The mental health impact of the COVID-19 pandemic on older adults: a systematic review and meta-analysis.

BACKGROUND: Early in the COVID-19 pandemic, many experts pointed to potential adverse mental health effects for older adults. By contrast, many studies in young to middle-aged adults found older age to be associated with reduced mental burden. However, a systematic review on older adults is missing. OBJECTIVES: To comprehensively assess the pandemic's mental health impact on older adults. DATA SOURCES: We searched nine databases from December 2019 to April 2022. STUDY SELECTION: We included longitudinal and repeated cross-sectional studies assessing pre- and/or peri-pandemic mental distress and/or positive mental health indicators (e.g. wellbeing) on at least two occasions. DATA SYNTHESIS: We identified 108 studies comprising 102,136 participants (≥60 years). After removal of outliers, there was a small increase in mental distress from pre-to-peri-pandemic assessments, standardised mean difference (SMD) = 0.10, 95% confidence interval (CI) [0.01, 0.18]. Furthermore, a small peri-pandemic decrease in anxiety symptoms was observed, whereas other symptoms remained unchanged. For positive mental health indicators, wellbeing and quality of life showed an initial decrease, whereas overall positive mental health increased during the pandemic, SMD = 0.08, 95% CI [0.01, 0.15]. Being female was related to larger peri-pandemic increases in mental distress. CONCLUSIONS: Based on many studies, this review demonstrated small decreases in mental health during early stages of the pandemic in older adults, with evidence for later recovery. These findings are similar to those for younger adults and correct earlier claims that older adults are at particular risk for negative mental health consequences. The results ask for further research into resilience and adaptation processes in older adults.

An empirical evaluation of the impact scenario of pooling bodies of evidence from randomized controlled trials and cohort studies in medical research.

BACKGROUND: Randomized controlled trials (RCTs) and cohort studies are the most common study design types used to assess treatment effects of medical interventions. We aimed to hypothetically pool bodies of evidence (BoE) from RCTs with matched BoE from cohort studies included in the same systematic review. METHODS: BoE derived from systematic reviews of RCTs and cohort studies published in the 13 medical journals with the highest impact factor were considered. We re-analyzed effect estimates of the included systematic reviews by pooling BoE from RCTs with BoE from cohort studies using random and common effects models. We evaluated statistical heterogeneity, 95% prediction intervals, weight of BoE from RCTs to the pooled estimate, and whether integration of BoE from cohort studies modified the conclusion from BoE of RCTs. RESULTS: Overall, 118 BoE-pairs based on 653 RCTs and 804 cohort studies were pooled. By pooling BoE from RCTs and cohort studies with a random effects model, for 61 (51.7%) out of 118 BoE-pairs, the 95% confidence interval (CI) excludes no effect. By pooling BoE from RCTs and cohort studies, the median I2 was 48%, and the median contributed percentage weight of RCTs to the pooled estimates was 40%. The direction of effect between BoE from RCTs and pooled effect estimates was mainly concordant (79.7%). The integration of BoE from cohort studies modified the conclusion (by examining the 95% CI) from BoE of RCTs in 32 (27%) of the 118 BoE-pairs, but the direction of effect was mainly concordant (88%). CONCLUSIONS: Our findings provide insights for the potential impact of pooling both BoE in systematic reviews. In medical research, it is often important to rely on both evidence of RCTs and cohort studies to get a whole picture of an investigated intervention-disease association. A decision for or against pooling different study designs should also always take into account, for example, PI/ECO similarity, risk of bias, coherence of effect estimates, and also the trustworthiness of the evidence. Overall, there is a need for more research on the influence of those issues on potential pooling.

Clinical and methodological implications for research elements in systematic reviews on COVID-19 treatment were often unstructured and under-reported: a metaresearch study.

OBJECTIVES: Numerous systematic reviews (SRs) have been published in the first months of the COVID-19 pandemic and clinical trials were designed rapidly highlighting the importance of informative implications for research (IfRs) sections in SRs. IfR is one item of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist and the Cochrane Handbook suggests considering population, intervention, control, outcome (PICO) and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) domains when developing IfR. We aimed (1) to assess whether SRs on COVID-19 treatments included any IfR statements and, for SRs with an IfR statement, (2) to examine which elements informed the IfR statement. STUDY DESIGN AND SETTING: We conducted a metaresearch study based on SRs on COVID-19 treatment identified in the Living OVerview of the Evidence COVID-19 database in May 2021 as part of another research project (CRD42021240423). We defined an IfR statement as at least one sentence that contained at least one bit of information that could be informative for planning future research. We extracted any IfR statements anywhere in the SRs on predefined IfR variables, in particular PICO elements, study design, and concepts underlying GRADE domains. Three authors extracted data independently after piloting the data extraction form. We resolved discrepancies in weekly discussions to ensure a high-quality data extraction. RESULTS: We included 326 SRs, of which 284 SRs (87.1%) stated IfR. Of these 284 SRs, 201 (70.8%) reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses and 66 (23.2%) using GRADE. IfR statements (n = 284) addressing PICO were unstructured and commonly reported 'population' (n = 195, 68.7%), 'intervention' (n = 242, 85.2%), and 'outcome' (n = 127, 44.7%) but not 'control' (n = 29, 10.2%). Concepts underlying GRADE domains were infrequently reported in IfR statements of SRs (n = 284): 'risk of bias' (n = 14, 4.9%), 'imprecision' (n = 8, 2.8%), 'inconsistency' (n = 7, 2.5%), 'publication bias' (n = 3, 1.1%), and 'indirectness' (n = 1, 0.4%). Additional IfR elements mentioned in IfR were 'better reporting' of future studies (n = 17, 6.0%) and 'standardization of procedures in clinical trials' (n = 12, 4.2%). CONCLUSION: Almost 90% of SRs on COVID-19 treatments reported IfR. IfR statements addressing PICO were unstructured across SRs and concepts underlying GRADE were rarely reported to inform IfR. Further work is needed to assess generalizability beyond COVID-19 and to define more precisely which IfR elements should be considered, and how they should be reported in SRs of interventions. Until then, considering PICO elements and concepts underlying GRADE to derive IfR seems to be a sensible starting point.

From standard systematic reviews to living systematic reviews.

Systematic reviews (SRs) have become a central tool for evidence-based health care over the last 30 years. The number of SRs being published has increased steadily. However, concerns have been raised regarding the duplication of work, methodological flaws and the currency of many systematic reviews, also in the context of the COVID-19 pandemic. Living systematic reviews (LSRs) offer a new approach to updating systematic reviews, particularly in high-priority research fields that face the challenge of dynamically evolving and sometimes uncertain evidence. Continual updates serve to ensure that LSRs remain current and methodologically rigorous. As a new element of the evidence ecosystem, LSRs can inform living guidelines and recommendations, user-adapted formats, decisions at the patient and system level as well as gaps in primary research.

Do journals publishing in the field of urology endorse reporting guidelines? A survey of author instructions.

INTRODUCTION: Reporting guidelines aim to ensure adequate and complete reporting of clinical studies and are an indispensable tool to translate scientific results into clinical practice. The extent to which reporting guidelines are incorporated into the author instructions of journals publishing in the field of urology remained unclear. MATERIALS AND METHODS: We assessed the author instructions of uro-nephrological journals indexed in 'Journal Citation Reports 2009'. Two authors independently assessed the author guidelines. We evaluated additional information including whether a journal was published by or in association with a medical association. Discrepancies were resolved by re-checking the respective author instructions and by discussion with a third author. RESULTS: The recommendations of the International Committee of Journal Editors were endorsed by 32 journals (58.2%) but were mentioned in 12 (37.5%) only to give general advice about manuscript preparation. Fourteen journals (25.5%) mentioned at least one reporting guideline, with CONSORT the most frequently cited. Journals with high impact factors were more likely to endorse CONSORT (p < 0.009). Other reporting guidelines were mentioned by <6% of the journals. CONCLUSION: All key stakeholders involved in the publication process should more frequently promote the awareness and use of reporting guidelines.

[Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise]. / Guidelines 2.0: Systematische Entwicklung einer umfassenden Checkliste für eine vertrauenswürdige Leitlinienentwicklung.

BACKGROUND: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. METHODS: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. RESULTS: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. INTERPRETATION: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.

Methodological quality was critically low in 9/10 systematic reviews in advanced cancer patients-A methodological study.

OBJECTIVE: To assess the methodological quality and the consideration of heterogeneity in systematic reviews (SRs). STUDY DESIGN AND SETTING: We conducted a methodological study (CRD42019134904) and searched three databases from January 2010 to July 2019. Interventional SRs with a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients were included. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 was used to evaluate the SRs' methodological quality. The consideration of heterogeneity was categorized in clinical or/and methodological heterogeneity and not explored. RESULTS: From 6234 identified references, 261 SRs were included. Most SRs had a critically low quality (230, 88.1%). The majority of them (209, 80.1%) was classified as critically low because of non-registration (222, 85.1%) combined with the non-reporting of excluded full-texts and missing justifications for exclusion (218, 83.5%). Heterogeneity in trial results was not explored at all in 51 (19.5%) SRs whereas clinical heterogeneity was considered in 117 (44.8%), methodological heterogeneity in 13 (5.0%), and both clinical and methodological heterogeneity in 80 (30.7%) SRs. CONCLUSION: The consideration of these findings in trainings for review authors and peer reviewers could improve the awareness of quality criteria and the quality of future SRs. TRIAL REGISTRATION: PROSPERO-ID: CRD42019134904.

Effects of nutrition intervention strategies in the primary prevention of overweight and obesity in school settings: a protocol for a systematic review and network meta-analysis.

BACKGROUND: Overweight and obesity in children and adolescents are major public health challenges affecting quality of life and representing important risk factors in the development of non-communicable diseases. School environments provide great possibilities for the primary prevention of overweight and obesity and different school-based nutrition interventions are available. However, existing research on school-based nutrition interventions has important limitations and no network meta-analysis (NMA) has been performed yet to compare all available interventions. Therefore, the present research project aims to investigate the impact of different nutrition interventions in the school setting by comparing and ranking them using NMA methodology. METHODS/DESIGN: A systematic literature search will be performed in 11 electronic databases (PubMed, the Cochrane Library, Web of Science, ERIC, PsycINFO, CAB Abstracts, Campbell Library, BiblioMap EPPI, Australian Education Index, Joanna Briggs Institute Evidence-Based Practice Database and Practice-based Evidence in Nutrition Database). Parallel or cluster randomized controlled trials (RCTs) meeting the following criteria will be included: (1) generally healthy school students aged 4-18 years, (2) school-based intervention with ≥ 1 nutrition component, and (3) assessed anthropometric (overweight/obesity risk, body weight change, weight Z-score, [standardized] body mass index, body fat, waist circumference) and/or diet-quality measures (daily intake of fruits and vegetables, fat, and sugar-sweetened beverages). Random effects pairwise and NMA will be performed for these outcomes and surface under the cumulative ranking curve (SUCRA) estimated (P-score). Where possible, component NMA (CNMA) will be used additionally. Subgroup analyses are carried out for intervention duration, gender, age of school students, socioeconomic status, and geographical location, and sensitivity analyses by excluding high risk of bias RCTs. DISCUSSION: This systematic review and NMA will be the first to both directly and indirectly compare and rank different school-based nutrition interventions for the primary prevention of overweight and obesity in childhood and adolescence. Our analyses will provide important insights about the effects of the different interventions and show which are the most promising. The results of our study can help inform the design of new studies and will be of value to anyone interested in developing successful, evidence-based nutrition interventions in school settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42020220451 .

[GRADE: Evidence to Decision (EtD) framework for coverage decisions]. / GRADE: Von der Evidenz zur Empfehlung oder Entscheidung ­ Entscheidungen zur Kostenerstattung.

BACKGROUND: Coverage decisions are decisions by third party payers about whether and how much to pay for technologies or services, and under what conditions. Given their complexity, a systematic and transparent approach is needed. The DECIDE project, a GRADE working group initiative funded by the European Union, has developed GRADE Evidence to Decision (EtD) frameworks for different types of decisions, including coverage ones. METHODS: We used an iterative approach, including brainstorming to generate ideas, consultation with stakeholders, user testing, and pilot testing of the framework. RESULTS: The general structure of the EtD includes formulation of the question, an assessment using 12 criteria, and conclusions. Criteria that are relevant for coverage decisions are similar to those for clinical recommendations from a population perspective. Important differences between the two include the decision-making processes, accountability, and the nature of the judgments that need to be made for some criteria. Although cost-effectiveness is a key consideration when making coverage decisions, it may not be the determining factor. Strength of recommendation is not directly linked to the type of coverage decisions, but when there are important uncertainties, it may be possible to cover an intervention for a subgroup, in the context of research, with price negotiation, or with restrictions. CONCLUSION: The EtD provides a systematic and transparent approach for making coverage decisions. It helps ensure consideration of key criteria that determine whether a technology or service should be covered and that judgments are informed by the best available evidence.

[GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence]. / GRADE-Leitlinien: 18. Wie ROBINS-I und andere Instrumente zur Einschätzung des Risikos für Bias von nicht-randomisierten Studien verwendet werden sollten, um die Vertrauenswürdigkeit eines Evidenzkörpers zu bewerten.

OBJECTIVE: To provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool as a part of GRADE's certainty rating process. STUDY DESIGN AND SETTING: The study design and setting comprised iterative discussions, testing in systematic reviews, and presentation at GRADE working group meetings with feedback from the GRADE working group. RESULTS: We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up. The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I. CONCLUSION: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias. Challenges remain, including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment.

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.

GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence.

OBJECTIVE: To provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool as a part of GRADE's certainty rating process. STUDY DESIGN AND SETTING: The study design and setting comprised iterative discussions, testing in systematic reviews, and presentation at GRADE working group meetings with feedback from the GRADE working group. RESULTS: We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up. The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I. CONCLUSIONS: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias. Challenges remain, including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment.

[GRADE: Evidence to Decision (EtD) frameworks - a systematic and transparent approach to making well informed healthcare choices. 1: Introduction]. / GRADE: Von der Evidenz zur Empfehlung oder Entscheidung - ein systematischer und transparenter Ansatz, um gut informierte Entscheidungen im Gesundheitswesen zu treffen. 1: Einleitung.

In healthcare, the processes, criteria, and evidence that decision makers use to reach their judgments often remain unclear. Decision makers sometimes neglect important criteria, give undue weight to criteria, or do not use the best available evidence to inform their judgments. Thus, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group developed a system to support transparent decision making. The purpose of the Evidence-to-Decision (EtD) framework is to help people use evidence in a structured and transparent way to inform decisions in the context of clinical recommendations, coverage decisions, and health system, or public health recommendations and decisions. EtD frameworks include the formulation of the question, an assessment of the evidence, and drawing conclusions. EtD frameworks inform users of recommendations about judgments that were made and the evidence supporting these judgments by making the basis for decisions transparent to target audiences. EtD frameworks also facilitate dissemination of recommendations.

[GRADE Guidelines: 16. GRADE evidence to decision frameworks for tests in clinical practice and public health]. / GRADE-Leitlinien: 16. Von der Evidenz zur Empfehlung oder Entscheidung ­ Vorgehen nach GRADE für Tests in der klinischen Praxis und in Public Health.

OBJECTIVE: To describe the Grading of Recommendations Assessment, Development and Evaluation (GRADE) interactive Evidence to Decision (EtD) frameworks for tests and test strategies for clinical, public health or coverage decisions. STUDY DESIGN AND SETTING: As part of the GRADE Working Group's DECIDE project we conducted workshops, user testing with systematic review authors, guideline developers and other decision makers, and piloted versions of the EtD framework. RESULTS: EtD frameworks for tests share the structure, explicitness, and transparency of other EtD frameworks. They require specifying the purpose of the test, linked or related management and the key outcomes of concern for different test results and subsequent management. The EtD criteria address test accuracy and assessments of the certainty of the additional evidence necessary for decision-making. When there is no direct evidence of test effects on patient important outcomes, formal or informal modeling is needed to estimate effects. We describe the EtD criteria based on examples developed with GRADEpro (www.gradepro.org), GRADE's software that also provides interactive Summary of Findings Tables. CONCLUSION: EtD frameworks for developing recommendations and making decisions about tests lay out the sequential steps in reviewing and assessing the different types of evidence that need to be linked.

GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADE-ADOLOPMENT.

BACKGROUND: Guideline developers can: (1) adopt existing recommendations from others; (2) adapt existing recommendations to their own context; or (3) create recommendations de novo. Monetary and nonmonetary resources, credibility, maximization of uptake, as well as logical arguments should guide the choice of the approach and processes. OBJECTIVES: To describe a potentially efficient model for guideline production based on adoption, adaptation, and/or de novo development of recommendations utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks. STUDY DESIGN AND SETTING: We applied the model in a new national guideline program producing 22 practice guidelines. We searched for relevant evidence that informs the direction and strength of a recommendation. We then produced GRADE EtDs for guideline panels to develop recommendations. RESULTS: We produced a total of 80 EtD frameworks in approximately 4 months and 146 EtDs in approximately 6 months in two waves. Use of the EtD frameworks allowed panel members understand judgments of others about the criteria that bear on guideline recommendations and then make their own judgments about those criteria in a systematic approach. CONCLUSION: The "GRADE-ADOLOPMENT" approach to guideline production combines adoption, adaptation, and, as needed, de novo development of recommendations. If developers of guidelines follow EtD criteria more widely and make their work publically available, this approach should prove even more useful.

Efficacy and safety of pharmacological agents in the treatment of erythema migrans in early Lyme borreliosis-systematic review protocol.

BACKGROUND: Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment. METHODS: To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach. DISCUSSION: Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care. PROSPERO: CRD42016037932.

Boosting qualifies capture-recapture methods for estimating the comprehensiveness of literature searches for systematic reviews.

OBJECTIVE: Capture-recapture methods were proposed to evaluate the comprehensiveness of systematic literature searches. We investigate the statistical feasibility of capture-recapture techniques with model selection for estimating the number of missing references in literature searches using two systematic reviews in gastroenterology and hematology. STUDY DESIGN AND SETTING: First, we compared manually selected Poisson regression models that differ with respect to included interactions. Secondly, we performed selection via componentwise boosting, which provides automatic variable selection. The proposed boosting technique is a regularized, stepwise procedure allowing to distinguish between mandatory and optional variables. Results from all models were compared based on Akaike's Information Criterion and the Bayesian Information Criterion. RESULTS: For the first example, the best manually selected model suggested a number of 82 missing articles (95% CI: 52-128), whereas the boosting technique provided 127 (95% CI: 86-186) missing articles. For the second example, 140 (95% CI: 116-168) missing articles were estimated for the manually selected and 188 (95% CI: 159-223) for the automatically selected model. CONCLUSION: Capture-recapture analysis requires the selection of an appropriate model. Because of problems of variable selection and overfitting, manual model selection yielded large estimates, varying markedly, with broad confidence intervals. By contrast, boosting was robust against overfitting and automatically created an appropriate model for inference.