigarettes, have been proposed as a substitute for those who are unwilling or unable to quit. Current systematic and narrative reviews on the health effects of ENDS use, particularly respiratory and cardiovascular effects, have come to differing conclusions. Objective We conducted two systematic reviews to critically assess and synthesize available human studies on the respiratory and cardiovascular health effects of ENDS substitution for people who smoke. The primary goal is to provide clinicians with evidence on the health effects of ENDS substitution to inform their treatment recommendations and plans. The twin goal of the reviews is to promote health literacy in ENDS users with facts on the health effects of ENDS. Methods These two reviews will be living systematic reviews. The systematic reviews will be initiated through a baseline review. Studies will be evaluated using the JBI quality assessment tools and a checklist of biases drawn from the Centre for Evidence Based Medicine Catalogue of Bias. A narrative synthesis is planned because of the heterogeneity of data. A search for recently published studies will be conducted every 3 months, and an updated review will be published every 6 months for the duration of the project or possibly longer. Results The baseline and updated reviews will be published in a peer-reviewed journal. The findings of the reviews will be reported in a white paper for clinicians and a fact sheet for people who use ENDS. Conclusions The substitution of ENDS for cigarettes is one way to potentially reduce the risks of smoking. Clinicians and their patients need to understand the potential benefits and possible risks of substituting ENDS for cigarettes. Our living systematic reviews seek to highlight the best and most up-to-date evidence in this highly contentious and fast-moving field of research. Trial Registration PROSPERO CRD42021239094; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=239094 International Registered Report Identifier (IRRID) DERR1-10.2196/29084

BACKGROUND Despite the clear risks of tobacco use, millions of people continue to smoke. Electronic nicotine delivery systems (ENDS), commonly called e-cigarettes, have been proposed as a substitute for those who are unwilling or unable to quit. Current systematic and narrative reviews on the health effects of ENDS use, particularly respiratory and cardiovascular effects, have come to differing conclusions. OBJECTIVE We conducted two systematic reviews to critically assess and synthesize available human studies on the respiratory and cardiovascular health effects of ENDS substitution for people who smoke. The primary goal is to provide clinicians with evidence on the health effects of ENDS substitution to inform their treatment recommendations and plans. The twin goal of the reviews is to promote health literacy in ENDS users with facts on the health effects of ENDS. METHODS These two reviews will be living systematic reviews. The systematic reviews will be initiated through a baseline review. Studies will be evaluated using the JBI quality assessment tools and a checklist of biases drawn from the Centre for Evidence Based Medicine Catalogue of Bias. A narrative synthesis is planned because of the heterogeneity of data. A search for recently published studies will be conducted every 3 months, and an updated review will be published every 6 months for the duration of the project or possibly longer. RESULTS The baseline and updated reviews will be published in a peer-reviewed journal. The findings of the reviews will be reported in a white paper for clinicians and a fact sheet for people who use ENDS. CONCLUSIONS The substitution of ENDS for cigarettes is one way to potentially reduce the risks of smoking. Clinicians and their patients need to understand the potential benefits and possible risks of substituting ENDS for cigarettes. Our living systematic reviews seek to highlight the best and most up-to-date evidence in this highly contentious and fast-moving field of research. CLINICALTRIAL PROSPERO CRD42021239094; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=239094 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/29084

Background The high impact of a cancer diagnosis on patients and their families and the increasing costs of cancer treatment call for optimal and efficient oncological care. To improve the quality of care and to minimize healthcare costs and its economic burden, many healthcare organizations introduce care pathways to improve efficiency across the continuum of cancer care. However, there is limited research on the effects of cancer care pathways in different settings. Methods The aim of this systematic review and meta-analysis described in this protocol is to synthesize existing literature on the effects of oncological care pathways. We will conduct a systematic search strategy to identify all relevant literature in several biomedical databases, including Cochrane library, MEDLINE, Embase, and CINAHL. We will follow the methodology of Cochrane Effective Practice and Organisation of Care (EPOC), and we will include randomized trials, non-randomized trials, controlled before-after studies, and interrupted time series studies. In addition, we will include full economic evaluations (cost-effectiveness analyses, cost-utility analyses, and cost-benefit analyses), cost analyses, and comparative resource utilization studies, if available. Two reviewers will independently screen all studies and evaluate those included for risk of bias. From these studies, we will extract data regarding patient, professional, and health systems outcomes. Our systematic review will follow the PRISMA set of items for reporting in systematic reviews and meta-analyses. Discussion Following the protocol outlined in this article, we aim to identify, assess, and synthesize all available evidence in order to provide an evidence base on the effects of oncological care pathways as reported in the literature. Systematic review registration PROSPERO CRD42017057592. Electronic supplementary material The online version of this article (10.1186/s13643-018-0693-x) contains supplementary material, which is available to authorized users.

ObjectiveThis study aims to better understand the current practice of clinical guideline adaptation and identify challenges raised in this process, given that published adapted clinical guidelines are generally of low quality, poorly reported and not based on published frameworks.DesignA qualitative study based on semistructured interviews. We conducted a framework analysis for the adaptation process, and thematic analysis for participants’ views and experiences about adaptation process.SettingNine guideline development organisations from seven countries.ParticipantsGuideline developers who have adapted clinical guidelines within the last 3 years. We identified potential participants through published adapted clinical guidelines, recommendations from experts, and a review of the Guideline International Network Conference attendees’ list.ResultsWe conducted ten interviews and identified nine adaptation methodologies. The reasons for adapting clinical guidelines include developingde novoclinical guidelines, implementing source clinical guidelines, and harmonising and updating existing clinical guidelines. We identified the following core steps of the adaptation process (1) selection of scope and source guideline(s), (2) assessment of source materials (guidelines, recommendations and evidence level), (3) decision-making process and (4) external review and follow-up process. Challenges on the adaptation of clinical guidelines include limitations from source clinical guidelines (poor quality or reporting), limitations from adaptation settings (lacking resources or skills), adaptation process intensity and complexity, and implementation barriers. We also described how participants address the complexities and implementation issues of the adaptation process.ConclusionsAdaptation processes have been increasingly used to develop clinical guidelines, with the emergence of different purposes. The identification of core steps and assessment levels could help guideline adaptation developers streamline their processes. More methodological research is needed to develop rigorous international standards for adapting clinical guidelines.

Recent systematic reviews and editorials suggest that many organizations that produce nutritional guideline recommendations do not adhere to internationally recognized standards set forth by the Institute of Medicine (IoM), Guidelines International Network (GIN), Appraisal of Guidelines Research and Evaluation (AGREE), and Grading Recommendations, Assessment, Development and Evaluation (GRADE).The potential solution is an independent group with content expertise and skilled in the methodology of systematic reviews and practice guidelines to produce trustworthy guideline recommendations, recommendations that are supported by publication in a top tier journal. The BMJ Rapid Recommendations project has recently demonstrated the feasibility and utility of this approach. Here, we are proposing trustworthy nutritional guideline recommendations based on internationally accepted guideline development standards, recommendations that will be informed by rigorous and novel systematic reviews of the benefits and harms associated with nutritional exposures, as well as studies on the values and preferences related to dietary behaviors among members of the international community.Adhering to international guideline standards, conducting high quality systematic reviews, and actively assessing the values and preferences of key stakeholders is expected to improve the quality of nutritional guidelines and their relevance to end-users, particularly patients and community members. We will send our work for peer review, and if found acceptable, we will publish our nutritional recommendations in top-tier general medicine journals.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement.A person's meat consumption is often determined by their values and preferences.To identify and evaluate evidence addressing health-related values and preferences regarding meat consumption.MEDLINE, EMBASE, Web of Science, Centre for Agriculture and Biosciences Abstracts, International System for Agricultural Science and Technology, and Food Science and Technology Abstracts were searched from inception to July 2018 without language restrictions.Pairs of reviewers independently screened search results and included quantitative and qualitative studies reporting adults' health-related values and preferences regarding meat consumption.Pairs of reviewers independently extracted data and assessed risk of bias.Data were synthesized into narrative form, and summaries were tabulated and certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Of 19 172 initial citations, 41 quantitative studies (38 addressed reasons for meat consumption and 5 addressed willingness to reduce meat consumption) and 13 qualitative studies (10 addressed reasons for meat consumption and 4 addressed willingness to reduce meat consumption) were eligible for inclusion. Thirteen studies reported that omnivores enjoy eating meat, 18 reported that these persons consider meat an essential component of a healthy diet, and 7 reported that they believe they lack the skills needed to prepare satisfactory meals without meat. Omnivores are generally unwilling to change their meat consumption. The certainty of evidence was low for both "reasons for meat consumption" and "willingness to reduce meat consumption in the face of undesirable health effects."Limited generalizability of findings to lower-income countries, low-certainty evidence for willingness to reduce meat consumption, and limited applicability to specific types of meat (red and processed meat).Low-certainty evidence suggests that omnivores are attached to meat and are unwilling to change this behavior when faced with potentially undesirable health effects.None. (PROSPERO: CRD42018088854).

[No abstract available]