Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk.

BACKGROUND: Screening mammography can detect breast cancer at an early stage. Supporters of adding ultrasonography to the screening regimen consider it a safe and inexpensive approach to reduce false-negative rates during screening. However, those opposed to it argue that performing supplemental ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments. OBJECTIVES: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography alone for breast cancer screening for women at average risk of breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov up until 3 May 2021. SELECTION CRITERIA: For efficacy and harms, we considered randomised controlled trials (RCTs) and controlled non-randomised studies enrolling at least 500 women at average risk for breast cancer between the ages of 40 and 75. We also included studies where 80% of the population met our age and breast cancer risk inclusion criteria. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full texts, assessed risk of bias, and applied the GRADE approach. We calculated the risk ratio (RR) with 95% confidence intervals (CI) based on available event rates. We conducted a random-effects meta-analysis. MAIN RESULTS: We included eight studies: one RCT, two prospective cohort studies, and five retrospective cohort studies, enrolling 209,207 women with a follow-up duration from one to three years. The proportion of women with dense breasts ranged from 48% to 100%. Five studies used digital mammography; one study used breast tomosynthesis; and two studies used automated breast ultrasonography (ABUS) in addition to mammography screening. One study used digital mammography alone or in combination with breast tomosynthesis and ABUS or handheld ultrasonography. Six of the eight studies evaluated the rate of cancer cases detected after one screening round, whilst two studies screened women once, twice, or more. None of the studies assessed whether mammography screening in combination with ultrasonography led to lower mortality from breast cancer or all-cause mortality. High certainty evidence from one trial showed that screening with a combination of mammography and ultrasonography detects more breast cancer than mammography alone. The J-START (Japan Strategic Anti-cancer Randomised Trial), enrolling 72,717 asymptomatic women, had a low risk of bias and found that two additional breast cancers per 1000 women were detected over two years with one additional ultrasonography than with mammography alone (5 versus 3 per 1000; RR 1.54, 95% CI 1.22 to 1.94). Low certainty evidence showed that the percentage of invasive tumours was similar, with no statistically significant difference between the two groups (69.6% (128 of 184) versus 73.5% (86 of 117); RR 0.95, 95% CI 0.82 to 1.09). However, positive lymph node status was detected less frequently in women with invasive cancer who underwent mammography screening in combination with ultrasonography than in women who underwent mammography alone (18% (23 of 128) versus 34% (29 of 86); RR 0.53, 95% CI 0.33 to 0.86; moderate certainty evidence). Further, interval carcinomas occurred less frequently in the group screened by mammography and ultrasonography compared with mammography alone (5 versus 10 in 10,000 women; RR 0.50, 95% CI 0.29 to 0.89; 72,717 participants; high certainty evidence). False-negative results were less common when ultrasonography was used in addition to mammography than with mammography alone: 9% (18 of 202) versus 23% (35 of 152; RR 0.39, 95% CI 0.23 to 0.66; moderate certainty evidence). However, the number of false-positive results and necessary biopsies were higher in the group with additional ultrasonography screening. Amongst 1000 women who do not have cancer, 37 more received a false-positive result when they participated in screening with a combination of mammography and ultrasonography than with mammography alone (RR 1.43, 95% CI 1.37 to 1.50; high certainty evidence). Compared to mammography alone, for every 1000 women participating in screening with a combination of mammography and ultrasonography, 27 more women will have a biopsy (RR 2.49, 95% CI 2.28 to 2.72; high certainty evidence). Results from cohort studies with methodological limitations confirmed these findings. A secondary analysis of the J-START provided results from 19,213 women with dense and non-dense breasts. In women with dense breasts, the combination of mammography and ultrasonography detected three more cancer cases (0 fewer to 7 more) per 1000 women screened than mammography alone (RR 1.65, 95% CI 1.0 to 2.72; 11,390 participants; high certainty evidence). A meta-analysis of three cohort studies with data from 50,327 women with dense breasts supported this finding, showing that mammography and ultrasonography combined led to statistically significantly more diagnosed cancer cases compared to mammography alone (RR 1.78, 95% CI 1.23 to 2.56; 50,327 participants; moderate certainty evidence). For women with non-dense breasts, the secondary analysis of the J-START study demonstrated that more cancer cases were detected when adding ultrasound to mammography screening compared to mammography alone (RR 1.93, 95% CI 1.01 to 3.68; 7823 participants; moderate certainty evidence), whilst two cohort studies with data from 40,636 women found no statistically significant difference between the two screening methods (RR 1.13, 95% CI 0.85 to 1.49; low certainty evidence). AUTHORS' CONCLUSIONS: Based on one study in women at average risk of breast cancer, ultrasonography in addition to mammography leads to more screening-detected breast cancer cases. For women with dense breasts, cohort studies more in line with real-life clinical practice confirmed this finding, whilst cohort studies for women with non-dense breasts showed no statistically significant difference between the two screening interventions. However, the number of false-positive results and biopsy rates were higher in women receiving additional ultrasonography for breast cancer screening. None of the included studies analysed whether the higher number of screen-detected cancers in the intervention group resulted in a lower mortality rate compared to mammography alone. Randomised controlled trials or prospective cohort studies with a longer observation period are needed to assess the effects of the two screening interventions on morbidity and mortality.

GRADE-Leitlinien zu Gerechtigkeit 4. Berücksichtigung der Gerechtigkeit im Gesundheitswesen bei der Entwicklung von GRADE-Leitlinien: von der Evidenz zur Empfehlung.

OBJECTIVES: The aim of this paper is to provide detailed guidance on how to incorporate health equity within the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evidence to decision process. STUDY DESIGN AND SETTING: We developed this guidance based on the GRADE evidence to decision frame-work, iteratively reviewing and modifying draft documents, in person discussion of project group members and input from other GRADE members. This is a German translation of the original paper published in English. RESULTS: Considering the impact on health equity may be required, both in general guidelines and guide-lines that focus on disadvantaged populations. We suggest two approaches to incorporate equity considerations: (1) assessing the potential impact of interventions on equity and (2) incorporating equity considerations when judging or weighing each of the evidence to decision criteria. We provide guidance and include illustrative examples. CONCLUSION: Guideline panels should consider the impact of recommendations on health equity with attention to remote and underserviced settings and disadvantaged populations. Guideline panels may wish to incorporate equity judgments across the evidence to decision framework. This is the fourth and final paper in a series about considering equity in the GRADE guideline development process. This series is coming from the GRADE equity subgroup.

The performance of anthropometric tools to determine obesity: a systematic review and meta-analysis.

The aim of this systematic review was to assess the performance of anthropometric tools to determine obesity in the general population (CRD42018086888). Our review included 32 studies. To detect obesity with body mass index (BMI), the meta-analyses rendered a sensitivity of 51.4% (95% CI 38.5-64.2%) and a specificity of 95.4% (95% CI 90.7-97.8%) in women, and 49.6% (95% CI 34.8-64.5%) and 97.3% (95% CI 92.1-99.1%), respectively, in men. For waist circumference (WC), the summary estimates for the sensitivity were 62.4% (95% CI 49.2-73.9%) and 88.1% for the specificity (95% CI 77.0-94.2%) in men, and 57.0% (95% CI 32.2-79.0%) and 94.8% (95% CI 85.8-98.2%), respectively, in women. The data were insufficient to pool the results for waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) but were similar to BMI and WC. In conclusion, BMI and WC have serious limitations for use as obesity screening tools in clinical practice despite their widespread use. No evidence supports that WHR and WHtR are more suitable than BMI or WC to assess body fat. However, due to the lack of more accurate and feasible alternatives, BMI and WC might still have a role as initial tools for assessing individuals for excess adiposity until new evidence emerges.

[GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence]. / GRADE-Leitlinien zu Gerechtigkeit 3: Berücksichtigung der Gerechtigkeit im Gesundheitswesen bei der Entwicklung von GRADE-Leitlinien: Vertrauenswürdigkeit der Evidenz beurteilen.

OBJECTIVES: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. STUDY DESIGN AND SETTING: Consensus-based guidance developed by the GRADE working group members and other methodologists. This is a German translation of the original paper published in English. RESULTS: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. CONCLUSION: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society.

Identifying outcomes for depression that matter to patients, informal caregivers, and health-care professionals: qualitative content analysis of a large international online survey.

BACKGROUND: Many clinical trials have assessed treatments for depressive disorders and bipolar depression. However, whether, and which, assessed outcome domains really matter to patients, informal caregivers, and health-care professionals remains unclear. METHODS: We did an international online survey in French, German, and English. Participants were adult patients with a history of depression, informal caregivers, and health-care professionals, recruited by purposeful sampling. To identify outcome domains, participants answered four open-ended questions about their expectations for depression treatment. We disseminated the survey without restriction via social media, patient and professional associations, and a media campaign. Four researchers independently did qualitative content analyses. We assessed data saturation using mathematical models to ensure the comprehensive identification of outcome domains. FINDINGS: Between April 5, 2018, and Dec 10, 2018, 1912 patients, 464 informal caregivers, and 627 health-care professionals from 52 countries provided 8183 open-ended answers. We identified 80 outcome domains related to symptoms (64 domains), such as mental pain (or psychological or psychic pain, 523 [17%] of 3003 participants) and motivation (384 [13%]), and functioning (16 domains), such as social isolation (541 [18%]). We identified 57 other outcome domains regarding safety of treatment, health care organisation, and social representation, such as stigmatisation (408 [14%]). INTERPRETATION: This study provides a list of outcome domains important to patients, informal caregivers, and health-care professionals. Unfortunately, many of these domains are rarely measured in clinical trials. Results from this study should set the foundation for a core outcome set for depression. FUNDING: Fondation pour la Recherche Medicale and NIHR Oxford Health Biomedical Research Centre.

Universal screening for SARS-CoV-2 infection: a rapid review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by the novel betacoronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most people infected with SARS-CoV-2 have mild disease with unspecific symptoms, but about 5% become critically ill with respiratory failure, septic shock and multiple organ failure. An unknown proportion of infected individuals never experience COVID-19 symptoms although they are infectious, that is, they remain asymptomatic. Those who develop the disease, go through a presymptomatic period during which they are infectious. Universal screening for SARS-CoV-2 infections to detect individuals who are infected before they present clinically, could therefore be an important measure to contain the spread of the disease. OBJECTIVES: We conducted a rapid review to assess (1) the effectiveness of universal screening for SARS-CoV-2 infection compared with no screening and (2) the accuracy of universal screening in people who have not presented to clinical care for symptoms of COVID-19. SEARCH METHODS: An information specialist searched Ovid MEDLINE and the Centers for Disease Control (CDC) COVID-19 Research Articles Downloadable Database up to 26 May 2020. We searched Embase.com, the CENTRAL, and the Cochrane Covid-19 Study Register on 14 April 2020. We searched LitCovid to 4 April 2020. The World Health Organization (WHO) provided records from daily searches in Chinese databases and in PubMed up to 15 April 2020. We also searched three model repositories (Covid-Analytics, Models of Infectious Disease Agent Study [MIDAS], and Society for Medical Decision Making) on 8 April 2020. SELECTION CRITERIA: Trials, observational studies, or mathematical modelling studies assessing screening effectiveness or screening accuracy among general populations in which the prevalence of SARS-CoV2 is unknown. DATA COLLECTION AND ANALYSIS: After pilot testing review forms, one review author screened titles and abstracts. Two review authors independently screened the full text of studies and resolved any disagreements by discussion with a third review author. Abstracts excluded by a first review author were dually reviewed by a second review author prior to exclusion. One review author independently extracted data, which was checked by a second review author for completeness and accuracy. Two review authors independently rated the quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for diagnostic accuracy studies and a modified form designed originally for economic evaluations for modelling studies. We resolved differences by consensus. We synthesized the evidence in narrative and tabular formats. We rated the certainty of evidence for days to outbreak, transmission, cases missed and detected, diagnostic accuracy (i.e. true positives, false positives, true negatives, false negatives) using the GRADE approach. MAIN RESULTS: We included 22 publications. Two modelling studies reported on effectiveness of universal screening. Twenty studies (17 cohort studies and 3 modelling studies) reported on screening test accuracy. Effectiveness of screening We included two modelling studies. One study suggests that symptom screening at travel hubs, such as airports, may slightly slow but not stop the importation of infected cases (assuming 10 or 100 infected travellers per week reduced the delay in a local outbreak to 8 days or 1 day, respectively). We assessed risk of bias as minor or no concerns, and certainty of evidence was low, downgraded for very serious indirectness. The second modelling study provides very low-certainty evidence that screening of healthcare workers in emergency departments using laboratory tests may reduce transmission to patients and other healthcare workers (assuming a transmission constant of 1.2 new infections per 10,000 people, weekly screening reduced infections by 5.1% within 30 days). The certainty of evidence was very low, downgraded for high risk of bias (major concerns) and indirectness. No modelling studies reported on harms of screening. Screening test accuracy All 17 cohort studies compared an index screening strategy to a reference reverse transcriptase polymerase chain reaction (RT-PCR) test. All but one study reported on the accuracy of single point-in-time screening and varied widely in prevalence of SARS-CoV-2, settings, and methods of measurement. We assessed the overall risk of bias as unclear in 16 out of 17 studies, mainly due to limited information on the index test and reference standard. We rated one study as being at high risk of bias due to the inclusion of two separate populations with likely different prevalences. For several screening strategies, the estimates of sensitivity came from small samples. For single point-in-time strategies, for symptom assessment, the sensitivity from 12 cohorts (524 people) ranged from 0.00 to 0.60 (very low-certainty evidence) and the specificity from 12 cohorts (16,165 people) ranged from 0.66 to 1.00 (low-certainty evidence). For screening using direct temperature measurement (3 cohorts, 822 people), international travel history (2 cohorts, 13,080 people), or exposure to known infected people (3 cohorts, 13,205 people) or suspected infected people (2 cohorts, 954 people), sensitivity ranged from 0.00 to 0.23 (very low- to low-certainty evidence) and specificity ranged from 0.90 to 1.00 (low- to moderate-certainty evidence). For symptom assessment plus direct temperature measurement (2 cohorts, 779 people), sensitivity ranged from 0.12 to 0.69 (very low-certainty evidence) and specificity from 0.90 to 1.00 (low-certainty evidence). For rapid PCR test (1 cohort, 21 people), sensitivity was 0.80 (95% confidence interval (CI) 0.44 to 0.96; very low-certainty evidence) and specificity was 0.73 (95% CI 0.39 to 0.94; very low-certainty evidence). One cohort (76 people) reported on repeated screening with symptom assessment and demonstrates a sensitivity of 0.44 (95% CI 0.29 to 0.59; very low-certainty evidence) and specificity of 0.62 (95% CI 0.42 to 0.79; low-certainty evidence). Three modelling studies evaluated the accuracy of screening at airports. The main outcomes measured were cases missed or detected by entry or exit screening, or both, at airports. One study suggests very low sensitivity at 0.30 (95% CI 0.1 to 0.53), missing 70% of infected travellers. Another study described an unrealistic scenario to achieve a 90% detection rate, requiring 0% asymptomatic infections. The final study provides very uncertain evidence due to low methodological quality. AUTHORS' CONCLUSIONS: The evidence base for the effectiveness of screening comes from two mathematical modelling studies and is limited by their assumptions. Low-certainty evidence suggests that screening at travel hubs may slightly slow the importation of infected cases. This review highlights the uncertainty and variation in accuracy of screening strategies. A high proportion of infected individuals may be missed and go on to infect others, and some healthy individuals may be falsely identified as positive, requiring confirmatory testing and potentially leading to the unnecessary isolation of these individuals. Further studies need to evaluate the utility of rapid laboratory tests, combined screening, and repeated screening. More research is also needed on reference standards with greater accuracy than RT-PCR. Given the poor sensitivity of existing approaches, our findings point to the need for greater emphasis on other ways that may prevent transmission such as face coverings, physical distancing, quarantine, and adequate personal protective equipment for frontline workers.

Evidence-based occupational health and safety interventions: a comprehensive overview of reviews.

OBJECTIVES: Occupational injuries and diseases are a huge public health problem and cause extensive suffering and loss of productivity. Nevertheless, many occupational health and safety (OHS) guidelines are still not based on the best available evidence. In the last decade, numerous systematic reviews on behavioural, relational and mixed interventions to reduce occupational injuries and diseases have been carried out, but a comprehensive synopsis is yet missing. The aim of this overview of reviews is to provide a comprehensive basis to inform evidence-based decision-making about interventions in the field of OHS. METHODS: We conducted an overview of reviews. We searched MEDLINE (Ovid), the Cochrane Library (Wiley), epistemonikos.org and Scopus (Elsevier) for relevant systematic reviews published between January 2008 and June 2018. Two authors independently screened abstracts and full-text publications and determined the risk of bias of the included systematic reviews with the ROBIS (Risk of Bias in Systematic Reviews) tool. RESULTS: We screened 2287 abstracts and 200 full-texts for eligibility. Finally, we included 25 systematic reviews with a low risk of bias for data synthesis and analysis. We identified systematic reviews on the prevention of occupational injuries, musculoskeletal, skin and lung diseases, occupational hearing impairment and interventions without specific target diseases. Several interventions led to consistently positive results on individual diseases; other interventions did not show any effects, or the studies are contradictory. We provide detailed results on all included interventions. DISCUSSION: To our knowledge, this is the first comprehensive overview of behavioural, relational and mixed interventions and their effectiveness in preventing occupational injuries and diseases. It provides policymakers with an important basis for making evidence-based decisions on interventions in this field. PROSPERO REGISTRATION NUMBER: CRD42018100341.

[GRADE equity guidelines 2: Considering health equity in GRADE guideline development - equity extension of the guideline development checklist]. / GRADE-Leitlinien zu Gerechtigkeit 2. Berücksichtigung der Gerechtigkeit im Gesundheitswesen bei der Entwicklung von GRADE-Leitlinien: Erweiterung der Checkliste zur Entwicklung von Leitlinien.

OBJECTIVE: To provide guidance for guideline developers on how to consider health equity at key stages of the guideline development process. STUDY DESIGN AND SETTING: Literature review followed by group discussions and consensus building. RESULTS: The key stages at which guideline developers could consider equity include setting priorities, guideline group membership, identifying the target audience(s), generating the guideline questions, considering the importance of outcomes and interventions, deciding what evidence to include and searching for evidence, summarizing the evidence and considering additional information, wording of recommendations, and evaluation and use. We provide examples of how guidelines have actually considered equity at each of these stages. CONCLUSION: Guideline projects should consider the aforementioned suggestions for recommendations that are equity sensitive.

[GRADE equity guidelines 1: Considering health equity in GRADE guideline development - introduction and rationale]. / GRADE-Leitlinien zu Gerechtigkeit 1. Berücksichtigung der Gerechtigkeit im Gesundheitswesen bei der Entwicklung von GRADE-Leitlinien: Einführung und Hintergründe.

OBJECTIVES: This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for developing clinical, public health, and health system guidelines. This article is a German translation of the original version published in English. STUDY DESIGN AND SETTING: We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. RESULTS: We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. CONCLUSION: Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.

Continuing education for the prevention of mild cognitive impairment and Alzheimer's-type dementia: a systematic review and overview of systematic reviews.

OBJECTIVE: To summarise evidence on the preventive effects of continuing education on mild cognitive impairment and Alzheimer's-type dementia in adults 45 years or older. DESIGN: Systematic review and overview of systematic reviews. DATA SOURCES: We systematically searched MEDLINE, PsycINFO, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, and Scopus for published studies and grey literature databases for unpublished studies from January 1990 to April 2018. METHODS: To assess evidence directly addressing our objectives, we conducted a systematic review. Because we were aware of a dearth of direct evidence, we also performed an overview of systematic reviews on leisure activities that mimic formal continuing education. We a priori established the inclusion and exclusion criteria. Two authors independently assessed inclusion and exclusion at the abstract and full-text level, rated the risk of bias, and determined the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation. We resolved all discrepancies by consensus. We synthesised the available evidence narratively. RESULTS: Our searches identified 4933 citations. For the systematic review, only two publications on the same prospective cohort study (Tasmanian Healthy Brain Project) met the inclusion criteria; for the overview of reviews, we included five systematic reviews. Based on 459 participants, preliminary data of the ongoing cohort study indicated that cognitive reserve statistically significantly increased in persons attending university classes compared with the control group (92.5% vs 55.7%, p<0.01). Likewise, language processing capacities statistically significantly improved (p<0.01). Episodic memory, working memory and executive function did not differ significantly between groups. Systematic reviews consistently reported a positive association between participation in cognitively stimulating leisure activities and reduced incidence of dementia and improved cognitive test performance. CONCLUSION: Available results demonstrate that cognitive reserve increases through continuing education and show a positive association of cognitive leisure activities with both improved cognitive function and lower dementia incidence. PROSPERO REGISTRATION NUMBER: CRD42017063944.

[Evidence-based recommendations for the revision of the Austrian periodic health examination]. / Evidenzbasierte Empfehlungen zur Überarbeitung der österreichischen Vorsorgeuntersuchung.

The Austrian periodic health examination (PHE) was introduced in 1974 as a health insurance benefit and was redesigned for the last time in 2005. Therefore, the aim of this work was to revise the scientific basis of the PHE using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We updated the scientific evidence of examinations and consultations that are currently part of the PHE and searched and integrated new examinations. We assessed the expectations of the population towards the PHE in three focus groups. A panel of experts developed evidence-based recommendations for the revised PHE. They formulated 26 recommendations on 20 target diseases or risk factors. In comparison to the previous PHE, the panel added screening for abdominal aortic aneurysm, osteoporotic fracture risk, and chronic kidney disease to the recommendations, while screening for asymptomatic bacteriuria, screening for iron deficiency/pernicious anaemia, and risk identification of glaucoma should no longer be included.

Screening for periodontal diseases by non-dental health professionals: a protocol for a systematic review and overview of reviews.

BACKGROUND: Periodontal diseases are responsible for a vast burden of disease globally and are associated with other severe illnesses such as cardiovascular diseases or diabetes. Tests for early diagnosis of periodontal diseases and effective treatments are available. The effectiveness of screening for periodontal diseases to detect periodontal diseases at an early stage during periodic health examinations at primary care facilities, however, is unclear. The objective of this systematic review is to assess the benefits and risks of screening for periodontal diseases in adults during the periodic health examinations. METHODS: We will use two methodological approaches: (1) a systematic review to assess the effectiveness and risk of harms of screening for periodontal diseases during periodic health examinations and (2) an overview of systematic reviews to determine the effectiveness of treatment approaches for early periodontal disease. We will search electronic databases (Ovid MEDLINE, Embase.com , the Cochrane Library, Epistemonikos, Centre for Reviews and Dissemination databases, PubMed (non-MEDLINE content)) for published studies as well as sources for grey literature to detect unpublished studies. Two authors will independently screen abstracts and full texts using pre-defined eligibility criteria, select studies, extract data, and assess the risk of bias of included studies or reviews. In general, we will conduct a systematic narrative synthesis. Criteria for conducting meta-analyses were defined a priori. Our primary outcomes of interest are tooth loss, loosening of teeth, and depletion of bone tissue. Secondary outcomes are gingivitis/gum inflammation, pocket depths, dental hygiene, lifestyle modifications (e.g., smoking, alcohol, nutrition), and toothache. We consulted a panel of experts and patient representatives to prioritize these outcomes. Two investigators will assess independently the certainty of the evidence for each outcome using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DISCUSSION: We anticipate that our review will highlight the gaps in the available evidence about the effectiveness of screening for periodontal diseases during periodic health examinations. Implications for screening programs may be based on linked evidence about the validity of available screening tools and the effectiveness of early treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017081150.

Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: A systematic review and network meta-analysis.

BACKGROUND: Second-generation antidepressants dominate the medical management of major depressive disorder (MDD). Levomilnacipran, vilazodone and vortioxetine are the latest therapeutic options approved for the treatment of MDD. This systematic review aims to compare the benefits and harms of vilazodone, levomilnacipran, and vortioxetine with one another and other second-generation antidepressants. METHODS: We searched electronic databases up to September 2017 and reviewed reference lists and pharmaceutical dossiers to detect published and unpublished studies. Two reviewers independently screened abstracts and full text articles, and rated the risk of bias of included studies. Randomized controlled trials (RCTs) and controlled observational studies including adult outpatients with MDD were eligible for inclusion. We conducted network meta-analyses on response to treatment using frequentist multivariate meta-analyses models. Placebo- and active-controlled trials were eligible for network meta-analyses. RESULTS: Twenty-four studies met our inclusion criteria. Direct comparisons were limited to vilazodone versus citalopram, and vortioxetine versus duloxetine, paroxetine, or venlafaxine XR (extended release). Results of head-to-head trials and network meta-analyses, overall, indicated similar efficacy among levomilnacipran, vilazodone, or vortioxetine and other second-generation antidepressants. Although rates of overall adverse events and discontinuation due to adverse events were similar, RCTs reported several differences in specific adverse events. For most outcomes the strength of evidence was low. LIMITATIONS: Limitations are the focus of literature searches on studies published in English, possible reporting biases, and general methodological limitations of network meta-analyses. CONCLUSIONS: Overall, the available evidence does not indicate greater benefits or fewer harms of levomilnacipran, vilazodone, and vortioxetine compared with other second-generation antidepressants.