Availability and quality of assessment instruments on patient-centredness in older adults with multimorbidity: a systematic review.

OBJECTIVE: Patient-centredness (PC) is central to the health care of older adults with multimorbidity, but knowledge about the psychometric quality of instruments measuring it in this group is scarce. Based on an integrative model of PC, we aimed to identify assessment instruments of PC for this particular group and evaluate their psychometric properties. METHODS: We systematically searched six electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO, Web of Science and PSYNDEX), initially covering research published up to 2018 and updated later to include work up to July 2022. In evaluating the psychometric properties of identified instruments, we followed the COSMIN methodology. RESULTS: We identified 12 studies reporting on 10 instruments measuring PC in the health care of older adults with multimorbidity. For these instruments, structural validity and internal consistency were the psychometric properties reported most often. Based on the COSMIN criteria, eight instruments received favourable ratings for internal consistency with respect to methodological quality ('very good'), measurement property ('sufficient') and overall quality of evidence ('moderate'). Ratings of structural validity varied more largely, with three to seven instruments showing at least adequate methodological quality, sufficient structural validity or moderate quality of evidence. CONCLUSIONS: Similar to comparable previous reviews, evidence on the psychometric properties of instruments assessing PC in the health care of older adults with multimorbidity was rather limited. Informed by comprehensive models of PC, further research should aim at developing measures of PC that stand out on a broader range of psychometric properties.

Assessing severe acute respiratory syndrome coronavirus 2 infectivity by reverse-transcription polymerase chain reaction: A systematic review and meta-analysis.

The cornerstone of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is reverse-transcription polymerase chain reaction (RT-PCR) of viral RNA. As a surrogate assay SARS-CoV-2 RNA detection does not necessarily imply infectivity. Only virus isolation in permissive cell culture systems can indicate infectivity. Here, we review the evidence on RT-PCR performance in detecting infectious SARS-CoV-2. We searched for any studies that used RT-PCR and cell culture to determine infectious SARS-CoV-2 in respiratory samples. We assessed (i) diagnostic accuracy of RT-PCR compared to cell culture as reference test, (ii) performed meta-analysis of positive predictive values (PPV) and (iii) determined the virus isolation probabilities depending on cycle threshold (Ct) or log10 genome copies/ml using logistic regression. We included 55 studies. There is substantial statistical and clinical heterogeneity. Seven studies were included for diagnostic accuracy. Sensitivity ranged from 90% to 99% and specificity from 29% to 92%. In meta-analysis, the PPVs varied across subgroups with different sampling times after symptom onset, with 1% (95% confidence interval [CI], 0%-7%) in sampling beyond 10 days and 27% (CI, 19%-36%) to 46% (CI, 33%-60%) in subgroups that also included earlier samples. Estimates of virus isolation probability varied between 6% (CI, 0%-100%) and 50% (CI, 0%-100%) at a Ct value of 30 and between 0% (CI, 0%-22%) and 63% (CI, 0%-100%) at 5 log10 genome copies/ml. Evidence on RT-PCR performance in detecting infectious SARS-CoV-2 in respiratory samples was limited. Major limitations were heterogeneity and poor reporting. RT-PCR and cell culture protocols need further standardisation.

Efficacy and safety of strong opioids for chronic noncancer pain and chronic low back pain: a systematic review and meta-analyses.

ABSTRACT: In recent years, long-term prescribing and use of strong opioids for chronic noncancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies, and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses compared the efficacy, safety, and tolerability of strong opioids with placebo or nonopioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in 4 electronic databases (MEDLINE, Web of Science, Cochrane Library, and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled randomized controlled trials for CLBP and 5 studies (2 randomized controlled trials and 3 nonrandomized studies) of opioids vs nonopioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise meta-analyses were performed for efficacy, safety, and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low to low certainty findings suggest that 4 to 15 weeks (short or intermediate term) opioid therapy in CLBP (compared with placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events, with likely no effect on disability. By contrast, long-term opioid therapy (≥6 months) in CNCP may not be superior to nonopioids in improving pain or disability or pain-related function but seems to be associated with more adverse events, opioid abuse or dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.

Status, use and impact of sharing individual participant data from clinical trials: a scoping review.

OBJECTIVES: To explore the impact of data-sharing initiatives on the intent to share data, on actual data sharing, on the use of shared data and on research output and impact of shared data. ELIGIBILITY CRITERIA: All studies investigating data-sharing practices for individual participant data (IPD) from clinical trials. SOURCES OF EVIDENCE: We searched the Medline database, the Cochrane Library, the Science Citation Index Expanded and the Social Sciences Citation Index via Web of Science, and preprints and proceedings of the International Congress on Peer Review and Scientific Publication. In addition, we inspected major clinical trial data-sharing platforms, contacted major journals/publishers, editorial groups and some funders. CHARTING METHODS: Two reviewers independently extracted information on methods and results from resources identified using a standardised questionnaire. A map of the extracted data was constructed and accompanied by a narrative summary for each outcome domain. RESULTS: 93 studies identified in the literature search (published between 2001 and 2020, median: 2018) and 5 from additional information sources were included in the scoping review. Most studies were descriptive and focused on early phases of the data-sharing process. While the willingness to share IPD from clinical trials is extremely high, actual data-sharing rates are suboptimal. A survey of journal data suggests poor to moderate enforcement of the policies by publishers. Metrics provided by platforms suggest that a large majority of data remains unrequested. When requested, the purpose of the reuse is more often secondary analyses and meta-analyses, rarely re-analyses. Finally, studies focused on the real impact of data-sharing were rare and used surrogates such as citation metrics. CONCLUSIONS: There is currently a gap in the evidence base for the impact of IPD sharing, which entails uncertainties in the implementation of current data-sharing policies. High level evidence is needed to assess whether the value of medical research increases with data-sharing practices.

Quantification and interpretation of attributable mortality in core clinical infectious disease journals.

Attributable mortality is an important metric that mirrors the public health effect of a potentially harmful infection by accounting not only for the effect of infection on mortality, but also for its prevalence within the target population. We did a systematic literature review to identify how attributable deaths were quantified and interpreted in core clinical infectious diseases journals between Jan 1, 2013, and April 6, 2020. Of the 1591 abstracts screened, 234 entered the primary analysis. Our summary of the epidemiological measures used in these articles reveals fundamental shortcomings in the conception of attributable mortality. Because of its importance as a basis for decision making on public health matters, it is essential to correctly quantify and report on attributable mortality. Our recommendation for quantification and reporting of attributable deaths aids clinical researchers in the correct statistical assessment of the burden of infections. Fictional as well as real data is used to illustrate these issues.

Quality and validity of large animal experiments in stroke: A systematic review.

An important factor for successful translational stroke research is study quality. Low-quality studies are at risk of biased results and effect overestimation, as has been intensely discussed for small animal stroke research. However, little is known about the methodological rigor and quality in large animal stroke models, which are becoming more frequently used in the field. Based on research in two databases, this systematic review surveys and analyses the methodological quality in large animal stroke research. Quality analysis was based on the Stroke Therapy Academic Industry Roundtable and the Animals in Research: Reporting In Vivo Experiments guidelines. Our analysis revealed that large animal models are utilized with similar shortcomings as small animal models. Moreover, translational benefits of large animal models may be limited due to lacking implementation of important quality criteria such as randomization, allocation concealment, and blinded assessment of outcome. On the other hand, an increase of study quality over time and a positive correlation between study quality and journal impact factor were identified. Based on the obtained findings, we derive recommendations for optimal study planning, conducting, and data analysis/reporting when using large animal stroke models to fully benefit from the translational advantages offered by these models.

Availability and Quality of Assessment Instruments on Patient-Centredness in the Multimorbid Elderly (AQuA-PCE): a study protocol of a systematic review.

INTRODUCTION: Elderly, multimorbid patients are a primary target group for patient-centred care, and fostering patient-centredness (PC) in this group has been associated with different healthcare aims such as safety and quality of healthcare. However, evidence on effects of patient-centred interventions is still limited and mixed. In part, the lack of consistent evidence has its roots in a conceptual uncertainty of the term 'PC', which also hampers the development of assessment tools for PC. Consequently, reviews on assessment instruments of PC reveal problems regarding the quality of identified assessment instruments and regarding their comparability. Some of these reviews focus on the elderly. However, while the concept of multimorbidity is partly inherent, this focus is not explicit in any of the reviews.The aim of this systematic review is to identify assessment instruments of PC in the multimorbid elderly, using a subgroup-specific definition of PC ('subgroup-specific integrative model of PC') as the conceptual underpinning, and to provide a critical quality appraisal of their psychometric properties. METHODS AND ANALYSIS: A comprehensive systematic literature search for assessment tools on PC will be conducted in the MEDLINE, CINAHL, EMBASE, PsycINFO, Web of Science and PSYNDEX electronic databases. The search strategy will be informed by the subgroup-specific integrative model of PC. The electronic literature search will be complemented by a hand-search combining citation tracking, search in project databases, and contacting authors from relevant studies/reviews. The literature search (systematic and hand-search) will cover the period from November, 2018 to December 2019.The retrieval of relevant studies will be conducted via title screening, abstract screening, and full-text eligibility assessment applying defined inclusion criteria. Full texts will be independently assessed by two team members. Data from the included articles will be extracted using a standardised extraction form and evaluated based on the COSMIN methodology for systematic reviews of patient-reported outcome measures, which focuses on the methodological quality of included studies as well as on the measurement properties of the assessment instruments. Data extraction and quality assessment will be conducted by two independent reviewers. ETHICS AND DISSEMINATION: The study has received approval from the Ethics Committee of the University of Freiburg (reference number 587/17). The results of the project will be disseminated via scientific oral presentations at national and international conferences and will be published in scientific journals. TRIAL REGISTRATION NUMBERS: CRD42018084057; DRKS00013309.

PET/CT-Based Response Evaluation in Cancer-a Systematic Review of Design Issues.

Positron emission tomography/x-ray computed tomography (PET/CT) has long been discussed as a promising modality for response evaluation in cancer. When designing respective clinical trials, several design issues have to be addressed, especially the number/timing of PET/CT scans, the approach for quantifying metabolic activity, and the final translation of measurements into a rule. It is unclear how well these issues have been tackled in quest of an optimised use of PET/CT in response evaluation. Medline via Ovid and Science Citation Index via Web of Science were systematically searched for articles from 2015 on cancer patients scanned with PET/CT before and during/after treatment. Reports were categorised as being either developmental or evaluative, i.e. focusing on either the establishment or the evaluation of a rule discriminating responders from non-responders. Of 124 included papers, 112 (90 %) were accuracy and/or prognostic studies; the remainder were response-curve studies. No randomised controlled trials were found. Most studies were prospective (62 %) and from single centres (85 %); median number of patients was 38.5 (range 5-354). Most (69 %) of the studies employed only one post-baseline scan. Quantification was mainly based on SUVmax (91 %), while change over time was most frequently used to combine measurements into a rule (79 %). Half of the reports were categorised as developmental, the other half evaluative. Most development studies assessed only one element (35/62, 56 %), most frequently the choice of cut-off points (25/62, 40 %). In summary, the majority of studies did not address the essential open issues in establishing PET/CT for response evaluation. Reasonably sized multicentre studies are needed to systematically compare the many different options when using PET/CT for response evaluation.

Impact of mechanical ventilation on the daily costs of ICU care: a systematic review and meta regression.

The impact of mechanical ventilation on the daily costs of intensive care unit (ICU) care is largely unknown. We thus conducted a systematic search for studies measuring the daily costs of ICU stays for general populations of adults (age ≥18 years) and the added costs of mechanical ventilation. The relative increase in the daily costs was estimated using random effects meta regression. The results of the analyses were applied to a recent study calculating the excess length-of-stay associated with ICU-acquired (ventilator-associated) pneumonia, a major complication of mechanical ventilation. The search identified five eligible studies including a total of 54 766 patients and ~238 037 patient days in the ICU. Overall, mechanical ventilation was associated with a 25.8% (95% CI 4.7%-51.2%) increase in the daily costs of ICU care. A combination of these estimates with standardised unit costs results in approximate daily costs of a single ventilated ICU day of €1654 and €1580 in France and Germany, respectively. Mechanical ventilation is a major driver of ICU costs and should be taken into account when measuring the financial burden of adverse events in ICU settings.

Health-related preferences of older patients with multimorbidity: an evidence map.

OBJECTIVES: To systematically identify knowledge clusters and research gaps in the health-related preferences of older patients with multimorbidity by mapping current evidence. DESIGN: Evidence map (systematic review variant). DATA SOURCES: MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Science Citation Index/Social Science Citation Index/-Expanded from inception to April 2018. STUDY SELECTION: Studies reporting primary research on health-related preferences of older patients (mean age ≥60 years) with multimorbidity (≥2 chronic/acute conditions). DATA EXTRACTION: Two independent reviewers assessed studies for eligibility, extracted data and clustered the studies using MAXQDA-18 content analysis software. RESULTS: The 152 included studies (62% from North America, 28% from Europe) comprised 57 093 patients overall (range 9-9105). All used an observational design except for one interventional study: 63 (41%) were qualitative (59 cross-sectional, 4 longitudinal), 85 (57%) quantitative (63 cross-sectional, 22 longitudinal) and 3 (2%) used mixed methods. The setting was specialised care in 85 (56%) and primary care in 54 (36%) studies. We identified seven clusters of studies on preferences: end-of-life care (n=51, 34%), self-management (n=34, 22%), treatment (n=32, 21%), involvement in shared decision making (n=25, 17%), health outcome prioritisation/goal setting (n=19, 13%), healthcare service (n=12, 8%) and screening/diagnostic testing (n=1, 1%). Terminology (eg, preferences, views and perspectives) and concepts (eg, trade-offs, decision regret, goal setting) used to describe health-related preferences varied substantially between studies. CONCLUSION: Our study provides the first evidence map on the preferences of older patients with multimorbidity. Included studies were mostly conducted in developed countries and covered a broad range of issues. Evidence on patient preferences concerning decision-making on screening and diagnostic testing was scarce. Differences in employed terminology, decision-making components and concepts, as well as the sparsity of intervention studies, are challenges for future research into evidence-based decision support seeking to elicit the preferences of older patients with multimorbidity and help them construct preferences. TRIAL REGISTRATION NUMBER: Open Science Framework (OSF): DOI 10.17605/OSF.IO/MCRWQ.

Evaluating the Diagnostic Accuracy of the Head-Impulse Test: A Scoping Review.

Importance: Vestibular symptoms rank among the most common complaints in medicine worldwide. Underlying disorders manifested by these symptoms are generally associated with an impairment of the vestibular-ocular reflex and can be assessed with different diagnostic procedures. In recent years, an increasing number of diagnostic test accuracy studies comparing various head-impulse test (HIT) methods with other diagnostic procedures have been published but not systematically reviewed. Objective: To conduct a scoping review and describe key characteristics of the growing number of diagnostic studies in patients presenting with vestibular symptoms. Evidence Review: In April 2017, published studies were identified through searches of 4 bibliographic databases: Medline, Science Citation Index Expanded, the Cochrane Library, and ScienceDirect. Studies were included if they provided diagnostic accuracy data (sensitivity and specificity) for any HIT method with reference to any other vestibular test or clinical diagnosis in patients with vestibular symptoms. Study key characteristics were extracted, and the current literature was described narratively. All analysis took place between June 2017 and July 2018. Findings: We identified a total of 27 diagnostic studies (including 3821 participants). There were disagreements between diagnostic test accuracy data both within and between studies when different HIT methods were compared with other diagnostic procedures. The proportion of correctly identified people having the disease (sensitivity) ranged between 0% and 100% (median, 41%), whereas the proportion of correctly identified people without the disease (specificity) was higher and ranged between 56% and 100% (median, 94%). Conclusions and Relevance: Based on the studies included in this review, sensitivity, specificity, and, more importantly, the risk of misdiagnosis and associated undertreatment or overtreatment cannot be reliably estimated by HIT methods for patients with vestibular symptoms. We recommend that further diagnostic studies consider (1) multiple possible underlying causes of vestibular symptoms and multiple test thresholds, (2) a representative sample of patients with and without the disease, and (3) reporting guidelines for diagnostic test accuracy studies.

Milk A1 ß-casein and health-related outcomes in humans: a systematic review.

CONTEXT: Various epidemiological studies suggest a positive association between exposure to cow's milk A1 ß-casein protein and risk for noncommunicable chronic diseases. The consumption of A2 cow's milk is increasing, likely because A2 milk is postulated to have positive effects on digestive health. OBJECTIVE: A systematic review was conducted to investigate associations between A1 ß-casein and health-related outcomes in humans. DATA SOURCES: Five electronic databases, 3 clinical trial registries, and the internet were searched systematically. STUDY SELECTION: Using predefined inclusion criteria, 2 authors independently selected studies investigating the effect of A1 ß-casein or ß-casomorphin-7 intake/exposure on any health-related outcome in humans. Discrepancies were resolved by consensus. DATA EXTRACTION: Two authors independently extracted data and assessed risk of bias. The certainty of evidence per outcome was evaluated using the GRADE approach. Discrepancies were resolved by consensus. RESULTS: Fifteen randomized controlled trials, 2 case-control studies, and 8 ecological studies were included. Most randomized controlled studies and case-control studies investigating a potential effect on various outcomes were based on intermediate markers and found no significant difference between the 2 milk types. In contrast, most ecological studies reported that population-level A1 ß-casein exposure is associated with adverse health outcomes. The certainty of the evidence for the included outcomes, as assessed by the GRADE approach, was rated as moderate for digestive symptoms and as low to very low for all other outcomes. CONCLUSIONS: Human-based evidence from clinical trials and epidemiological studies published prior to October 2017 provides moderate certainty for adverse digestive health effects of A1 ß-casein compared with A2 ß-casein but low or very low certainty for other health effects. These conclusions may change in the future, given the emergent nature of this topic and the ongoing research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42016043795.

Large animals in neurointerventional research: A systematic review on models, techniques and their application in endovascular procedures for stroke, aneurysms and vascular malformations.

Neuroendovascular procedures have led to breakthroughs in the treatment of ischemic stroke, intracranial aneurysms, and intracranial arteriovenous malformations. Due to these substantial successes, there is continuous development of novel and refined therapeutic approaches. Large animal models feature various conceptual advantages in translational research, which makes them appealing for the development of novel endovascular treatments. However, the availability and role of large animal models have not been systematically described so far. Based on comprehensive research in two databases, this systematic review describes current large animal models in neuroendovascular research including their primary use. It may therefore serve as a compact compendium for researchers entering the field or looking for opportunities to refine study concepts. It also describes particular applications for ischemic stroke and aneurysm therapy, as well as for the treatment of arteriovenous malformations. It focuses on most promising study designs and readout parameters, as well as on important pitfalls in endovascular translational research including ways to circumvent them.

Cohort studies were found to be frequently biased by missing disease information due to death.

OBJECTIVES: In epidemiologic cohort studies with missing disease information due to death (MDID), conventional analyses right-censoring death cases at the last observation or at death may yield significant bias in relative risk and hazard ratio estimates. The aim of this study was to investigate susceptibility to this bias and assess its potential direction and magnitude. STUDY DESIGN AND SETTING: Literature review of selected epidemiologic, geriatric, and environmental journals in 2011-2012 and simulation study of various conventional approaches to handling missing disease data. A study was considered susceptible to MDID bias if disease information was collected at follow-up visits only, and a conventional analysis was performed on the data. RESULTS: Of 125 identified studies, 58 (46.4%, 95% confidence interval [CI]: 37.7-55.1%) were classified as susceptible to MDID bias, of which six (10.3%, 95% CI: 2.5-18.2%) attempted to address this in sensitivity analyses. The simulation revealed that depending on the analytic strategy for handling missing disease data, the potential exists for significant under- or over-estimation of risk factor effect estimates. CONCLUSION: Awareness of MDID bias is important as more adequate analysis methods exist permitting an unbiased analysis. Recommendations for better reporting and analysis of MDID are provided.

Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis.

Importance: Controversies about the choice of antibiotic agent and treatment modality exist in the management of erythema migrans in early cutaneous Lyme borreliosis (LB). Objective: To conduct a network meta-analysis (NMA) of all randomized clinical trials on various antibiotic agents and treatment modalities in early cutaneous LB. Data Sources: Electronic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception until July 2017. The reference lists of the included studies were hand searched, authors were contacted, and ongoing trials were searched at ClinicalTrials.gov. Study Selection: One reviewer screened the titles and abstracts of the 9975 reports identified by the electronic searches. Full-text copies of 161 potentially relevant articles were obtained, and 2 reviewers independently assessed those articles for inclusion. Adults with a physician-confirmed early localized skin infection who were treated with antibiotics of any dose or duration were included. Data Extraction and Synthesis: Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analyses on treatment effects and adverse outcomes were calculated with a frequentist approach using the R package netmeta. The Grading of Recommendations Assessment, Development and Evaluation guidance for NMA was used to assess the certainty of evidence. Main Outcomes and Measures: Treatment effects for response to treatment (resolution of symptoms) and treatment-related adverse events. Results: Overall, 19 studies (2532 patients) were included. The mean patient age ranged between 37 and 56 years, and the percentage of female patients ranged from 36% to 60%. The antibiotics investigated were doxycycline, cefuroxime axetil, ceftriaxone, amoxicillin, azithromycin, penicillin V, and minocycline. Pooled effect sizes from NMAs did not suggest any significant differences in treatment response by antibiotic agent (eg, amoxicillin vs doxycycline odds ratio, 1.26; 95% CI, 0.41-3.87), dose, or duration (eg, doxycycline, 200 mg/d for 3 weeks, vs doxycycline, 200 mg/d for 2 weeks, odds ratio, 1.28; 95% CI, 0.49-3.34). Treatment failures were rare at both 2 months (4%; 95% CI, 2%-5%) and 12 months (2%, 95% CI, 1%-3%) after treatment initiation. There were also no differences in the effect sizes among antibiotic agents and treatment modalities for treatment-related adverse outcomes, which were generally mild to moderate. Certainty of evidence was categorized as low and very low mostly because of imprecision, indirectness, and study limitations (high risk of bias) of the included studies. Conclusions and Relevance: This NMA suggests that neither the antibiotic agent nor treatment modality contributed to comparative effectiveness or drug-related adverse outcomes. This finding is relevant for physicians treating patients with LB and for patient decision making.

Prophylactic antibiotics before cord clamping in cesarean delivery: a systematic review.

INTRODUCTION: The number of clinical trials investigating the optimal timing of prophylactic antibiotics in cesarean section has increased rapidly over the last few years. We conducted a systematic review to inform up-to-date evidence-based guidelines to prevent postpartum infectious morbidity in the mother and rule out any safety issues related to antepartum antibiotic exposure in infants. MATERIAL AND METHODS: Four bibliographic databases were searched for published reports of trials. Ongoing or unpublished studies were searched in Clinicaltrials.gov and the World Health Organization registry platform. Randomized controlled trials comparing antibiotic prophylaxis before and after cord clamping in cesarean section were eligible. Maternal and neonatal outcomes were assessed, and certainty of evidence graded. RESULTS: In total, 18 randomized controlled trials met the inclusion criteria. Those women who received antibiotics preoperatively were 28% (relative risk 0.72, 95% confidence interval 0.56-0.92, nine studies, 4342 women, high quality of evidence) less likely to show infectious morbidity as compared with those who received antibiotics after cord clamping. The risk of endomyometritis and/or endometritis was reduced by 43% (relative risk 0.57, 95% confidence interval 0.40-0.82, 13 studies, 6250 women, high quality of evidence) and the risk of wound infection by 38% (relative risk 0.62, 95% confidence interval 0.47-0.81, 14 studies, 6450 women, high quality of evidence) in those who received antibiotics preoperatively as compared to those who received antibiotics after cord clamping. For other maternal infections no significant differences were identified. The risk for neonatal outcomes, such as deaths attributed to infection, sepsis, neonatal antibiotic treatment, intensive care unit admission or antibiotic-related adverse events, was not found to be different, either clinically or statistically, when antibiotics were given before or after cord clamping (moderate to low quality of evidence). CONCLUSIONS: The evidence in favor of prophylactic antibiotic administration before, in comparison with after, cord clamping for major maternal infections was of high quality, meaning that further research would be unlikely to change the confidence in these findings. However, we recommend additional research reflecting the precision of the effect estimates for neonatal outcomes.

Deferasirox for managing iron overload in people with thalassaemia.

BACKGROUND: Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed. OBJECTIVES: To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015. SELECTION CRITERIA: Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. MAIN RESULTS: Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence). AUTHORS' CONCLUSIONS: Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine.

Dealing with foreign cultural paradigms: A systematic review on intercultural challenges of international medical graduates.

OBJECTIVES: An increasing number of International Medical Graduates (IMG), who are defined to be physicians working in a country other than their country of origin and training, immigrate to Western countries. In order to ensure safe and high-quality patient care, they have to take medical and language tests. This systematic review aims to (1) collect all empiric research on intercultural communication of IMGs in medical settings, (2) identify and categorize all text passages mentioning intercultural issues in the included studies, and (3) describe the most commonly reported intercultural areas of communication of IMGs. METHODS: This review was based on the PRISMA-Guidelines for systematic reviews. We conducted a broad and systematic electronic literature search for empiric research in the following databases: MEDLINE, BIOSIS Citation Index, BIOSIS Previews, KCI-Korean Journal Database and SciELO Citation Index. The search results were synthesized and analyzed with the aid of coding systems. These coding systems were based on textual analysis and derived from the themes and topics of the results and discussion sections from the included studies. A quality assessment was performed, comparing the studies with their corresponding checklist (COREQ or STROBE). Textual results of the studies were extracted and categorized. RESULTS: Among 10,630 search results, 47 studies were identified for analysis. 31 studies were qualitative, 12 quantitative and 4 studies used mixed methods. The quality assessment revealed a low level of quality of the studies in general. The following intercultural problems were identified: IMGs were not familiar with shared decision-making and lower hierarchies in the health care system in general. They had difficulties with patient-centered care, the subtleties of the foreign language and with the organizational structures of the new health care system. In addition, they described the medical education in their home countries as science-oriented, without focusing on psychosocial aspects. CONCLUSION: There is a need for a better training of IMGs on culture-related and not culture-related topics in the new workplace country. The topics that emerged in this review constitute a basis for developing these courses. Further empiric research is needed to describe the findings of this review more precisely and should be in accordance with the existing reporting guidelines.

Systemic Immunomodulating Therapies for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis.

Importance: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse reactions with high mortality. There is no evidence-based treatment, but various systemic immunomodulating therapies are used. Objectives: To provide an overview on possible immunomodulating treatments for SJS/TEN and estimate their effects on mortality compared with supportive care. Data Sources: A literature search was performed in December 2012 for articles published in MEDLINE, MEDLINE Daily, MEDLINE Inprocess, Web of Science, EMBASE, Scopus, and the Cochrane Library (Central) from January 1990 through December 2012, and updated in December 2015, in the English, French, Spanish, and German languages looking for treatment proposals for SJS/TEN. Other sources were screened manually. Study Selection: Initially, 157 randomized and nonrandomized studies on therapies (systemic immunomodulating therapies or supportive care) for SJS/TEN were selected. Data Extraction and Synthesis: Relevant data were extracted from articles. Authors were contacted for further information. Finally, 96 studies with sufficient information regarding eligibility and adequate quality scores were considered in the data synthesis. All steps were performed independently by 2 investigators. Meta-analyses on aggregated study data (random-effects model) and individual patient data (IPD) (logistic regression adjusted for confounders) were performed to assess therapeutic efficacy. In the analysis of IPD, 2 regression models, stratified and unstratified by study, were fitted. Main Outcomes and Measures: Therapy effects on mortality were expressed in terms of odds ratios (ORs) with 95% CIs. Results: Overall, 96 studies (3248 patients) were included. Applied therapies were supportive care or systemic immunomodulating therapies, including glucocorticosteroids, intravenous immunoglobulins, cyclosporine, plasmapheresis, thalidomide, cyclophosphamide, hemoperfusion, tumor necrosis factor inhibitors, and granulocyte colony-stimulating factors. Glucocorticosteroids were associated with a survival benefit for patients in all 3 analyses but were statistically significant in only one (aggregated data: OR, 0.5; 95%% CI, 0.3-1.01; IPD, unstratified: OR, 0.7; 95% CI, 0.5-0.97; IPD, stratified: OR, 0.8; 95% CI, 0.4-1.3). Despite the low patient size, cyclosporine was associated with a promising significant result in the only feasible analysis of IPD (unstratified model) (OR, 0.1; 95% CI, 0.0-0.4). No beneficial findings were observed for other therapies, including intravenous immunoglobulins. Conclusions and Relevance: Although all analyses, including the unstratified model, had limitations, glucocorticosteroids and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN. Further evaluation in prospective studies is required. However, this work provides a comprehensive overview on proposed systemic immunomodulating treatments for SJS/TEN, which is of great relevance for treating physicians.

Methods for detecting, quantifying, and adjusting for dissemination bias in meta-analysis are described.

OBJECTIVE: To systematically review methodological articles which focus on nonpublication of studies and to describe methods of detecting and/or quantifying and/or adjusting for dissemination in meta-analyses. To evaluate whether the methods have been applied to an empirical data set for which one can be reasonably confident that all studies conducted have been included. STUDY DESIGN AND SETTING: We systematically searched Medline, the Cochrane Library, and Web of Science, for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for dissemination bias in meta-analyses. RESULTS: The literature search retrieved 2,224 records, of which we finally included 150 full-text articles. A great variety of methods to detect, quantify, or adjust for dissemination bias were described. Methods included graphical methods mainly based on funnel plot approaches, statistical methods, such as regression tests, selection models, sensitivity analyses, and a great number of more recent statistical approaches. Only few methods have been validated in empirical evaluations using unpublished studies obtained from regulators (Food and Drug Administration, European Medicines Agency). CONCLUSION: We present an overview of existing methods to detect, quantify, or adjust for dissemination bias. It remains difficult to advise which method should be used as they are all limited and their validity has rarely been assessed. Therefore, a thorough literature search remains crucial in systematic reviews, and further steps to increase the availability of all research results need to be taken.