Rapid Review of Therapy Protocols for Public Health Emergencies.

How research during a public health emergency is conducted is recognized as essential to the public health response to that emergency. Such research needs to undergo substantive and meaningful ethical review in a timely manner. Rapid ethical review may be accomplished through a number of mechanisms, including use of local rapid-response institutional review boards (IRBs). We describe use of such a model in the setting of the 2014 Ebola virus disease epidemic and the Rapid-Response IRB's subsequent transition to a multisite single IRB model during the current Covid-19 pandemic. The rapid-response review model is characterized by a small IRB with extensive use of alternate members with specific expertise and by close collaboration with the investigator in an iterative process.

Synthesising the evidence for effective hand hygiene in community settings: an integrated protocol for multiple related systematic reviews.

INTRODUCTION: Despite evidence for the efficacy and effectiveness of hand hygiene in reducing the transmission of infectious diseases, there are gaps in global normative guidance around hand hygiene in community settings. The goal of this review is to systematically retrieve and synthesise available evidence on hand hygiene in community settings across four areas: (1) effective hand hygiene; (2) minimum requirements; (3) behaviour change and (4) government measures. METHODS AND ANALYSIS: This protocol entails a two-phased approach to identify relevant studies for multiple related systematic reviews. Phase 1 involves a broad search to capture all studies on hand hygiene in community settings. Databases, trial registries, expert consultations and hand searches of reference lists will be used to ensure an exhaustive search. A comprehensive, electronic search strategy will be used to identify studies indexed in PubMed, Web of Science, EMBASE, CINAHL, Global Health, Cochrane Library, Global Index Medicus, Scopus, PAIS Index, WHO IRIS, UN Digital Library and World Bank eLibrary published in English from January 1980 to March 2023. The outcome of phase 1 will be a reduced sample of studies from which further screening, specific to research questions across the four key areas can be performed. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Quantitative and qualitative data will be extracted following best practices. We will assess all studies using the Mixed Method Appraisal Tool. All effect measures pertaining to review outcomes will be reported and a narrative synthesis of all studies will be presented including 'data-driven' descriptive themes and 'theory-driven' analytical themes as applicable. ETHICS AND DISSEMINATION: This systematic review is exempt from ethics approval because the work is carried out on published documents. The findings of the reviews will be disseminated in related peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42023429145.

Recommendations for hand hygiene in community settings: a scoping review of current international guidelines.

BACKGROUND: Hand hygiene is an important measure to prevent disease transmission. OBJECTIVE: To summarise current international guideline recommendations for hand hygiene in community settings and to assess to what extent they are consistent and evidence based. ELIGIBILITY CRITERIA: We included international guidelines with one or more recommendations on hand hygiene in community settings-categorised as domestic, public or institutional-published by international organisations, in English or French, between 1 January 1990 and 15 November 2021. DATA SOURCES: To identify relevant guidelines, we searched the WHO Institutional Repository for Information Sharing Database, Google, websites of international organisations, and contacted expert organisations and individuals. CHARTING METHODS: Recommendations were mapped to four areas related to hand hygiene: (1) effective hand hygiene; (2) minimum requirements; (3) behaviour change and (4) government measures. Recommendations were assessed for consistency, concordance and whether supported by evidence. RESULTS: We identified 51 guidelines containing 923 recommendations published between 1999 and 2021 by multilateral agencies and international non-governmental organisations. Handwashing with soap is consistently recommended as the preferred method for hand hygiene across all community settings. Most guidelines specifically recommend handwashing with plain soap and running water for at least 20 s; single-use paper towels for hand drying; and alcohol-based hand rub (ABHR) as a complement or alternative to handwashing. There are inconsistent and discordant recommendations for water quality for handwashing, affordable and effective alternatives to soap and ABHR, and the design of handwashing stations. There are gaps in recommendations on soap and water quantity, behaviour change approaches and government measures required for effective hand hygiene. Less than 10% of recommendations are supported by any cited evidence. CONCLUSION: While current international guidelines consistently recommend handwashing with soap across community settings, there remain gaps in recommendations where clear evidence-based guidance might support more effective policy and investment.

Burden of disease attributable to unsafe drinking water, sanitation, and hygiene in domestic settings: a global analysis for selected adverse health outcomes.

BACKGROUND: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels. METHODS: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH. FINDINGS: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH. INTERPRETATION: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns. FUNDING: WHO and Foreign, Commonwealth & Development Office.

Letter to the Editor Regarding Eosinophilic Otitis Media.

We commend Varghese et al. for "mandating a different outlook" in their recent article on eosinophilic otitis media (EOM). Their statements are supported by medical literature dating back to 1931, reported by Proetz, Shambaugh, Zhang, Draper, Doyle, Pelikan, Ojala, McMahan, Tomonaga, Nsouli, Lasisi, Nguyen, Tian, Sobol, Smirnova, Shim, Smirnova, Luong, and ourselves. Allergy causes EOM and it responds to immunotherapy.

Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.

BACKGROUND: Estimates of the effectiveness of water, sanitation, and hygiene (WASH) interventions that provide high levels of service on childhood diarrhoea are scarce. We aimed to provide up-to-date estimates on the burden of disease attributable to WASH and on the effects of different types of WASH interventions on childhood diarrhoea in low-income and middle-income countries (LMICs). METHODS: In this systematic review and meta-analysis, we updated previous reviews following their search strategy by searching MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index for studies of basic WASH interventions and of WASH interventions providing a high level of service, published between Jan 1, 2016, and May 25, 2021. We included randomised and non-randomised controlled trials conducted at household or community level that matched exposure categories of the so-called service ladder approach of the Sustainable Development Goal (SDG) for WASH. Two reviewers independently extracted study-level data and assessed risk of bias using a modified Newcastle-Ottawa Scale and certainty of evidence using a modified Grading of Recommendations, Assessment, Development, and Evaluation approach. We analysed extracted relative risks (RRs) and 95% CIs using random-effects meta-analyses and meta-regression models. This study is registered with PROSPERO, CRD42016043164. FINDINGS: 19 837 records were identified from the search, of which 124 studies were included, providing 83 water (62 616 children), 20 sanitation (40 799 children), and 41 hygiene (98 416 children) comparisons. Compared with untreated water from an unimproved source, risk of diarrhoea was reduced by up to 50% with water treated at point of use (POU): filtration (n=23 studies; RR 0·50 [95% CI 0·41-0·60]), solar treatment (n=13; 0·63 [0·50-0·80]), and chlorination (n=25; 0·66 [0·56-0·77]). Compared with an unimproved source, provision of an improved drinking water supply on premises with higher water quality reduced diarrhoea risk by 52% (n=2; 0·48 [0·26-0·87]). Overall, sanitation interventions reduced diarrhoea risk by 24% (0·76 [0·61-0·94]). Compared with unimproved sanitation, providing sewer connection reduced diarrhoea risk by 47% (n=5; 0·53 [0·30-0·93]). Promotion of handwashing with soap reduced diarrhoea risk by 30% (0·70 [0·64-0·76]). INTERPRETATION: WASH interventions reduced risk of diarrhoea in children in LMICs. Interventions supplying either water filtered at POU, higher water quality from an improved source on premises, or basic sanitation services with sewer connection were associated with increased reductions. Our results support higher service levels called for under SDG 6. Notably, no studies evaluated interventions that delivered access to safely managed WASH services, the level of service to which universal coverage by 2030 is committed under the SDG. FUNDING: WHO, Foreign, Commonwealth & Development Office, and National Institute of Environmental Health Sciences.

Developing a Rapid Response Single IRB Model for Conducting Research During a Public Health Emergency.

Research is foundational for evidence-based management of patients. Clinical research, however, takes time to plan, conduct, and disseminate-a luxury that is rarely available during a public health emergency. The University of Nebraska Medical Center (UNMC) developed a single institutional review board (IRB), with a vision to establish a rapid review resource for a network focused on clinical research of emerging pathogens in the United States. A core aspect of successful initiation of research during a pandemic or epidemic is the ability to operationalize an approach for rapid ethical review of human subject research and conduct those reviews at multiple sites-without losing any of the substantive aspects of ethics review. This process must be cultivated in anticipation of a public health emergency. US guidance for operationalizing IRB review for multisite research in a public health emergency is not well studied and processes are not well established. UNMC sought to address operational gaps and identify the unique procedural needs of rapid response single IRB (RR-sIRB) review of multisite research by conducting a series of preparedness exercises to develop and test the RR-sIRB model. For decades, emergency responder, healthcare, and public health organizations have conducted emergency preparedness exercises to test requirements for emergency response. In this article, we describe 2 types of simulation exercises conducted by UNMC: workshops and tabletops. This effort represents a unique use of emergency preparedness exercises to develop, refine, and test rapid review functions for an sIRB and to validate readiness of regulatory research processes. Such processes are crucial for conducting rapid, ethical, and sound clinical research in public health emergencies.

Research During the Pandemic: Views from Both Sides of the Fence.

The SARS-CoV-2 pandemic has affected practically every aspect of life across the globe for the past year or more; the practice of clinical research not the least. Clinician scientists attempting to start or continue work both related and unrelated to the disease itself have faced ethical, oversight, or regulatory challenges. No aspect of the clinical trial enterprise was unaffected. These narratives detail some of the barriers encountered and how the investigators coped (or didn't cope). Common themes emerged, ranging from a need to contribute, which drove the researchers to frustration with real and perceived obstructions (both old and new). The narratives disclose common ethical issues related to research during a pandemic: issues both qualitatively and quantitatively different from other human subject research; challenges both new and novel, as well as those previously seen, but writ large in the face of the crisis. The narratives also offer words of advice from the trenches and speak to successes, both large and small, and to the value of teamwork and focus on a common goal.

Intradermal Testing Doubles Identification of Allergy among 110 Immunotherapy-Responsive Patients with Eustachian Tube Dysfunction.

The purpose of this study was to determine whether the sensitivity advantage of intradermal dilutional testing (IDT) is clinically relevant in patients with obstructive Eustachian tube dysfunction (ETD) or otitis media with effusion (OME). This retrospective, private-practice cohort study compared the sensitivity of skin prick tests (SPT) vs. IDT in 110 adults and children with suspected allergy and OME. Primary outcome measure was symptom resolution from allergy immunotherapy (AIT). IDT identified 57% more patients as being allergic, and 8.6 times more reactive allergens than would have been diagnosed using only SPT. Patients diagnosed by IDT had the same degree of symptom improvement from immunotherapy, independent of allergen sensitivity (66% by SPT vs. 63% by IDT; p = 0.69, not different). Low-sensitivity allergy tests, which may fail to identify allergy in over two thirds of children aged 3 to 15 as being atopic, or among 60% of patients with ETD, may explain why many physicians do not consider allergy as a treatable etiology for their patient's OME/ETD. IDT offers superior sensitivity over SPT for detecting allergens clinically relevant to treating OME/ETD. These data strongly support increased utilization of intradermal testing and invite additional clinical outcome studies.

Vulnerability in Research: Basic Ethical Concepts and General Approach to Review.

Background: The concept of vulnerability is a cornerstone of the theoretical basis and practical application of ethics in human subjects research. Risks to humans participating in research must be minimized; that is, subjects must be offered protection from risks. Vulnerable subjects require additional protections. Methods: This paper reviews the ethical and conceptual basis of vulnerability within the context of human subjects research and suggests a basic approach that institutional review boards (IRBs) can use when considering if the research includes adequate safeguards to protect the rights and welfare of subjects who are likely to be vulnerable. Results: Two distinct approaches to describing the features that make a person vulnerable are the categorical approach and the contextual approach. The categorical approach considers certain groups or populations as vulnerable. This approach is not optimal because it does not address persons with multiple vulnerabilities, does not account for variation in the degree of vulnerability within the group based on individual characteristics, and classifies certain persons as vulnerable rather than identifying situations in which individuals might be considered vulnerable. The alternate contextual approach allows for a more nuanced understanding of the nature of the vulnerability than the categorical approach and therefore a more focused approach to safeguards. The IRB is charged with ensuring that additional safeguards to protect the rights and welfare of subjects who are likely to be vulnerable are included in the study under review. To make this determination, the IRB might be advised to consider two questions: (1) is inclusion necessary? and (2) if so, are safeguards adequate? Conclusion: Although vulnerability is often presented as a yes/no consequence related to some characteristic of a group, a more accurate approach is to consider vulnerability as occurring along a spectrum of seriousness and as a consequence of situations and context. With this idea in mind, investigators and IRBs are advised to take a stepwise approach to determining if the study meets the regulatory and ethical admonition to ensure that safeguards protect the rights and welfare of vulnerable subjects.

Advanced Preparation Makes Research in Emergencies and Isolation Care Possible: The Case of Novel Coronavirus Disease (COVID-19).

The optimal time to initiate research on emergencies is before they occur. However, timely initiation of high-quality research may launch during an emergency under the right conditions. These include an appropriate context, clarity in scientific aims, preexisting resources, strong operational and research structures that are facile, and good governance. Here, Nebraskan rapid research efforts early during the 2020 coronavirus disease pandemic, while participating in the first use of U.S. federal quarantine in 50 years, are described from these aspects, as the global experience with this severe emerging infection grew apace. The experience has lessons in purpose, structure, function, and performance of research in any emergency, when facing any threat.

The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement.

BACKGROUND: Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. MAIN BODY: Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. CONCLUSION: These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

Burden of disease from inadequate water, sanitation and hygiene for selected adverse health outcomes: An updated analysis with a focus on low- and middle-income countries.

BACKGROUND: To develop updated estimates in response to new exposure and exposure-response data of the burden of diarrhoea, respiratory infections, malnutrition, schistosomiasis, malaria, soil-transmitted helminth infections and trachoma from exposure to inadequate drinking-water, sanitation and hygiene behaviours (WASH) with a focus on low- and middle-income countries. METHODS: For each of the analysed diseases, exposure levels with both sufficient global exposure data for 2016 and a matching exposure-response relationship were combined into population-attributable fractions. Attributable deaths and disability-adjusted life years (DALYs) were estimated for each disease and, for most of the diseases, by country, age and sex group separately for inadequate water, sanitation and hygiene behaviours and for the cluster of risk factors. Uncertainty estimates were computed on the basis of uncertainty surrounding exposure estimates and relative risks. FINDINGS: An estimated 829,000 WASH-attributable deaths and 49.8 million DALYs occurred from diarrhoeal diseases in 2016, equivalent to 60% of all diarrhoeal deaths. In children under 5 years, 297,000 WASH-attributable diarrhoea deaths occurred, representing 5.3% of all deaths in this age group. If the global disease burden from different diseases and several counterfactual exposure distributions was combined it would amount to 1.6 million deaths, representing 2.8% of all deaths, and 104.6 million DALYs in 2016. CONCLUSIONS: Despite recent declines in attributable mortality, inadequate WASH remains an important determinant of global disease burden, especially among young children. These estimates contribute to global monitoring such as for the Sustainable Development Goal indicator on mortality from inadequate WASH.

The Special Pathogens Research Network: Enabling Research Readiness.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.

A Faecal Contamination Index for interpreting heterogeneous diarrhoea impacts of water, sanitation and hygiene interventions and overall, regional and country estimates of community sanitation coverage with a focus on low- and middle-income countries.

OBJECTIVES: The impact on diarrhoea of sanitation interventions has been heterogeneous. We hypothesize that this is due to the level of prevailing faecal environmental contamination and propose a Faecal Contamination Index (FAECI) of selected WASH indicators (objective 1). Additionally, we provide estimates of the proportion of the population living in communities above certain sanitation coverage levels (objective 2). METHODS: Objective 1: Faecal contamination post-intervention was estimated from WASH intervention reports. WASH indicators composing the FAECI included eight water, sanitation and hygiene practice indicators, which were selected for their relevance for health and data availability at study- and country-level. The association between the estimated level of faecal environmental contamination and diarrhoea was examined using meta-regression. Objective 2: A literature search was conducted to identify health-relevant community sanitation coverage thresholds. To estimate total community coverage with basic sanitation in low- and middle-income countries, at relevant thresholds, household surveys with data available at primary sampling unit (PSU)-level were analysed according to the identified thresholds, at country-, regional- and overall level. RESULTS: Objective 1: We found a non-linear association between estimated environmental faecal contamination and sanitation interventions' impact on diarrhoeal disease. Diarrhoea reductions were highest at lower faecal contamination levels, and no diarrhoea reduction was found when contamination increased above a certain level. Objective 2: Around 45% of the population lives in communities with more than 75% of coverage with basic sanitation and 24% of the population lives in communities above 95% coverage, respectively. CONCLUSIONS: High prevailing faecal contamination might explain interventions' poor effectiveness in reducing diarrhoea. The here proposed Faecal Contamination Index is a first attempt to estimate the level of faecal contamination in communities. Much of the world's population currently lives in faecally contaminated environments as indicated by low community sanitation coverage.