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Strongyloidiasis is a soil-transmitted helminthiasis that is estimated to affect 300-600 million people across Asia, Africa, South and central America, and the Pacific. This neglected parasitic disease is most known for its ability to persist as a lifelong infection due to autoinfection and its risk of hyperinfection and disseminated disease during immunosuppression, which has a more than 60% case fatality. Despite the large global burden of strongyloidiasis, there have been no large-scale public health programmes or WHO guidelines directed towards its control and elimination. However, over the past decade, key scientific and policy changes along with requests from endemic countries have led to WHO incorporating strongyloidiasis into its 2021-30 roadmap and public health targets for control and elimination of neglected tropical diseases. In 2024, WHO published its first guideline on public health control of strongyloidiasis with a single recommendation: in endemic settings with a Strongyloides stercoralis infection prevalence of 5% or higher (measured either with Baermann or agar plate culture from stool specimens), WHO conditionally recommends mass drug administration with single-dose ivermectin (200 μg/kg; oral therapy) in all age groups from 5 years and older to reduce strongyloidiasis. This Review, written by the 2023-24 strongyloidiasis guidelines development group along with WHO colleagues and international experts, presents a summary of the recently published WHO guideline recommendation for strongyloidiasis, and the supporting evidence, considerations for public health implementation, and future research needs., Competing Interests: Declaration of interests The authors of this Review participated in the WHO guideline development for strongyloidiasis, which, in some cases, included compensation for time, travel, expertise, and research products related to development of the guidelines. LM and DM are currently employed by WHO. AM was formally employed by WHO. RSB reports research grants and a patent related to strongyloidiasis diagnostics, which are outside the scope of this Review and their role as Vice President of Strongyloides Australia. AK reports an affiliation as an independent consultant with Liconsa Labs, which is a producer of a WHO-prequalified generic ivermectin. FM reports being Vice Board Chair of the organisation Uniting to Combat NTDs. JB declares employment with the Public Health Agency of Canada; however, this Review was not undertaken under the auspices of the Public Health Agency of Canada as part of JB's employment responsibilities. NCL is supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases) under award R01AI179771. The content of this Review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors declare no competing interests. This Review was funded by WHO. The funder had no role in the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication., (© 2024 World Health Organization. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The first version of the World Health Organization Model list of essential medicines contained 186 medicines in 1977 and has evolved to include 502 medicines in 2023. Over time, different articles criticized the methods and process for decisions; however, the list holds global relevance as a model list to over 150 national lists. Given the global use of the model list, reflecting on its future role is imperative to understand how the list should evolve and respond to the needs of Member States. In 2023, the model list Expert Committee recommended the World Health Organization (WHO) to initiate a process to revise the procedures for updating the model list and the criteria guiding decisions. Here, we offer an agenda outlining priority areas and a vision for an authoritative model list. The main areas include improving transparency and trustworthiness of the recommendations; strengthening connection to national lists; and continuing the debate on the principles that should guide the model list, in particular the role of cost and price of essential medicines. These reflections are intended to support efforts ensuring the continued impact of this policy tool., Competing Interests: Governments are paying increased attention to conflicts of interest, and applications to the model list may come from those with vested financial interests.32 Indeed, companies’ global market strategy may drive their desire to apply to the model list. The challenge lies in ensuring that interest is adequately managed so that the expert committee can decide on unbiased available evidence. Equally, attention to conflicts of interest among the committee’s members is critical to ensuring robust, defensible and trustworthy WHO recommendations. When selecting essential medicines, the committee’s experts can learn from WHO’s guideline recommendation development process, where in response to criticism, a process to overhaul the management of interests was implemented, mitigating risks of undue influence.33,34 However, even the introduction of detailed disclosure forms for WHO experts and strong mitigation strategies may not completely avoid risks of actual or perceived interests and biases. For example, in 2019, concerns about perceived experts’ conflicts of interest were among the reasons to discontinue two WHO guidelines on opioid use.35 While identifying and managing obvious, direct conflicts of interest in the model list process is possible, for example the exclusion of an expert who has received payments from a pharmaceutical industry, mechanisms to identify and manage indirect and less obvious conflicts of interest are more challenging, such as the influence of pervasive pharmaceutical marketing on forming an expert opinion., ((c) 2024 The authors; licensee World Health Organization.)

Objectives: To compare the efficacy of influenza vaccines of any valency for adults 60 years and older., Design and Setting: Systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs). MEDLINE, EMBASE, JBI Evidence-Based Practice (EBP) Database, PsycINFO, and Cochrane Evidence -Based Medicine database were searched from inception to 20 June 20, 2022. Two reviewers screened, abstracted, and appraised articles (Cochrane Risk of Bias (ROB) 2.0 tool) independently. We assessed certainty of findings using Confidence in Network Meta-Analysis and Grading of Recommendations, Assessment, Development and Evaluations approaches. We performed random-effects meta-analysis and network meta-analysis (NMA), and estimated odds ratios (ORs) for dichotomous outcomes and incidence rate ratios (IRRs) for count outcomes along with their corresponding 95% confidence intervals (CIs) and prediction intervals., Participants: Older adults (≥60 years old) receiving an influenza vaccine licensed in Canada or the USA (vs placebo, no vaccine, or any other licensed vaccine), at any dose., Main Outcome Measures: Laboratory-confirmed influenza (LCI) and influenza-like illness (ILI). Secondary outcomes were the number of vascular adverse events, hospitalisation for acute respiratory infection (ARI) and ILI, inpatient hospitalisation, emergency room (ER) visit for ILI, outpatient visit, and mortality, among others., Results: We included 41 RCTs and 15 companion reports comprising 8 vaccine types and 206 032 participants. Vaccines may prevent LCI compared with placebo, with high-dose trivalent inactivated influenza vaccine (IIV3-HD) (NMA: 9 RCTs, 52 202 participants, OR 0.23, 95% confidence interval (CI) (0.11 to 0.51), low certainty of evidence) and recombinant influenza vaccine (RIV) (OR 0.25, 95%CI (0.08 to 0.73), low certainty of evidence) among the most efficacious vaccines. Standard dose trivalent IIV3 (IIV3-SD) may prevent ILI compared with placebo, but the result was imprecise (meta-analysis: 2 RCTs, 854 participants, OR 0.39, 95%CI (0.15 to 1.02), low certainty of evidence). Any HD was associated with prevention of ILI compared with placebo (NMA: 9 RCTs, 65 658 participants, OR 0.38, 95%CI (0.15 to 0.93)). Adjuvanted quadrivalent IIV (IIV4-Adj) may be associated with the least vascular adverse events, but the results were very uncertain (NMA: eight 8 RCTs, 57 677 participants, IRR 0.18, 95%CI (0.07 to 0.43), very low certainty of evidence). RIV on all-cause mortality may be comparable to placebo (NMA: 20 RCTs, 140 577 participants, OR 1.01, 95%CI (0.23 to 4.49), low certainty of evidence)., Conclusions: This systematic review demonstrated efficacy associated with IIV3-HD and RIV vaccines in protecting older persons against LCI. RIV vaccine may reduce all-cause mortality when compared with other vaccines, but the evidence is uncertain. Differences in efficacy between influenza vaccines remain uncertain with very low to moderate certainty of evidence., Prospero Registration Number: CRD42020177357., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML have been reviewed and categorized into three groups: Access, Watch, and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance and the implications for their appropriate use. The 2023 AWaRe classification provides empirical guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe, focussing on the clinical evidence base that guided the selection of Access, Watch, or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimizing the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update national prescribing guidelines, and supervise antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Guidelines and essential medicine lists (EMLs) bear similarities and differences in the process that lead to decisions. Access to essential medicines is central to achieve universal health coverage. The World Health Organization (WHO) EML has guided prioritization of essential medicines globally for nearly 50 years, and national EMLs (NEMLs) exist in over 130 countries. Guideline and EML decisions, at WHO or national levels, are not always coordinated and aligned. We sought to explore challenges, and potential solutions, for decision-making to support trustworthy medicine selection for EMLs from a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group perspective. We primarily focus on the WHO EML; however, our findings may be applicable to NEML decisions as well., Study Design and Setting: We identified key challenges in connecting the EML to health guidelines by involving a broad group of stakeholders and assessing case studies including real applications to the WHO EML, South Africa NEML, and a multiple sclerosis guideline connected to a WHO EML application for multiple sclerosis treatments. To address challenges, we utilized the results of a survey and feedback from the stakeholders, and iteratively met as a project group. We drafted a conceptual framework of challenges and potential solutions. We presented a summary of the results for feedback to all attendees of the GRADE Working Group meetings in November 2022 (approximately 120 people) and in May 2023 (approximately 100 people) before finalizing the framework., Results: We prioritized issues and insights/solutions that addressed the connections between the EML and health guidelines. Our suggested solutions include early planning alignment of guideline groups and EMLs, considering shared participation to strengthen linkage, further clarity on price/cost considerations, and using explicit shared criteria to make guideline and EML decisions. We also provide recommendations to strengthen the connection between WHO EML and NEMLs including through contextualization methods., Conclusion: This GRADE concept article, jointly developed by key stakeholders from the guidelines and EMLs field, identified key conceptual issues and potential solutions to support the continued advancement of trustworthy EMLs. Adopting structured decision criteria that can be linked to guideline recommendations bears the potential to advance health equity and gaps in availability of essential medicines within and between countries., Competing Interests: Declaration of competing interest Tamara Kredo is a member of the South African National Essential Medicines List Committee and Standard Treatment Guidelines; Co-lead of South African GRADE Network; Cochrane Board member; Member of the National Advisory Group on Immunisation. Trudy Leong is a member of the SA GRADE Network. Michael McCaul is a Member of the South African Primary Health Care and Adult Hospital Level Expert Review Committee; Founding member of the SA GRADE Network. The remaining authors are all members of the GRADE Working Group, however, have no other interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Essential medicine lists (EMLs) are important medicine prioritization tools used by the World Health Organization (WHO) EML and over 130 countries. The criteria used by WHO's Expert Committee on the Selection and Use of Essential Medicines has parallels to the GRADE Evidence-to-Decision (EtD) frameworks. In this study, we explored the EtD frameworks and a visual abstract as adjunctive tools to strengthen the integrate evidence and improve the transparency of decisions of EML applications. We conducted user-experience testing interviews of key EML stakeholders using Morville's honeycomb model. Interviews explored multifaceted dimensions (e.g., usability) on two EML applications for the 2021 WHO EML-long-acting insulin analogues for diabetes and immune checkpoint inhibitors for lung cancer. Using a pre-determined coding framework and thematic analysis we iteratively improved both the EtD framework and the visual abstract. We coded the transcripts of 17 interviews with 13 respondents in 103 locations of the interview texts across all dimensions of the user-experience honeycomb. Respondents felt the EtD framework and visual abstract presented complementary useful and findable adjuncts to the traditional EML application. They felt this would increase transparency and efficiency in evidence assessed by EML committees. As EtD frameworks are also used in health practice guidelines, including those by the WHO, respondents articulated that the adoption of the EtD by EML applications represents a tangible mechanism to align EMLs and guidelines, decrease duplication of work and improve coordination. Improvements were made to clarify instructions for the EtD and visual abstract, and to refine the design and content included. 'Availability' was added as an additional criterion for EML applications to highlight this criterion in alignment with WHO EML criteria. EtD frameworks and visual abstracts present additional important tools to communicate evidence and support decision-criteria in EML applications, which have global health impact. Access to essential medicines is important for achieving universal health coverage, and the development of essential medicine lists should be as evidence-based and trustworthy as possible., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. TK: Member of the South African National Essential Medicines List Committee and Standard Treatment Guidelines; Co-lead of South African GRADE Network., (Copyright: © 2024 Piggott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We evaluated the uptake of medicines licensed as orphan drugs by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) into the WHO Model list of essential medicines and the WHO Model list of essential medicines for children from 1977 to 2021., Methods: We collated and analysed data on drug characteristics, reasons for adding or rejecting medicines, and time between regulatory approval and inclusion in the lists. We compared trends in listing orphan drugs before and after revisions to the inclusion criteria of the essential medicines lists in 2001, as well as differences in trends for listing orphan and non-orphan drugs, respectively., Findings: The proportion of orphan drugs in the essential medicines lists increased from 1.9% (4/208) in 1977 to 14.6% (70/478) in 2021. While orphan drugs for communicable diseases have remained stable over time, we observed a considerable shift towards more orphan drugs for noncommunicable diseases, particularly for cancer. The median period for inclusion in the essential medicines lists after either FDA or EMA first approval was 13.5 years (range: 1-28 years). Limited clinical evidence base and uncertainty about the magnitude of net benefit were the most frequent reasons to reject proposals to add new orphan drugs to the essential medicines lists., Conclusion: Despite lack of a global definition of rare diseases, the essential medicines lists have broadened their scope to include medicines for rare conditions. However, the high costs of many listed orphan drugs pose accessibility and reimbursement challenges in resource-constrained settings., ((c) 2024 The authors; licensee World Health Organization.)

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS., Competing Interests: Competing interests: This work was supported by grants from Canadian Institutes of Health (FRN VR4-172741 and GA3-177732) and WHO during the conduct of the study. EA, HJS and PA-C report contribution to the development of the original five criteria for assessing the appropriateness of issuing good practice statements. The remaining authors have nothing else to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Established in 2015, the Multi-Stakeholder Engagement (MuSE) Consortium is an international network of over 120 individuals interested in stakeholder engagement in research and guidelines. The MuSE group is developing guidance for stakeholder engagement in the development of health and healthcare guideline development. The development of this guidance has included multiple meetings with stakeholders, including patients, payers/purchasers of health services, peer review editors, policymakers, program managers, providers, principal investigators, product makers, the public, and purchasers of health services and has identified a number of key issues. These include: (1) Definitions, roles, and settings (2) Stakeholder identification and selection (3) Levels of engagement, (4) Evaluation of engagement, (5) Documentation and transparency, and (6) Conflict of interest management. In this paper, we discuss these issues and our plan to develop guidance to facilitate stakeholder engagement in all stages of the development of health and healthcare guideline development., (© 2023. The Author(s).)

Background: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted., Objectives: Conduct (a) a Delphi process to determine expert opinion on an item's inclusion and (b) a knowledge user survey to widen its impact., Design: Cross-sectional survey and Delphi process., Methods: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users' views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks., Results: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors' conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines., Conclusions: This Delphi process and knowledge user survey informs the development of the RoB NMA tool., Competing Interests: Competing interests: AAV was an Associate Editor for the journal, but was not involved with the decision or peer-review process., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The World Health Organization Model List of Essential Medicines has led to at least 137 national lists. Essential medicines should be grounded in evidence-based guideline recommendations and explicit decision criteria. Essential medicines should be available, accessible, affordable, and the supporting evidence should be accompanied by a rating of the certainty one can place in it. Our objectives were to identify criteria and considerations that should be addressed in moving from a guideline recommendation regarding a medicine to the decision of whether to add, maintain, or remove a medicine from an essential medicines list. We also seek to explore opportunities to improve organizational processes to support evidence-based health decision-making more broadly., Methods: We conducted a qualitative study with semistructured interviews of key informant stakeholders in the development and use of guidelines and essential medicine lists (EMLs). We used an interpretive descriptive analysis approach and thematic analysis of interview transcripts in NVIVO v12., Results: We interviewed 16 key informants working at national and global levels across all WHO regions. We identified five themes: three descriptive/explanatory themes 1) EMLs and guidelines, the same, but different; 2) EMLs can drive price reductions and improve affordability and access; 3) Time lag and disconnect between guidelines and EMLs; and two prescriptive themes 4) An "evidence pipeline" could improve coordination between guidelines and EMLs; 5) Facilitating the link between the WHO Model List of Essential Medicines (WHO EML) and national EMLs could increase alignment., Conclusion: We found significant overlap and opportunities for alignment between guideline and essential medicine decision processes. This finding presents opportunities for guideline and EML developers to enhance strategies for collaboration. Future research should assess and evaluate these strategies in practice to support the shared goal of guidelines and EMLs: improvements in health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Antibiotics are often prescribed inappropriately, either when they are not necessary or with an unnecessarily broad spectrum of activity. AWaRe (AccessWatchReserve) is a system developed by WHO to classify antibiotics based on their spectrum of activity and potential for favouring the development of antibiotic resistance (Access: narrow spectrum/low potential for resistance; Watch: broader spectrum/higher potential for resistance; Reserve: last resort antibiotics to use very selectively). The WHO target is that by 2023, at least 60% of prescribed antibiotics globally should be from the Access category. The WHO AWaRe Book aims to improve empiric antibiotic prescribing by providing simple guidance for common infections based on the principles of AWaRe in alignment with the Model Lists of Essential Medicines for adults and children., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The selection of cancer medicines for national procurement requires deliberate evaluation of population benefit, budget impact, sustainability, and health system capacity. However, this process is complicated by numerous challenges, including the large volume and rapid pace of newly developed therapies offering marginal gains at prohibitively high prices. The WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) have undergone a series of evidence-based updates to ensure recommended cancer medicines offer meaningful clinical benefit. This Health Policy paper describes how cancer medicines are listed on the EML and EMLc, including two updated WHO processes: (1) the formation of the Cancer Medicines Working Group, and (2) additional selection principles for recommending cancer medicines, including a minimum overall survival benefit of 4-6 months with improvement to quality of life compared with standard treatment. These updates, along with proposals to include formal price considerations, additional selection criteria, and multisectoral collaboration (eg, voluntary licensing) promote procurement of high-value essential cancer medicines on national formularies in the context of supporting sustainable health systems to achieve universal health coverage., Competing Interests: Declaration of interests BG declares consulting fees from Vivio Health in matters unrelated to this manuscript. EGEdV declares research support from Amgen, Genentech, Roche, CytomX, G1 Therapeutics, Bayer, Synthon, Servier, Regeneron, Crescendo Biologics, GE Healthcare, and AstraZeneca; and consulting fees from National Surgical Adjuvant Breast and Bowel Project, Daiichi Sankyo, and Crescendo Biologics, in matters unrelated to this manuscript. All other authors declare no competing interests., (Copyright © 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY-NC-ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Objectives: To evaluate the development and quality of actionable statements that qualify as good practice statements (GPS) reported in COVID-19 guidelines., Design and Setting: Systematic review . We searched MEDLINE, MedSci, China National Knowledge Infrastructure (CNKI), databases of Grading of Recommendations Assessment, Development and Evaluation (GRADE) Guidelines, NICE, WHO and Guidelines International Network (GIN) from March 2020 to September 2021. We included original or adapted recommendations addressing any COVID-19 topic., Main Outcome Measures: We used GRADE Working Group criteria for assessing the appropriateness of issuing a GPS: (1) clear and actionable; (2) rationale necessitating the message for healthcare practice; (3) practicality of systematically searching for evidence; (4) likely net positive consequences from implementing the GPS and (5) clear link to the indirect evidence. We assessed guideline quality using the Appraisal of Guidelines for Research and Evaluation II tool., Results: 253 guidelines from 44 professional societies issued 3726 actionable statements. We classified 2375 (64%) as GPS; of which 27 (1%) were labelled as GPS by guideline developers. 5 (19%) were labelled as GPS by their authors but did not meet GPS criteria. Of the 2375 GPS, 85% were clear and actionable; 59% provided a rationale necessitating the message for healthcare practice, 24% reported the net positive consequences from implementing the GPS. Systematic collection of evidence was deemed impractical for 13% of the GPS, and 39% explained the chain of indirect evidence supporting GPS development. 173/2375 (7.3%) statements explicitly satisfied all five criteria. The guidelines' overall quality was poor regardless of the appropriateness of GPS development and labelling., Conclusions: Statements that qualify as GPS are common in COVID-19 guidelines but are characterised by unclear designation and development processes, and methodological weaknesses., Competing Interests: Competing interests: HJS, AS, VAW report grants from Canadian Instituites of Health during the conduct of the study—FRN VR4-172741 & GA3-177732. RAM reports grants from WHO, grants from ASH, grants from ACR, other from Boehringer ingelheim international, grants from NIDDK, outside the submitted work. EA, PA-C and HJS report contribution to the development of the original five criteria for assessing the appropriateness of issuing good practice statements. The remaining authors have nothing else to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Health research teams increasingly partner with stakeholders to produce research that is relevant, accessible, and widely used. Previous work has covered stakeholder group identification., Objective: We aimed to develop factors for health research teams to consider during identification and invitation of individual representatives in a multi-stakeholder research partnership, with the aim of forming equitable and informed teams., Design: Consensus development., Participants: We involved 16 stakeholders from the international Multi-Stakeholder Engagement (MuSE) Consortium, including patients and the public, providers, payers of health services/purchasers, policy makers, programme managers, peer review editors, and principal investigators., Approach: We engaged stakeholders in factor development and as co-authors of this manuscript. Using a modified Delphi approach, we gathered stakeholder views concerning a preliminary list of 18 factors. Over two feedback rounds, using qualitative and quantitative analysis, we concentrated these into ten factors., Key Results: We present seven highly desirable factors: 'expertise or experience', 'ability and willingness to represent the stakeholder group', 'inclusivity (equity, diversity and intersectionality)', 'communication skills', 'commitment and time capacity', 'financial and non-financial relationships and activities, and conflict of interest', 'training support and funding needs'. Additionally, three factors are desirable: 'influence', 'research relevant values', 'previous stakeholder engagement'., Conclusions: We present factors for research teams to consider during identification and invitation of individual representatives in a multi-stakeholder research partnership. Policy makers and guideline developers may benefit from considering the factors in stakeholder identification and invitation. Research funders may consider stipulating consideration of the factors in funding applications. We outline how these factors can be implemented and exemplify how their use has the potential to improve the quality and relevancy of health research., (© 2022. The Author(s).)

Objectives: To assess whether the use of the revised Cochrane risk of bias tool for randomized trials (RoB2) in systematic reviews (SRs) adheres to RoB2 guidance., Methods: We searched MEDLINE, Embase, Cochrane Library from 2019 to May 2021 to identify SRs using RoB2. We analyzed methods and results sections to see whether risk of bias was assessed at outcome measure level and applied to primary outcomes of the SR as per RoB2 guidance. The relation between SR characteristics and adequacy of RoB2 use was examined by logistic regression analysis., Results: Two hundred-eight SRs were included. We could assess adherence in 137 SRs as 12 declared using RoB2 but actually used RoB1 and 59 did not report the number of primary outcomes. The tool usage was adherent in 69.3% SRs. Considering SRs with multiple primary outcomes, adherence dropped to 28.8%. We found a positive association between RoB2 guidance adherence and the methodological quality of the reviews assessed by AMSTAR2 (p-for-trend 0.007). Multivariable regression analysis suggested journal impact factor [first quartile vs. other quartiles] was associated with RoB2 adherence (OR 0.34; 95% CI: 0.16-0.72)., Conclusions: Many SRs did not adhere to RoB2 guidance as they applied the tool at the study level rather than at the outcome measure level. Lack of adherence was more likely among low and very low quality reviews., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To examine the comparative efficacy and complications of long-acting and intermediate-acting insulin for different patient characteristics for type 1 diabetes mellitus (T1DM)., Design: Systematic review and individual patient data (IPD) network meta-analysis (NMA)., Data Sources: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through June 2015., Eligibility Criteria: Randomised controlled trials (RCTs) on adults with T1DM assessing glycosylated haemoglobin (A1c) and severe hypoglycaemia in long-acting and intermediate-acting insulin regimens., Data Extraction and Synthesis: We requested IPD from authors and funders. When IPD were not available, we used aggregate data. We conducted a random-effects model, and specifically a one-stage IPD-NMA for those studies providing IPD and a two-stage IPD-NMA to incorporate those studies not providing IPD., Results: We included 28 RCTs plus one companion report, after screening 6680 titles/abstracts and 205 full-text articles. Of the 28 RCTs, 27 studies provided data for the NMA with 7394 participants, of which 12 RCTs had IPD on 4943 participants. The IPD-NMA for A1c suggested that glargine once daily (mean difference [MD]=-0.31, 95% confidence interval [CI]: -0.48 to -0.14) and detemir once daily (MD=-0.25, 95% CI: -0.41 to -0.09) were superior to neutral protamine Hagedorn (NPH) once daily. NPH once/two times per day improved A1c compared with NPH once daily (MD=-0.30, 95% CI: -0.50 to -0.11). Results regarding complications in severe hypoglycaemia should be considered with great caution due to inconsistency in the evidence network. Accounting for missing data, there was no evidence of inconsistency and long-acting insulin regimens ranked higher regarding reducing severe hypoglycaemia compared with intermediate-acting insulin regimens (two-stage NMA: glargine two times per day SUCRA (Surface Under the Cumulative Ranking curve)=89%, detemir once daily SUCRA=77%; one-stage NMA: detemir once daily/two times per day SUCRA=85%). Using multiple imputations and IPD only, complications in severe hypoglycaemia increased with diabetes-related comorbidities (regression coefficient: 1.03, 95% CI: 1.02 to 1.03)., Conclusions: Long-acting insulin regimens reduced A1c compared with intermediate-acting insulin regimens and were associated with lower severe hypoglycaemia. Of the observed differences, only glargine once daily achieved a clinically significant reduction of 0.30%. Results should be interpreted with caution due to very low quality of evidence., Prospero Registration Number: CRD42015023511., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: MS reports grants from: (1) the ADILA project (Antimicrobial Resistance, Prescribing, and Consumption Data to Inform Country Antibiotic Guidance and Local Action; funder, Wellcome Trust; grant holder, St Georges; April, 2022–October, 2025); (2) Impact of oral step-down to amoxicillin or co-amoxiclav and of duration of antibiotic therapy on effectiveness, safety and selection of antibiotic resistance in severe childhood community-acquired pneumonia (CAP): a randomised controlled trial (PediCAP; funder, EDCTP; grant holder, PENTA; April 2014–March, 2024; and (3) NeoAMR Global Neonatal Sepsis Observational Study (NeoOBS): a prospective cohort study of sepsis in hospitalised neonates (funder, DNDi; grant holder, GARDP; September, 2017–August, 2024, (€1 826 618 total) – Chief Investigator (5%). MS also reports roles as Member of the WHO Essential Medicines List (EML) Committee (from 2016) and Chair of the EML Antibiotic Working Group (from 2019). ML reports participation on advisory boards for Sunovion pharmaceuticals (payment for advisory board on pneumonia) and Paladin Labs (payment for advisory board on dalbavancin). He also reports payments to him, and McMaster University made by the WHO EML team. SH reports grants paid by the European Commission to his institution (University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland). CP reports that she currently works for the French Ministry of Health, coordinating the Antimicrobial Resistance National Action Plan. All other authors declare no competing interests.

Background: Antibiotic use drives antibiotic resistance., Objectives: To systematically review the literature and estimate associations between prior exposure to antibiotics across World Health Organization's (WHO) AWaRe categories (Access, Watch, Reserve) and isolation of critical and high-priority multidrug resistant organisms (MDROs) on the WHO priority pathogen list., Data Sources: Embase, Ovid Medline, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov (from inception to 20/08/2020)., Study Eligibility Criteria: Case-control, cohort, or experimental studies that assessed the risk of infection/colonization with MDROs., Participants: Inpatients or outpatients of any age and sex., Interventions: Prior exposure to antibiotics that could be categorized into the AWaRe framework., Data Analysis: Tailored design-specific checklists applied to each included study. For each antibiotic/class, crude odds ratios (ORs) were pooled through random-effects meta-analyses, both overall and by MDRO. Heterogeneity was examined., Results: We identified 349 eligible studies. All were observational, prone to bias due to design and lack of adjustment for confounding, and not primarily designed to compare associations across AWaRe categories. We found statistically significant associations between prior exposure to almost all antibiotics/classes across AWaRe categories and colonization/infection with any MDRO. We observed higher ORs for Watch and Reserve antibiotics than with Access antibiotics. First generation cephalosporins (Access) had the least association with any MDRO colonization/infection (58 studies; OR = 1.2 [95% CI: 1.0-1.4]), whereas strongest associations were estimated for linezolid (Reserve) (22 studies; OR = 2.6 [95% CI: 2.1-3.1]), followed by carbapenems (Watch) (237 studies; OR = 2.3 [95% CI: 2.1-2.5]). There was high heterogeneity for all antibiotic/MDRO associations., Conclusions: Optimising use of Access antibiotics is likely to reduce the selection of MDROs and global antibiotic resistance. Despite data limitations, our study offers a strong rationale for further adoption of AWaRe as an important tool to improve antibiotic use globally., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The WHO essential medicines list (EML) guides selection of drugs for national formularies. Here, we evaluate which medicines are considered highest priority by Indian oncologists and the extent to which they are available in routine practice., Methods: This is a secondary analysis of an electronic survey developed by the WHO EML Cancer Medicine Working Group. The survey was distributed globally using a hierarchical snowball method to physicians who prescribe systemic anticancer therapy. The survey captured the 10 medicines oncologists considered highest priority for population health and their availability in routine practice., Results: The global study cohort included 948 respondents from 82 countries; 98 were from India and 67 were from other low- and middle-income countries. Compared with other low- and middle-income countries, the Indian cohort was more likely to be medical oncologist (70% v 31%, P < .001) and work exclusively in the private health system (52% v 17%, P < .001). 14/20 most commonly selected medicines were conventional cytotoxic drugs. Universal access to these medicines was reported by a minority of oncologists; risks of significant out-of-pocket expenditures for each medicine were reported by 19%-58% of oncologists. Risk of catastrophic expenditure was reported by 58%-67% of oncologists for rituximab and trastuzumab. Risks of financial toxicity were substantially higher within the private health system compared with the public system., Conclusion: Most high-priority cancer medicines identified by Indian oncologists are generic chemotherapy agents that provide substantial improvements in survival and are already included in WHO EML. Access to these treatments remains limited by major financial burdens experienced by patients. This is particularly acute within the private health system. Strategies are urgently needed to ensure that high-quality cancer care is affordable and accessible to all patients in India.

Objectives: To describe divergence between actionable statements issued by coronavirus disease 2019 (COVID-19) guideline developers cataloged on the "COVID-19 Recommendations and Gateway to Contextualization" platform., Study Design and Setting: We defined divergence as at least two comparable actionable statements with different explicit judgments of strength, direction, or subgroup consideration of the population or intervention. We applied a content analysis to compare guideline development methods for a sample of diverging statements and to evaluate factors associated with divergence., Results: Of the 138 guidelines evaluated, 85 (62%) contained at least one statement that diverged from another guideline. We identified 223 diverging statements in these 85 guidelines. We grouped statements into 66 clusters. Each cluster addressed the same population, intervention, and comparator group or just similar interventions. Clinical practice statements were more likely to diverge in an explicit judgment of strength or direction compared to public health statements. Statements were more likely to diverge in strength than direction. The date of publication, used evidence, interpretation of evidence, and contextualization considerations were associated with divergence., Conclusion: More than half of the assessed guidelines issued at least one diverging statement. This study helps in understanding the types of differences between guidelines issuing comparable statements and factors associated with their divergence., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Access to essential cancer medicines is a major determinant of childhood cancer outcomes globally. The degree to which pediatric oncologists deem medicines listed on WHO's Model List of Essential Medicines for Children (EMLc) essential is unknown, as is the extent to which such medicines are accessible on the front lines of clinical care., Methods: An electronic survey developed was distributed through the International Society of Pediatric Oncology mailing list to members from 87 countries. Respondents were asked to select 10 cancer medicines that would provide the greatest benefit to patients in their context; subsequent questions explored medicine availability and cost. Descriptive and bivariate statistics compared access to medicines between low- and lower-middle-income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs)., Results: Among 159 respondents from 44 countries, 43 (27%) were from LMICs, 79 (50%) from UMICs, and 37 (23%) from HICs. The top five medicines were methotrexate (75%), vincristine (74%), doxorubicin (74%), cyclophosphamide (69%), and cytarabine (65%). Of the priority medicines identified, 87% (27 of 31) are represented on the 2021 EMLc and 77% (24 of 31) were common to the lists generated by LMIC, UMIC, and HIC respondents. The proportion of respondents indicating universal availability for each of the top medicines ranged from 9% to 46% for LMIC, 25% to 89% for UMIC, and 67% to 100% for HIC. Risk of catastrophic expenditure was more common in LMIC (8%-20%), compared with UMIC (0%-28%) and HIC (0%)., Conclusion: Most medicines that oncologists deem essential for childhood cancer treatment are currently included on the EMLc. Barriers remain in access to these medicines, characterized by gaps in availability and risks of catastrophic expenditure for families that are most pronounced in low-income settings but evident across all income contexts., Competing Interests: Scott C. HowardConsulting or Advisory Role: Sanofi, BTG, ServierSpeakers' Bureau: Sanofi, Jazz Pharmaceuticals Dorothy LombeThis author is a member of the Journal of Global Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Bishal GyawaliThis author is a member of the Journal of Global Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Vivio Health Felipe RoitbergHonoraria: Boehringer Ingelheim, AstraZeneca, Oncologia BrasilConsulting or Advisory Role: MSD OncologyResearch Funding: Roche (Inst), Boehringer Ingelheim (Inst), MSD (Inst), Bayer (Inst), AstraZeneca (Inst), Takeda (Inst) Elisabeth G. E. De VriesConsulting or Advisory Role: Daiichi Sankyo (Inst), NSABP Foundation (Inst), Crescendo Biologics (Inst)Research Funding: Amgen (Inst), Synthon (Inst), CytomX Therapeutics (Inst), Regeneron (Inst), G1 Therapeutics (Inst), Bayer (Inst), Roche (Inst), Genentech (Inst), Servier (Inst), Crescendo Biologics (Inst)Uncompensated Relationships: ESMO (Inst)Uncompensated Relationships: World Health Organization (Inst)Uncompensated Relationships: RECIST (Inst) Richard SullivanThis author is a member of the Journal of Global Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Honoraria: PfizerConsulting or Advisory Role: Pfizer (Inst)No other potential conflicts of interest were reported.

Background: Overlapping systematic reviews (SRs) are increasingly frequent in the medical literature. They can easily generate discordant evidence, as estimates of effect sizes and their interpretation might differ from one source to another., Objective: To analyze how methodologists and clinicians make a decision when faced with discordant evidence formalized in structured tables., Methods: We conducted a 16-item survey exploring how methodologists and clinicians would react when presented with multiple Summary of Findings (SoF) tables (generated using the GRADE tool) derived from 4 overlapping and discordant SRs and meta-analyses on thrombolytic therapy for intermediate-risk pulmonary embolism. SoF tables reported 4 different magnitudes of effects and overall certainty. Participants were asked to provide their recommendations regarding the intervention and the reasons behind their conclusion., Results: Of the 80 invitees, 41 (51%) participated. The majority described themselves as "somewhat familiar" or experts with SoF tables. The majority recommended the therapy (pharmacological systemic thrombolysis), grading the recommendation as weak positive. Certainty of evidence and benefit-risk balance were the two criteria that prevailed in generating the recommendation. When faced with overlapping meta-analyses, the preferred approach was to use only high-quality SRs and exclude redundant SRs. Several participants suggested integrating the SoF tables with additional information, such as a more comprehensive evaluation of the risk of bias of systematic reviews (71%), heterogeneity/inconsistency (68%) and studies included within each SR (62%)., Conclusion: When faced with multiple controversial SR results, the type and completeness of reported information in SoF tables affect experts' ability to make recommendations. Developers of the SoF table should consider collating key information from overlapping and potentially discordant reviews., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Puljak, Parmelli, Capobussi, Gonzalez-Lorenzo, Squizzato, Moja and Riva.)

Clinicians, patients, policy makers, funders, programme managers, regulators, and science communities invest considerable amounts of time and energy in influencing or making decisions at various levels, using systematic reviews, health technology assessments, guideline recommendations, coverage decisions, selection of essential medicines and diagnostics, quality assurance and improvement schemes, and policy and evidence briefs. The criteria and methods that these actors use in their work differ (eg, the role economic analysis has in decision making), but these methods frequently overlap and exist together. Under the aegis of WHO, we have brought together representatives of different areas to reconcile how the evidence that influences decisions is used across multiple health system decision levels. We describe the overlap and differences in decision-making criteria between different actors in the health sector to provide bridging opportunities through a unifying broad framework that we call theory of everything. Although decision-making activities respond to system needs, processes are often poorly coordinated, both globally and on a country level. A decision made in isolation from other decisions on the same topic could cause misleading, unnecessary, or conflicted inputs to the health system and, therefore, confusion and resource waste., Competing Interests: Declaration of interests HJS is cochair of the GRADE Working Group and reports honoraria from WHO. MF reports support from HTAnalyze Consultoria e Treinamento outside the submitted work. EP and LN are employed by the European Commission. All other authors declared no competing interests., (Copyright © 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Influenza is one of the most common respiratory viral infections worldwide. Numerous vaccines are used to prevent influenza. Their selection should be informed by the best available evidence. We aimed to estimate the comparative efficacy and safety of seasonal influenza vaccines in children, adults and the elderly., Methods: We conducted a systematic review and network meta-analysis (NMA). We searched the Cochrane Library Central Register of Controlled Trials, MEDLINE and EMBASE databases, and websites of regulatory agencies, through December 15th, 2020. We included placebo- or no vaccination-controlled, and head-to-head randomized clinical trials (RCTs). Pairs of reviewers independently screened the studies, abstracted the data, and appraised the risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was laboratory-confirmed influenza. We also synthesized data for hospitalization, mortality, influenza-like illness (ILI), pneumonia or lower respiratory-tract disease, systemic and local adverse events (AEs). We estimated summary risk ratios (RR) using pairwise and NMA with random effects. This study is registered with PROSPERO, number CRD42018091895., Findings: We identified 13,439 citations. A total of 231 RCTs were included after screening: 11 studies did not provide useful data for the analysis; 220 RCTs [100,677 children (< 18 years) and 329,127 adults (18-60 years) and elderly (≥ 61 years)] were included in the NMA. In adults and the elderly, all vaccines, except the trivalent inactivated intradermal vaccine (3-IIV ID), were more effective than placebo in reducing the risk of laboratory-confirmed influenza, with a RR between 0.33 (95% credible interval [CrI] 0.21-0.55) for trivalent inactivated high-dose (3-IIV HD) and 0.56 (95% CrI 0.41-0.74) for trivalent live-attenuated vaccine (3-LAIV). In adults and the elderly, compared with trivalent inactivated vaccine (3-IIV), no significant differences were found for any, except 3-LAIV, which was less efficacious [RR 1.41 (95% CrI 1.04-1.88)]. In children, compared with placebo, RR ranged between 0.13 (95% CrI 0.03-0.51) for trivalent inactivated vaccine adjuvanted with MF59/AS03 and 0.55 (95% CrI 0.36-0.83) for trivalent inactivated vaccine. Compared with 3-IIV, 3-LAIV and trivalent inactivated adjuvanted with MF59/AS03 were more efficacious [RR 0.52 (95% CrI 0.32-0.82) and RR 0.23 (95% CrI 0.06-0.87)] in reducing laboratory-confirmed influenza. With regard to safety, higher systemic AEs rates after vaccination with 3-IIV, 3-IIV HD, 3-IIV ID, 3-IIV MF59/AS03-adj, quadrivalent inactivated (4-IIV), quadrivalent adjuvanted (4-IIV MF59/AS03-adj), quadrivalent recombinant (4-RIV), 3-LAIV or quadrivalent live attenuated (4-LAIV) vaccines were noted in adults and the elderly [RR 1.5 (95% CrI 1.18-1.89) to 1.15 (95% CrI 1.06-1.23)] compared with placebo. In children, the systemic AEs rate after vaccination was not significantly higher than placebo., Interpretation: All vaccines cumulatively achieved major reductions in the incidence of laboratory-confirmed influenza in children, adults, and the elderly. While the live-attenuated was more efficacious than the inactivated vaccine in children, many vaccine types can be used in adults and the elderly., Funding: The directorate general of welfare, Lombardy region., Competing Interests: EP declares support for attending meeting and travel by Sanofi and Seqirus and, participation in Advisory Board of Sanofi. CG declares participation in Advisory Board of Sanofi. SM, TL, SG, MGL, GC, DC, SB and LM declare no competing interests., (© 2022 The Author(s).)

The World Health Organization's Model List of Essential Medicines for Children (EMLc) presents a list of the most efficacious, safe, and cost-effective medicines for priority conditions, intended for use in children up to 12 years of age. However, gaps in global availability and use of age-appropriate formulations of medicines for children still exist. To address these shortcomings, a comprehensive analysis of the appropriateness of formulations of essential medicines for children is being undertaken through the Global Accelerator for Paediatric Formulations (GAP-f) network, a WHO network launched in 2020 to respond to the paediatric treatment gap. This article describes the development and application of a paediatric Quality Target Product Profile (pQTPP) tool by WHO, to retrospectively evaluate the paediatric age-appropriateness of formulations on the EMLc and identify potential formulation gaps, to inform the review of the EMLc in 2023. A combination of paediatric-centric and global health-focused attributes and targets were defined, taking into consideration regulatory agency paediatric development guidelines and literature sources, and a qualitative scoring system was developed and tested. Example evaluations of paracetamol and clofazimine are provided, illustrating the tool's use. The assessment of EMLc formulations is ongoing and shortcomings and gaps in EMLc formulations have already been identified. The pQTTP tool may also be applied to national lists and prospectively when designing new paediatric formulations.

Objectives: Examining the availability of essential medicines is a necessary step to monitor country-level progress towards universal health coverage. We compared the 2017 essential medicine lists (EML) of 137 countries to the WHO Model List to assess differences by drug class and country setting., Methods: We extracted all medicines prioritised at country level from most recently available national EMLs and compared each national EML with the 2017 WHO Model List of Essential Medicines (MLEM) as the reference standard. We assess EMLs by WHO region and for different types of medicine subgroups (eg, cancer, anti-infectives, cardiac, psychiatric and anaesthesia medicines) using within second-level anatomical therapeutic class (ATC) drug classes of the ATC Index., Results: We included 406 medicines from WHO's 2017 MLEM to compare to 137 concurrent national EMLs. We found a median of 315 (range from 44 to 983) medicines listed on national EMLs. The global median F1 score was 0.59 (IQR 0.47-0.70, maximum possible score indicating alignment with MLEM is 1). The F1 score was the highest (ie, most similar to MLEM) in the South-East Asia region and the lowest in the European region (ie, most dissimilar to MLEM). The F1 score was highest for stomatological preparations (median: 1.00), gynaecological-anti-infectives and antiseptics (median: 1.00), and medicated dressings (median: 1.00), and lowest for 9 anatomical or pharmacological groups (median: 0.00, eg, treatments for bone diseases, digestive enzymes)., Conclusions: Most countries are expected to improve their national health coverage by 2030 offering access to essential medicines, but our results revealed substantial gaps in selection of medicines at the national level compared with those recommended by WHO. It is crucial that governments consider investing in those effective medicines that are now neglected and continue monitoring progress towards essential medicine access as part of universal health coverage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the effectiveness of interventions for acute and subacute non-specific low back pain (NS-LBP) based on pain and disability outcomes., Design: A systematic review of the literature with network meta-analysis., Data Sources: Medline, Embase and CENTRAL databases were searched from inception until 17 October 2020., Eligibility Criteria for Selecting Studies: Randomised clinical trials (RCTs) involving adults with NS-LBP who experienced pain for less than 6 weeks (acute) or between 6 and 12 weeks (subacute)., Results: Forty-six RCTs (n=8765) were included; risk of bias was low in 9 trials (19.6%), unclear in 20 (43.5%), and high in 17 (36.9%). At immediate-term follow-up, for pain decrease, the most efficacious treatments against an inert therapy were: exercise (standardised mean difference (SMD) -1.40; 95% confidence interval (CI) -2.41 to -0.40), heat wrap (SMD -1.38; 95% CI -2.60 to -0.17), opioids (SMD -0.86; 95% CI -1.62 to -0.10), manual therapy (SMD -0.72; 95% CI -1.40 to -0.04) and non-steroidal anti-inflammatory drugs (NSAIDs) (SMD -0.53; 95% CI -0.97 to -0.09). Similar findings were confirmed for disability reduction in non-pharmacological and pharmacological networks, including muscle relaxants (SMD -0.24; 95% CI -0.43 to -0.04). Mild or moderate adverse events were reported in the opioids (65.7%), NSAIDs (54.3%) and steroids (46.9%) trial arms., Conclusion: With uncertainty of evidence, NS-LBP should be managed with non-pharmacological treatments which seem to mitigate pain and disability at immediate-term. Among pharmacological interventions, NSAIDs and muscle relaxants appear to offer the best harm-benefit balance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

This article is about current challenges to evidence-based medicine (EMB) in Italy. The authors, who share a 20-year commitment to the field of clinical research, discuss what they define as a phase of "stagnation" in practicing and teaching methods and research tactics, both in clinical and academic settings. Early success of EBM cultural movement was not persistent. The authors reason about how the teaching of EBM has remained a niche, concerning few professionals compared to the needs of the country. The authors identify some reasons that might have led to inconsistent attention to research methodology and address ways to strengthen the contribution of academic medicine to clinical research.

Objective: To propose a taxonomy and framework that identifies and presents actionable statements in guidelines., Study Design and Setting: We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework., Results: The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process., Conclusion: The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users., (Copyright © 2021. Published by Elsevier Inc.)

Limited access to key diagnostic tools is detrimental to priority health needs of populations. Ear pain, tenderness, itching, and different degree of hearing loss are common problems which require otoscopy as first diagnostic assessment. Where an otoscope is not available because of budget constraints, a self-fabricated low-cost otoscope might represent a feasible opportunity. In this paper, we share the design and construction process of an open-source, 3D printed, otoscope. The prototype was compared to a commercial solution, demonstrating similar overall quality between the instruments., (© 2021. The Author(s).)

Background: The WHO Essential Medicines List (EML) identifies priority medicines that are most important to public health. Over time, the EML has included an increasing number of cancer medicines. We aimed to investigate whether the cancer medicines in the EML are aligned with the priority medicines of frontline oncologists worldwide, and the extent to which these medicines are accessible in routine clinical practice., Methods: This international, cross-sectional survey was developed by investigators from a range of clinical practice settings across low-income to high-income countries, including members of the WHO Essential Medicines Cancer Working Group. A 28-question electronic survey was developed and disseminated to a global network of oncologists in 89 countries and regions by use of a hierarchical snowball method; each primary contact distributed the survey through their national and regional oncology associations or personal networks. The survey was open from Oct 15 to Dec 7, 2020. Fully qualified physicians who prescribe systemic anticancer therapy to adults were eligible to participate in the survey. The primary question asked respondents to select the ten cancer medicines that would provide the greatest public health benefit to their country; subsequent questions explored availability and cost of cancer medicines. Descriptive statistics were used to compare access to medicines between low-income and lower-middle-income countries, upper-middle-income countries, and high-income countries., Findings: 87 country-level contacts and two regional networks were invited to participate in the survey; 46 (52%) accepted the invitation and distributed the survey. 1697 respondents opened the survey link; 423 were excluded as they did not answer the primary study question and 326 were excluded because of ineligibility. 948 eligible oncologists from 82 countries completed the survey (165 [17%] in low-income and lower-middle-income countries, 165 [17%] in upper-middle-income countries, and 618 [65%] in high-income countries). The most commonly selected medicines were doxorubicin (by 499 [53%] of 948 respondents), cisplatin (by 470 [50%]), paclitaxel (by 423 [45%]), pembrolizumab (by 414 [44%]), trastuzumab (by 402 [42%]), carboplatin (by 390 [41%]), and 5-fluorouracil (by 386 [41%]). Of the 20 most frequently selected high-priority cancer medicines, 19 (95%) are currently on the WHO EML; 12 (60%) were cytotoxic agents and 13 (65%) were granted US Food and Drug Administration regulatory approval before 2000. The proportion of respondents indicating universal availability of each top 20 medication was 9-54% in low-income and lower-middle-income countries, 13-90% in upper-middle-income countries, and 68-94% in high-income countries. The risk of catastrophic expenditure (spending >40% of total consumption net of spending on food) was more common in low-income and lower-middle-income countries, with 13-68% of respondents indicating a substantial risk of catastrophic expenditures for each of the top 20 medications in lower-middle-income countries versus 2-41% of respondents in upper-middle-income countries and 0-9% in high-income countries., Interpretation: These data demonstrate major barriers in access to core cancer medicines worldwide. These findings challenge the feasibility of adding additional expensive cancer medicines to the EML. There is an urgent need for global and country-level policy action to ensure patients with cancer globally have access to high priority medicines., Funding: None., Competing Interests: Declaration of interests FR, LM, and AI are employees of WHO. MS, DL, LM, EGEDV, DT, FR, RS, BG, and CMB are members of the WHO Essential Medicines List Cancer Medicine Working Group. EGEDV reports institutional financial support for research from Amgen, Bayer, Crescendo Biologics, CytomX Therapeutics, G1 Therapeutics, Genentech, Regeneron, Roche, Servier, and Synthon, and institutional financial support for participation on data safety monitoring boards and advisory boards of Daiichi Sankyo, NSABP, and Crescendo Biologics. FR reports honoraria for lectures from Dr Reddy's and payments for participation on advisory boards from Boehringer-Ingelheim and MSD. BG reports consulting fees from Vivio Health. All other authors declare no competing interests., (© 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: The WHO Model List of Essential Medicines classified antibiotics into Access, Watch, and Reserve (AWaRe) categories for the treatment of 31 priority bacterial infections as a tool to facilitate antibiotic stewardship and optimal use. We compared the listing of antibiotics on national essential medicines lists (NEMLs) to those in the 2019 WHO Model List and the AWaRe classification database to determine the degree to which NEMLs are in alignment with the AWaRe classification framework recommended by WHO., Methods: In this cross-sectional study, we obtained up-to-date (data after 2017) NEMLs from our Global Essential Medicines (GEM) database, WHO online resources, and individual countries' websites. From the 2019 WHO Model List we extracted, as a reference standard, a list of 37 antibiotics (44 unique antibiotics after accounting for combination drugs or therapeutically equivalent drugs as specified by WHO) that were considered essential in treating 31 of the most common and severe clinical infectious syndromes (priority infections). From the WHO AWaRe Classification Database, which contains commonly used antibiotics globally, we extracted a list of 122 AWaRe antibiotics listed by at least one country in the GEM database. We then assessed individual countries' NEMLs for listing of the 44 essential and 122 commonly used antibiotics, overall and according to AWaRe classification group. We also evaluated and summarised the listing of both first-choice and second-choice treatments for the 31 priority infections. A total coverage score was calculated for each country by assigning a treatment score of 0-3 for each priority infection on the basis of whether first-choice and second-choice treatments, according to the 2019 WHO Model List, were included in the country's NEML. Coverage scores were then compared against the score of the 2019 WHO Model List and across World Bank income groups and WHO regions., Findings: As of July 7, 2020, we had up-to-date NEMLs for 138 countries. Of the 44 unique essential antibiotics, 24 were Access, 15 were Watch, and five were Reserve. The median number of total essential antibiotics listed across the 138 NEMLs was 26 (IQR 21-32). 102 (74%) countries listed at least 22 (50%) of the 44 essential antibiotics. The median number of total AWaRe antibiotics listed by the 138 countries was 35 (IQR 29-46), of Access antibiotics was 18 (16-21), of Watch antibiotics was 16 (11-22), and of Reserve antibiotics was one (0-2). 56 (41%) countries did not list any essential Reserve antibiotics. 131 (95%) countries had coverage scores of at least 60, equivalent to at least 75% of the score of the 2019 WHO Model List, which was 80. Nine (7%) countries listed fewer than 12 of 24 essential Access antibiotics, and seven (5%) did not list sufficient first-choice and second-choice treatments for priority infections (ie, they had coverage scores lower than 60). Of the 31 priority infections, acute neonatal meningitis and high-risk febrile neutropenia did not have enough listed treatments, with 82 (59%) countries listing no treatment for acute neonatal meningitis and 84 (61%) countries listing only a first-choice treatment, only a second-choice treatment, or no treatment for high-risk febrile neutropenia. Coverage scores differed between countries on the basis of World Bank income groups (p=0·025)., Interpretation: Our findings highlight potential changes to the antibiotics included in NEMLs that would increase adherence to international guidance aimed at effectively treating infectious diseases while addressing antimicrobial resistance., Funding: Canadian Institutes of Health Research and Ontario Strategy for Patient Oriented Research Support Unit., Competing Interests: Declaration of interests NP reports grants from Canadian Institutes of Health Research and Ontario Strategy for Patient Oriented Research Support Unit, during the conduct of the study. ML reports grants and personal fees from WHO and Sunovion Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Poor control of cardiovascular disease accounts for a substantial proportion of the disease burden in developing countries, but often essential anticoagulant medicines for preventing strokes and embolisms are not widely available. In 2019, direct oral anticoagulants were added to the World Health Organization's WHO Model list of essential medicines . The aims of this paper are to summarize the benefits of direct oral anticoagulants for patients with cardiovascular disease and to discuss ways of increasing their usage internationally. Although the cost of direct oral anticoagulants has provoked debate, the affordability of introducing these drugs into clinical practice could be increased by: price negotiation; pooled procurement; competitive tendering; the use of patent pools; and expanded use of generics. In 2017, only 14 of 137 countries that had adopted national essential medicines lists included a direct oral anticoagulant on their lists. This number could increase rapidly if problems with availability and affordability can be tackled. Once the types of patient likely to benefit from direct oral anticoagulants have been clearly defined in clinical practice guidelines, coverage can be more accurately determined and associated costs can be better managed. Government action is required to ensure that direct oral anticoagulants are covered by national budgets because the absence of reimbursement remains an impediment to achieving universal coverage. Tackling cardiovascular disease with the aid of direct oral anticoagulants is an essential component of efforts to achieve the World Health Organization's target of reducing premature deaths due to noncommunicable disease by 25% by 2025., ((c) 2021 The authors; licensee World Health Organization.)

Background: Kinesio Taping (KT) is one of the conservative treatments proposed for rotator cuff disease. KT is an elastic, adhesive, latex-free taping made from cotton, without active pharmacological agents. Clinicians have adopted it in the rehabilitation treatment of painful conditions, however, there is no firm evidence on its benefits., Objectives: To determine the benefits and harms of KT in adults with rotator cuff disease., Search Methods: We searched the Cochrane Library, MEDLINE, Embase, PEDro, CINAHL, Clinicaltrials.gov and WHO ICRTP registry to July 27 2020, unrestricted by date and language., Selection Criteria: We included randomised and quasi-randomised controlled trials (RCTs) including adults with rotator cuff disease. Major outcomes were overall pain, function, pain on motion, active range of motion, global assessment of treatment success, quality of life, and adverse events., Data Collection and Analysis: We used standard methodologic procedures expected by Cochrane., Main Results: We included 23 trials with 1054 participants. Nine studies (312 participants) assessed the effectiveness of KT versus sham therapy and fourteen studies (742 participants) assessed the effectiveness of KT versus conservative treatment. Most participants were aged between 18 and 50 years. Females comprised 52% of the sample. For the meta-analysis, we considered the last available measurement within 30 days from the end of the intervention. All trials were at risk of performance, selection, reporting, attrition, and other biases.  Comparison with sham taping Due to very low-certainty evidence, we are uncertain whether KT improves overall pain, function, pain on motion and active range of motion compared with sham taping. Mean overall pain (0 to 10 scale, 0 no pain) was 2.96 points with sham taping and 3.03 points with KT (3 RCTs,106 participants), with an absolute difference of 0.7% worse, (95% CI 7.7% better to 9% worse) and a relative difference of 2% worse (95% CI 21% better to 24% worse) at four weeks. Mean function (0 to 100 scale, 0 better function) was 47.1 points with sham taping and 39.05 points with KT (6 RCTs, 214 participants), with an absolute improvement of 8% (95% CI 21% better to 5% worse)and a relative improvement of 15% (95% CI 40% better to 9% worse) at four weeks. Mean pain on motion (0 to 10 scale, 0 no pain) was 4.39 points with sham taping and 2.91 points with KT even though not clinically important (4 RCTs, 153 participants), with an absolute improvement of 14.8% (95% CI 22.5% better to 7.1% better) and a relative improvement of 30% (95% CI 45% better to 14% better) at four weeks. Mean active range of motion (shoulder abduction) without pain was 174.2 degrees with sham taping and 184.43 degrees with KT (2 RCTs, 68 participants), with an absolute improvement of 5.7% (95% CI 8.9% worse to 20.3% better) and a relative improvement of 6% (95% CI 10% worse to 22% better) at two weeks. No studies reported global assessment of treatment success. Quality of life was reported by one study but data were disaggregated in subscales. No reliable estimates for adverse events (4 studies; very low-certainty) could be provided due to the heterogeneous description of events in the sample. Comparison with conservative treatments Due to very low-certainty evidence, we are uncertain if KT improves overall pain, function, pain on motion and active range of motion compared with conservative treatments. However, KT may improve quality of life (low certainty of evidence).  Mean overall pain (0 to 10 scale, 0 no pain) was 0.9 points with conservative treatment and 0.46 points with KT (5 RCTs, 266 participants), with an absolute improvement of 4.4% (95% CI 13% better to 4.6% worse) and a relative improvement of 15% (95% CI 46% better to 16% worse) at six weeks. Mean function (0 to 100 scale, 0 better function) was 46.6 points with conservative treatment and 33.47 points with KT (14 RCTs, 499 participants), with an absolute improvement of 13% (95% CI 24% better to 2% better) and a relative improvement of 18% (95% CI 32% better to 3% better) at four weeks. Mean pain on motion (0 to 10 scale, 0 no pain) was 4 points with conservative treatment and 3.94 points with KT (6 RCTs, 225 participants), with an absolute improvement of 0.6% (95% CI 7% better to 8% worse) and a relative improvement of 1% (95% CI 12% better to 10% worse) at four weeks. Mean active range of motion (shoulder abduction) without pain was 156.6 degrees with conservative treatment and 159.64 degrees with KT (3 RCTs, 143 participants), with an absolute improvement of 3% (95% CI 11% worse to 17 % better) and a relative improvement of 3% (95% CI 9% worse to 14% better) at six weeks.  Mean of quality of life (0 to 100, 100 better quality of life) was 37.94 points with conservative treatment and 56.64 points with KT (1 RCTs, 30 participants), with an absolute improvement of 18.7% (95% CI 14.48% better to 22.92% better) and a relative improvement of 53% (95% CI 41% better to 65% better) at four weeks.  No studies were found for global assessment of treatment success. No reliable estimates for adverse events (7 studies, very low certainty of evidence) could be provided due to the heterogeneous description of events in the whole sample., Authors' Conclusions: Kinesio taping for rotator cuff disease has uncertain effects in terms of self-reported pain, function, pain on motion and active range of motion when compared to sham taping or other conservative treatments as the certainty of evidence was very low. Low-certainty evidence shows that kinesio taping may improve quality of life when compared to conservative treatment. We downgraded the evidence for indirectness due to differences among co-interventions, imprecision due to small number of participants across trials as well as selection bias, performance and detection bias. Evidence on adverse events was scarce and uncertain. Based upon the data in this review, the evidence for the efficacy of KT seems to demonstrate little or no benefit., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To compare antibiotic sales in eight high-income countries using the 2019 World Health Organization (WHO) Access, Watch and Reserve (AWaRe) classification and the target of 60% consumption of Access category antibiotics., Methods: We analysed data from a commercial database of sales of systemic antibiotics in France, Germany, Italy, Japan, Spain, Switzerland, United Kingdom of Great Britain and Northern Ireland, and United States of America over the years 2013-2018. We classified antibiotics according to the 2019 AWaRe categories: Access, Watch, Reserve and Not Recommended. We measured antibiotic sales per capita in standard units (SU) per capita and calculated Access group sales as a percentage of total antibiotic sales., Findings: In 2018, per capita antibiotic sales ranged from 7.4 SU (Switzerland) to 20.0 SU (France); median sales of Access group antibiotics were 10.9 SU per capita (range: 3.5-15.0). Per capita sales declined moderately over 2013-2018. The median percentage of Access group antibiotics was 68% (range: 22-77 %); the Access group proportion increased in most countries between 2013 and 2018. Five countries exceeded the 60% target; two countries narrowly missed it (> 55% in Germany and Italy). Sales of Access antibiotics in Japan were low (22%), driven by relatively high sales of oral cephalosporins and macrolides., Conclusion: We have identified changes to prescribing that could allow countries to achieve the WHO target. The 60% Access group target provides a framework to inform national antibiotic policies and could be complemented by absolute measures and more ambitious values in specific settings., ((c) 2021 The authors; licensee World Health Organization.)

Background: Increasing availability of competing biosimilar alternatives makes it challenging to make treatment decisions. The purpose of this review is to evaluate the comparative efficacy and safety of ultra-long-/long-/intermediate-acting insulin products and biosimilar insulin compared to human/animal insulin in adults with type 1 diabetes mellitus (T1DM)., Methods: MEDLINE, EMBASE, CENTRAL, and grey literature were searched from inception to March 27, 2019. Randomized controlled trials (RCTs), quasi-experimental studies, and cohort studies of adults with T1DM receiving ultra-long-/long-/intermediate-acting insulin, compared to each other, as well as biosimilar insulin compared to human/animal insulin were eligible for inclusion. Two reviewers independently screened studies, abstracted data, and appraised risk-of-bias. Pairwise meta-analyses and network meta-analyses (NMA) were conducted. Summary effect measures were mean differences (MD) and odds ratios (OR)., Results: We included 65 unique studies examining 14,200 patients with T1DM. Both ultra-long-acting and long-acting insulin were superior to intermediate-acting insulin in reducing A1c, FPG, weight gain, and the incidence of major, serious, or nocturnal hypoglycemia. For fasting blood glucose, long-acting once a day (od) was superior to long-acting twice a day (bid) (MD - 0.44, 95% CI: - 0.81 to - 0.06) and ultra-long-acting od was superior to long-acting bid (MD - 0.73, 95% CI - 1.36 to - 0.11). For weight change, long-acting od was inferior to long-acting bid (MD 0.58, 95% CI: 0.05 to 1.10) and long-acting bid was superior to long-action biosimilar od (MD - 0.90, 95% CI: - 1.67 to - 0.12)., Conclusions: Our results can be used to tailor insulin treatment according to the desired results of patients and clinicians and inform strategies to establish a competitive clinical market, address systemic barriers, expand the pool of potential suppliers, and favor insulin price reduction., Prospero Registration: CRD42017077051., (© 2021. Society of General Internal Medicine.)

Objectives: Guidelines that include antimicrobial recommendations should explicitly consider contextual factors that influence antimicrobial resistance and their downstream effects on resistance selection. The objectives were to analyse (1) how, and to what extent, tuberculosis, gonorrhoea and respiratory tract infection guidelines are considering antimicrobial resistance; (2) are of acceptable quality and (3) if they can be easily contextualised to fit the needs of specific populations and health systems., Methods: We conducted a systematic review and searched Ovid MEDLINE and Embase from 1 January 2007 to 7 June 2019 for tuberculosis, gonorrhoea and respiratory tract infection guidelines published in English. We also searched guideline databases, key websites and reference lists. We identified guidelines and recommendations that considered contextual factors including antimicrobial resistance, values, resource use, equity, acceptability and feasibility. We assessed quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II tool focusing on the domains scope and purpose, rigour of development, and editorial independence., Results: We screened 10 365 records, of which 74 guidelines met inclusion criteria. Of these guidelines, 39% (n=29/74) met acceptable quality scores. Approximately two-thirds of recommendations considered antimicrobial resistance at the population and/or outcome level. Five of the 29 guidelines reported all factors required for recommendation contextualisation. Equity was the least considered across guidelines., Discussion: Relatively few guidelines for highly prevalent infectious diseases are considering resistance at a local level, and many do not consider contextual factors necessary for appropriate antimicrobial use. Improving the quality of guidelines targeting specific regional areas is required., Prospero Registration Number: CRD42020145235., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Not much is known about how accurate and reproducible different thermometers are at diagnosing patients with suspected fever. The study aims at evaluating which peripheral thermometers are more accurate and reproducible. We searched Medline, Embase, Scopus, WOS, CENTRAL, and Cinahl to perform: (1) diagnostic accuracy meta-analysis (MA) using rectal mercury-in-glass or digital thermometry as reference, and bivariate models for pooling; (2) network MA to estimate differences in mean temperature between devices; (3) Bland-Altman method to estimate 95% coefficient of reproducibility. PROSPERO registration: CRD42020174996. We included 46 studies enrolling more than 12,000 patients. Using 38 °C (100.4 ℉) as cut-off temperature, temporal infrared thermometry had a sensitivity of 0.76 (95% confidence interval, 0.65, 0.84; low certainty) and specificity of 0.96 (0.92, 0.98; moderate certainty); tympanic infrared thermometry had a sensitivity of 0.77 (0.60,  0.88; low certainty) and specificity of 0.98 (0.95, 0.99; moderate certainty). For all the other index devices, it was not possible to pool the estimates. Compared to the rectal mercury-in-glass thermometer, mean temperature differences were not statistically different from zero for temporal or tympanic infrared thermometry; the median coefficient of reproducibility ranged between 0.53 °C [0.95 ℉] for infrared temporal and 1.2 °C [2.16 ℉] for axillary digital thermometry. Several peripheral thermometers proved specific, but not sensitive for diagnosing fever with rectal thermometry as a reference standard, meaning that finding a temperature below 38 °C does not rule out fever. Fixed differences between temperatures together with random error means facing differences between measurements in the order of 2 °C [4.5 ℉]. This study informs practitioners of the limitations associated with different thermometers; peripheral ones are specific but not sensitive.

The coronavirus disease 2019 (COVID-19) pandemic and antimicrobial resistance (AMR) are parallel and interacting health emergencies that provide the opportunity for mutual learning. As their measures and consequences are comparable, the COVID-19 pandemic helps to illustrate the potential long-term impact of AMR, which is less acute but not less crucial. They may also impact each other as there is a push to use existing antimicrobials to treat critically ill COVID-19 patients in the absence of specific treatments. Attempts to manage the spread of COVID-19 may also lead to a slowdown in AMR. Understanding how COVID-19 affects AMR trends and what we can expect if these trends remain the same or worsen will help us to plan the next steps for tackling AMR. Researchers should start collecting data to measure the impact of current COVID-19 policies and programs on AMR., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: The pipeline of new antibacterials remains limited. Reasons include low research investments, limited commercial prospects, and scientific challenges. To complement existing initiatives such as research grants, governments are exploring policy options for providing new market incentives to drug developers., Materials and Methods: Reimbursement interventions for antibacterials in France, Germany, Sweden, US, and UK were reviewed and analysed by the authors., Results: In France, Germany, and the US, implemented interventions centre on providing exceptions in cost-containment mechanisms to allow higher prices for certain antibacterials. In the US, also, certain antibacterials are granted additional years of protection from generic competition (exclusivity) and faster regulatory review. The UK is piloting a model that will negotiate contracts with manufacturers to pay a fixed annual fee for ongoing supply of as many units as needed. Sweden is piloting a model that will offer manufacturers of selected antibacterials contracts that would guarantee a minimum annual revenue. A similar model of guaranteed minimal annual revenues is under consideration in the US (PASTEUR Act)., Conclusions: The UK and Sweden are piloting entirely novel procurement and reimbursement models. Existing interventions in the US, France, and Germany represent important, but relatively minor interventions. More countries should explore the use of novel models and international coordination will be important for 'pull' incentives to be effective. If adopted, the PASTEUR legislation in the US would constitute a significant 'pull' incentive., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The presence of SARS-CoV-2 in raw wastewaters has been demonstrated in many countries affected by this pandemic. Nevertheless, virus presence and infectivity in treated wastewaters, but also in the receiving water bodies are still poorly investigated. In this study, raw and treated samples from three wastewater treatment plants, and three river samples within the Milano Metropolitan Area, Italy, were surveyed for SARS-CoV-2 RNA detection by means of real time RT-PCR and infectivity test on culture cells. SARS-CoV-2 RNA was detected in raw, but not in treated wastewaters (four and two samples, respectively, sampled in two dates). The isolated virus genome was sequenced, and belonged to the strain most spread in Europe and similar to another found in the same region. RNA presence in raw wastewater samples decreased after eight days, probably following the epidemiological trend estimated for the area. Virus infectivity was always null, indicating the natural decay of viral pathogenicity in time from emission. Samples from receiving rivers (three sites, sampled in the same dates as wastewaters) showed in some cases a positivity to real time RT-PCR, probably due to non-treated, or inefficiently treated discharges, or to the combined sewage overflows. Nevertheless, also for rivers infectivity was null. Risks for public health should be limited, although a precautionary approach to risk assessment is here advocated, giving the preliminary nature of the presented data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Family doctors can have an active role in identifying significant population needs and solutions. During the COVID-19 epidemic, patient home monitoring with pulse oximetry has been a key aspect of care of patients. However, pandemics bring shortage of medical equipment such as pulse oximeters. Through the local maker community, in a matter of days four "smart" pulse oximeters were built. Following Internet of Things principles, the prototypes were programmed to transmit real-time data through Wi-Fi directly to the doctors. Each pulse oximeter served a family doctor during the pandemic. In this article we describe the process that led to the production of the technology and provide detailed instructions, which have also been shared in maker-oriented websites. Dissemination can potentially lead to additional small-scale productions, limiting future shortages.

Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Model List often includes a single medicine as representative of a group of equivalent and interchangeable medicines. The representative medicine of that group is listed with an accompanying 'square box' symbol. The intended purpose of the square box is to highlight pharmacological classes or groups of medicines for which countries, institutions and health professionals can assume homogeneous therapeutic efficacy and safety and select the most appropriate single medicine based on price, local availability, and acceptability. Though this concept of therapeutic equivalence within a therapeutic class has been endorsed by most authoritative textbooks of pharmacology since Goodman & Gilman's The Pharmacological Basis of Therapeutics and evidence-based guidelines, marketing forces have often made claims on individual drugs to distinguish them beyond relevant differences shown by reliable evidence: this has generated the concept of "me-too drugs" with its double meaning- i.e. , market latecomers differing minimally from products preceding them and whose marketing budgets have significant opportunity costs, or medicines which may be useful to substitute for equivalent products in the event of shortages. The square box concept is applied in the context of a comprehensive list: therapeutic equivalence or interchangeability cannot always be easily established. Different interpretations have been applied to different groups of medicines over the 40+ year history of the Model List. This paper presents the concept of the square box, provides key examples and guidance on how square box listings should be practically interpreted in the development and implementation of national essential medicine lists, considers the applicability of a square box listing concept to biologic medicines and proposes that an updated review of the square box concept and listings is warranted., (Copyright © 2020 Cappello, Moja, Figueras and Magrini.)

Introduction: Clinical practice guidelines need rigorous and transparent methods for summarizing the evidence, rate its certainty and moving from evidence to recommendations. We describe an intervention to support local efforts to provide optimal and safer care bridging the gap between researchers and local busy clinicians., Methods: A group of methodologists provided a wide range of research services to the medical community of a local non-teaching general hospital in Italy. Methodological support encompassed synthesis of evidence, rating of uncertainty and moving from evidence to recommendations. Local professionals were asked to judge GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology and its impact on patients' safety, professional liability, and guideline reliability. The research team then reflected on the barriers of implementing GRADE in local settings., Results: Seven clinical recommendations about frequent complex medical conditions were produced. Few local clinicians completed the project. All clinicians found the GRADE methodology a guarantee for defending excellent standards of care. However, we identified a diffuse sense of inability to improve clinical behaviours as negative effects of general poor working conditions, in particular the strained health care workforce., Discussion: Current financial constraints may be impeding the ability of clinicians in improving their clinical practice through adaptation and use of evidence. A successful integration of evidence-based guidelines cannot be separated from an activate promotion by the institutional management.

Background: At birth, infants' lungs are fluid-filled. For newborns to have a successful transition, this fluid must be replaced by air to enable gas exchange. Some infants are judged to have inadequate breathing at birth and are resuscitated with positive pressure ventilation (PPV). Giving prolonged (sustained) inflations at the start of PPV may help clear lung fluid and establish gas volume within the lungs., Objectives: To assess the benefits and harms of an initial sustained lung inflation (SLI) (> 1 second duration) versus standard inflations (≤ 1 second) in newborn infants receiving resuscitation with intermittent PPV., Search Methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 3), MEDLINE via PubMed (1966 to 1 April 2019), Embase (1980 to 1 April 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 1 April 2019). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles to identify randomised controlled trials and quasi-randomised trials., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing initial sustained lung inflation (SLI) versus standard inflations given to infants receiving resuscitation with PPV at birth., Data Collection and Analysis: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomisation, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean standard deviation (SD), and weighted mean difference (WMD) for continuous data. We used the GRADE approach to assess the quality of evidence., Main Results: Ten trials enrolling 1467 infants met our inclusion criteria. Investigators in nine trials (1458 infants) administered sustained inflation with no chest compressions. Use of sustained inflation had no impact on the primary outcomes of this review: mortality in the delivery room (typical RR 2.66, 95% confidence interval (CI) 0.11 to 63.40 (I² not applicable); typical RD 0.00, 95% CI -0.02 to 0.02; I² = 0%; 5 studies, 479 participants); and mortality during hospitalisation (typical RR 1.09, 95% CI 0.83 to 1.43; I² = 42%; typical RD 0.01, 95% CI -0.02 to 0.04; I² = 24%; 9 studies, 1458 participants). The quality of the evidence was low for death in the delivery room because of limitations in study design and imprecision of estimates (only one death was recorded across studies). For death before discharge the quality was moderate: with longer follow-up there were more deaths (n = 143) but limitations in study design remained. Among secondary outcomes, duration of mechanical ventilation was shorter in the SLI group (mean difference (MD) -5.37 days, 95% CI -6.31 to -4.43; I² = 95%; 5 studies, 524 participants; low-quality evidence). Heterogeneity, statistical significance, and magnitude of effects of this outcome are largely influenced by a single study at high risk of bias: when this study was removed from the analysis, the size of the effect was reduced (MD -1.71 days, 95% CI -3.04 to -0.39; I² = 0%). Results revealed no differences in any of the other secondary outcomes (e.g. risk of endotracheal intubation outside the delivery room by 72 hours of age (typical RR 0.91, 95% CI 0.79 to 1.04; I² = 65%; 5 studies, 811 participants); risk of surfactant administration during hospital admission (typical RR 0.99, 95% CI 0.91 to 1.08; I² = 0%; 9 studies, 1458 participants); risk of chronic lung disease (typical RR 0.99, 95% CI 0.83 to 1.18; I² = 0%; 4 studies, 735 participants); pneumothorax (typical RR 0.89, 95% CI 0.57 to 1.40; I² = 34%; 8 studies, 1377 infants); or risk of patent ductus arteriosus requiring pharmacological treatment (typical RR 0.99, 95% CI 0.87 to 1.12; I² = 48%; 7 studies, 1127 infants). The quality of evidence for these secondary outcomes was moderate (limitations in study design ‒ GRADE) except for pneumothorax (low quality: limitations in study design and imprecision of estimates ‒ GRADE). We could not perform any meta-analysis in the comparison of the use of initial sustained inflation versus standard inflations in newborns receiving resuscitation with chest compressions because we identified only one trial for inclusion (a pilot study of nine preterm infants)., Authors' Conclusions: Our meta-analysis of nine studies shows that sustained lung inflation without chest compression was not better than intermittent ventilation for reducing mortality in the delivery room (low-quality evidence ‒ GRADE) or during hospitalisation (moderate-quality evidence ‒ GRADE), which were the primary outcomes of this review. However, the single largest study, which was well conducted and had the greatest number of enrolled infants, was stopped early for higher mortality rate in the sustained inflation group. When considering secondary outcomes, such as rate of intubation, rate or duration of respiratory support, or bronchopulmonary dysplasia, we found no benefit of sustained inflation over intermittent ventilation (moderate-quality evidence ‒ GRADE). Duration of mechanical ventilation was shortened in the SLI group (low-quality evidence ‒ GRADE); this result should be interpreted cautiously, however, as it might have been influenced by study characteristics other than the intervention. There is no evidence to support the use of sustained inflation based on evidence from our review., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To assess antibiotic availability and use in health facilities in low- and middle-income countries, using the service provision assessment and service availability and readiness assessment surveys., Methods: We obtained data on antibiotic availability at 13 561 health facilities in 13 service provision assessment and 8 service availability and readiness assessment surveys. In 10 service provision assessment surveys, child consultations with health-care providers were observed, giving data on antibiotic use in 22 699 children. Antibiotics were classified as access, watch or reserve, according to the World Health Organization's AWaRe categories. The percentage of health-care facilities across countries with specific antibiotics available and the proportion of children receiving antibiotics for key clinical syndromes were estimated., Findings: The surveys assessed the availability of 27 antibiotics (19 access, 7 watch, 1 unclassified). Co-trimoxazole and metronidazole were most widely available, being in stock at 89.5% (interquartile range, IQR: 11.6%) and 87.1% (IQR: 15.9%) of health facilities, respectively. In contrast, 17 other access and watch antibiotics were stocked, by fewer than a median of 50% of facilities. Of the 22 699 children observed, 60.1% (13 638) were prescribed antibiotics (mostly co-trimoxazole or amoxicillin). Children with respiratory conditions were most often prescribed antibiotics (76.1%; 8972/11 796) followed by undifferentiated fever (50.1%; 760/1518), diarrhoea (45.7%; 1293/2832) and malaria (30.3%; 352/1160)., Conclusion: Routine health facility surveys provided a valuable data source on the availability and use of antibiotics in low- and middle-income countries. Many access antibiotics were unavailable in a majority of most health-care facilities., ((c) 2020 The authors; licensee World Health Organization.)

Background: Data extraction from reports about experimental or observational studies is a crucial methodological step informing evidence syntheses, such as systematic reviews (SRs) and overviews of SRs. Reporting discrepancies were defined as pairs of statements that could not both be true. Authors of SRs and overviews of SRs can encounter reporting discrepancies among multiple sources when extracting data-a manuscript and a conference abstract, and a manuscript and a clinical trial registry. However, these discrepancies can also be found within a single manuscript published in a scientific journal., Objectives: Hereby, we describe examples of internal reporting discrepancies that can be found in a single source, with the aim of raising awareness among authors of SRs and overviews of SRs about such potential methodological issues., Conclusions: Authors of SRs and overviews of SRs should check whether the same information is reported in multiple places within a study and compare that information. Independent data extraction by two reviewers increases the chance of finding discrepancies, if they exist. We provide advice on how to deal with different types of discordances and how to report such discordances when conducting SRs and overviews of SRs., (Copyright © 2019 Elsevier Inc. All rights reserved.)