Erratum: One welfare: Linking poverty, equid ownership and equid welfare in the brick kilns of India - ERRATUM.

[This corrects the article DOI: 10.1017/S0962728600032504.].

When complexity matters: a step-by-step guide to incorporating a complexity perspective in guideline development for public health and health system interventions.

BACKGROUND: Guidelines on public health and health system interventions often involve considerations beyond effectiveness and safety to account for the impact that these interventions have on the wider systems in which they are implemented. This paper describes how a complexity perspective may be adopted in guideline development to facilitate a more nuanced consideration of a range of factors pertinent to decisions regarding public health and health system interventions. These factors include acceptability and feasibility, and societal, economic, and equity and equality implications of interventions. MAIN MESSAGE: A 5-step process describes how to incorporate a complexity perspective in guideline development with examples to illustrate each step. The steps include: (i) guideline scoping, (ii) formulating questions, (iii) retrieving and synthesising evidence, (iv) assessing the evidence, and (v) developing recommendations. Guideline scoping using stakeholder consultations, complexity features, evidence mapping, logic modelling, and explicit decision criteria is emphasised as a key step that informs all subsequent steps. CONCLUSIONS: Through explicit consideration of a range of factors and enhanced understanding of the specific circumstances in which interventions work, a complexity perspective can yield guidelines with better informed recommendations and facilitate local adaptation and implementation. Further work will need to look into the methods of collecting and assessing different types of evidence beyond effectiveness and develop procedural guidance for prioritising across a range of decision criteria.

Identifying research questions for HIV, tuberculosis, tuberculosis-HIV, malaria, and neglected tropical diseases through the World Health Organization guideline development process: a retrospective analysis, 2008-2018.

OBJECTIVES: World Health Organization (WHO) guidelines for health programmes and healthcare delivery are the foundation of its technical leadership in public health and essential to decision-making globally. A key function of guideline development is to identify areas in which further evidence is needed because filling these gaps will lead to future improvements in population health. The objective of this study was to examine the knowledge gaps and research questions for addressing those gaps generated through the WHO guideline development process, with the goal of informing future strategies for improving and strengthening the guideline development process. STUDY DESIGN: We did a systematic, retrospective analysis of research questions identified in the published guidelines. METHODS: We analyzed guidelines published between January 1, 2008, and December 31, 2018, by the Communicable Diseases Cluster in five disease areas: tuberculosis (TB), HIV, malaria, TB-HIV, and neglected tropical diseases (NTDs). Research questions were extracted independently by two researchers. We analyzed the distribution of research questions by disease and by topic category and did a qualitative assessment of optimum practice for research question generation during the guideline development process. RESULTS: A total of 48 guidelines were included: 26 on HIV, 1 on malaria, 11 on TB, 5 on TB/HIV, and 5 on NTDs. Overall, 36 (75%) guidelines encompassed a total of 360 explicit research questions; the remainder did not contain specific research questions. The number of research questions that focused on TB was 49, TB/HIV was 38, HIV was 250, and NTDs was 23. The number of research questions that focused on diagnosis was 43 (11.9%) of 360, prevention was 62 (17.2%), treatment was 103 (28.6%), good practice was 12 (3.3%), service delivery was 86 (23.8%), and other areas was 54 (15%). Research questions were often not formulated in a specific or actionable way and were hard to identify in the guideline. Examples of good practice identified by the review team involved the generation of specific and narrowly defined research questions, with accompanying recommendations for appropriate study design. CONCLUSIONS: The WHO must strengthen its approach to identifying and presenting research questions during the guideline development process. Ensuring access to research questions is a key next step in adding value to the guideline development process.

Routes of transmission of influenza A H1N1, SARS CoV, and norovirus in air cabin: Comparative analyses.

Identifying the exact transmission route(s) of infectious diseases in indoor environments is a crucial step in developing effective intervention strategies. In this study, we proposed a comparative analysis approach and built a model to simulate outbreaks of 3 different in-flight infections in a similar cabin environment, that is, influenza A H1N1, severe acute respiratory syndrome (SARS) coronavirus (CoV), and norovirus. The simulation results seemed to suggest that the close contact route was probably the most significant route (contributes 70%, 95% confidence interval [CI]: 67%-72%) in the in-flight transmission of influenza A H1N1 transmission; as a result, passengers within 2 rows of the index case had a significantly higher infection risk than others in the outbreak (relative risk [RR]: 13.4, 95% CI: 1.5-121.2, P = .019). For SARS CoV, the airborne, close contact, and fomite routes contributed 21% (95% CI: 19%-23%), 29% (95% CI: 27%-31%), and 50% (95% CI: 48%-53%), respectively. For norovirus, the simulation results suggested that the fomite route played the dominant role (contributes 85%, 95% CI: 83%-87%) in most cases; as a result, passengers in aisle seats had a significantly higher infection risk than others (RR: 9.5, 95% CI: 1.2-77.4, P = .022). This work highlighted a method for using observed outbreak data to analyze the roles of different infection transmission routes.

Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND: To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists. METHODS: Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion. RESULTS: One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance. CONCLUSIONS: AT9 methodology reflects the current science of evidence-based clinical practice guideline development, with reliance on high-quality systematic reviews, a standardized process for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts of interest followed by management of disclosed conflicts, and extensive peer review.(AU)

Quantitative anti-F1 and anti-V IgG ELISAs as serological correlates of protection against plague in female Swiss Webster mice.

A recombinant fusion protein composed of Yersinia pestis fraction 1 capsule (F1) and virulence-associated V antigen (V) (F1-V) has been developed as the next-generation vaccine against plague. In this study, female Swiss Webster mice received a single intramuscular vaccination with one of eight doses of the F1-V vaccine and exposed 4 weeks later to either Y. pestis CO92 or C12 organisms by the subcutaneous or aerosol routes of infection. Quantitative anti-F1 and anti-V immunoglobulin G (IgG) ELISAs were used to examine the relationship between survival outcome and antibody titers to F1 and V. Results suggested that each 1log(10) increase in week 4 quantitative anti-F1 and anti-V IgG ELISA titers were associated with a 1.7-fold (p=0.0051) and 2.5-fold (p=0.0054) increase in odds of survival, respectively, against either bubonic or pneumonic plague and may serve as serological correlates of protection.

Exenatide efficacy and safety: a systematic review.

OBJECTIVE: To examine the efficacy, effectiveness and side effects of exenatide when compared with oral glucose-lowering agents or insulin therapy. RESEARCH DESIGN AND METHODS: Relevant citations were identified from searches of multiple bibliographic databases supplemented with searches of the US Food and Drug Administration website and other sources. A qualitative synthesis was performed, with a random effects meta-analysis when appropriate. RESULTS: We identified 17 studies. In placebo-controlled trials of subjects with poorly controlled diabetes (with both groups receiving various oral glucose-lowering agents), exenatide 10 microg twice daily improved glycated haemoglobin (HbA(1c)) by approximately 1.0% over 30 weeks [pooled estimate -0.97%, 95% confidence interval (CI), -1.16 to -0.79%, P < 0.0001] and exenatide treatment over 16-30 weeks was associated with weight loss of 1.0-2.5 kg. Exenatide appeared to confer a similar benefit to various insulin regimes for glycaemic control at follow-up between 16 and 52 weeks (pooled estimate HbA(1c)-0.04%, 95% CI, -0.14 to 0.06%, P = 0.41), but was advantageous over insulin with respect to weight loss (3-6 kg loss at up to 52 weeks of follow-up). Nausea was the most common adverse event in placebo- and active-controlled trials. Rates of hypoglycaemia were similar in exenatide and insulin groups, but were higher with exenatide 10 microg twice daily compared with placebo and hypoglycaemia was most frequent when a sulphonylurea was administered. CONCLUSIONS: In subjects with poorly controlled diabetes, exenatide was associated with a reduction in HbA(1c) that was similar to introducing another oral agent or insulin. Weight loss may be an advantage with exenatide. Long-term studies in diverse and unselected populations are needed to clarify the benefit vs. harm profile of this drug.

Effect of aluminum hydroxide adjuvant and formaldehyde in the formulation of rPA anthrax vaccine.

The serological response and efficacy of Bacillus anthracis recombinant protective antigen (rPA) vaccines formulated with aluminum hydroxide adjuvant, either with or without formaldehyde, were evaluated in rabbits. Rabbits that had been injected with a single dose of 25 microg of rPA adsorbed to 500 microg of aluminum in aluminum hydroxide gel (Alhydrogel) had a significantly higher quantitative anti-rPA IgG ELISA titers (p<0.0001) and toxin neutralizing antibody (TNA) assay titers (p<0.0001) than rabbits tested at the next lowest concentration of aluminum (158 microg). Rabbits injected with two doses of 50 microg of rPA formulated with 500 microg of aluminum also had significantly higher serological responses, as measured by a quantitative anti-rPA IgG ELISA (p<0.0001) and TNA assay (p<0.0001), than sera from rabbits injected with a rPA vaccine formulated without adjuvant. Short-term protection against an aerosol spore challenge (448 LD(50)), however, was not significantly different between the two groups (12/12 and 11/12, respectively). Rabbits injected with a single dose of 50 microg of rPA formulated with 500 microg of aluminum and 0.2% formaldehyde had significantly higher ELISA (p<0.0001) and TNA assay (p<0.0001) titers than rabbits that had been injected with a rPA vaccine formulated with adjuvant but without formaldehyde. Short-term protection against a 125 LD(50) parenteral spore challenge, however, was not significantly different between the two groups (14/24 and 9/24, respectively; p=0.2476). Under the conditions tested in the rabbit animal model, significantly higher serological responses were observed in rabbits that had been injected with rPA formulated with aluminum hydroxide gel adjuvant and formaldehyde. However, differences in short-term efficacy were not observed.

Effectiveness of community health workers in the care of persons with diabetes.

AIMS: The purpose of this systematic review was to examine the effectiveness of community health workers in supporting the care of persons with diabetes. METHODS: Computerized searches were conducted of multiple electronic bibliographic dababases until March 2004. We identified studies in any language and of any design that examined the effectiveness of diabetes-related interventions involving community health workers and reported outcomes in persons with diabetes. Results were synthesized narratively. RESULTS: Eighteen studies were identified, including eight randomized controlled trials. Most studies focused on minority populations in the USA. The roles and duties of community health workers in diabetes care were varied, ranging from substantial involvement in patient care to providing instrumental assistance in education sessions taught by other health professionals. Participants were generally satisfied with their contacts with community health workers and participant knowledge increased. Improvements in physiological measures were noted for some interventions and positive changes in lifestyle and self-care were noted in a number of studies. There were few data on economic outcomes, but several studies demonstrated a decrease in inappropriate health care utilization. CONCLUSIONS: Diabetes programmes include community health workers as team members in a variety of roles. There are some preliminary data demonstrating improvements in participant knowledge and behaviour. Much additional research, however, is needed to understand the incremental benefit of community health workers in multicomponent interventions and to identify appropriate settings and optimal roles for community health workers in the care of persons with diabetes.

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits.

The next-generation human anthrax vaccine developed by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) is based upon purified Bacillus anthracis recombinant protective antigen (rPA) adsorbed to aluminum hydroxide adjuvant (Alhydrogel). In addition to being safe, and effective, it is important that such a vaccine be fully characterized. Four major protein isoforms detected in purified rPA by native PAGE during research and development were reduced to two primary isoforms in bulk material produced by an improved process performed under Good Manufacturing Practices (GMP). Analysis of both rPA preparations by a protein-isoaspartyl-methyl-transferase assay (PIMT) revealed the presence of increasing amounts of iso-aspartic acid correlating with isoform content and suggesting deamidation as the source of rPA charge heterogeneity. Additional purification of GMP rPA by anion exchange chromatography separated and enriched the two principal isoforms. The in vitro and in vivo biological activities of each isoform were measured in comparison to the whole GMP preparation. There was no significant difference in the biological activity of each isoform compared to GMP rPA when analyzed in the presence of lethal factor using a macrophage lysis assay. Vaccination with the two individual isoforms revealed no differences in cytotoxicity neutralization antibody titers when compared to the GMP preparation although one isoform induced more anti-PA IgG antibody than the GMP material. Most importantly, each of the two isoforms as well as the whole GMP preparation protected 90-100% of rabbits challenged parenterally with 129 LD50 of B. anthracis Ames spores. The equivalent biological activity and vaccine efficacy of the two isoforms suggests that further processing to separate isoforms is unnecessary for continued testing of this next-generation anthrax vaccine.