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.

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.

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.

Improving water, sanitation and hygiene in health-care facilities, Liberia.

PROBLEM: The lack of proper water and sanitation infrastructures and poor hygiene practices in health-care facilities reduces facilities' preparedness and response to disease outbreaks and decreases the communities' trust in the health services provided. APPROACH: To improve water and sanitation infrastructures and hygiene practices, the Liberian health ministry held multistakeholder meetings to develop a national water, sanitation and hygiene and environmental health package. A national train-the-trainer course was held for county environmental health technicians, which included infection prevention and control focal persons; the focal persons acted as change agents. LOCAL SETTING: In Liberia, only 45% of 701 surveyed health-care facilities had an improved water source in 2015, and only 27% of these health-care facilities had proper disposal for infectious waste. RELEVANT CHANGES: Local ownership, through engagement of local health workers, was introduced to ensure development and refinement of the package. In-county collaborations between health-care facilities, along with multisectoral collaboration, informed national level direction, which led to increased focus on water and sanitation infrastructures and uptake of hygiene practices to improve the overall quality of service delivery. LESSONS LEARNT: National level leadership was important to identify a vision and create an enabling environment for changing the perception of water, sanitation and hygiene in health-care provision. The involvement of health workers was central to address basic infrastructure and hygiene practices in health-care facilities and they also worked as stimulators for sustainable change. Further, developing a long-term implementation plan for national level initiatives is important to ensure sustainability.

An ethical framework for responding to drug shortages in pediatric oncology.

The frequency of drug shortages has increased considerably over the last decade. Important ethical issues arise whenever the supply of an effective drug is insufficient to meet demand. Using the ethical principles of beneficence, non-maleficence, and justice, institutions can guide prioritization of drug distribution before a shortage occurs to avoid unfair and unethical distribution of resources. This analysis will give a historical context for drug shortages, identify, and explore the central ethical concerns raised by drug shortages, and propose an ethical framework for addressing them in the context of pediatric oncology.

From joint thinking to joint action: a call to action on improving water, sanitation, and hygiene for maternal and newborn health.

Yael Velleman and colleagues argue for stronger integration between the water, sanitation, and hygiene (WASH) and maternal and newborn health sectors. Please see later in the article for the Editors' Summary.

Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: systematic review and meta-regression.

OBJECTIVE: To assess the impact of inadequate water and sanitation on diarrhoeal disease in low- and middle-income settings. METHODS: The search strategy used Cochrane Library, MEDLINE & PubMed, Global Health, Embase and BIOSIS supplemented by screening of reference lists from previously published systematic reviews, to identify studies reporting on interventions examining the effect of drinking water and sanitation improvements in low- and middle-income settings published between 1970 and May 2013. Studies including randomised controlled trials, quasi-randomised trials with control group, observational studies using matching techniques and observational studies with a control group where the intervention was well defined were eligible. Risk of bias was assessed using a modified Ottawa-Newcastle scale. Study results were combined using meta-analysis and meta-regression to derive overall and intervention-specific risk estimates. RESULTS: Of 6819 records identified for drinking water, 61 studies met the inclusion criteria, and of 12,515 records identified for sanitation, 11 studies were included. Overall, improvements in drinking water and sanitation were associated with decreased risks of diarrhoea. Specific improvements, such as the use of water filters, provision of high-quality piped water and sewer connections, were associated with greater reductions in diarrhoea compared with other interventions. CONCLUSIONS: The results show that inadequate water and sanitation are associated with considerable risks of diarrhoeal disease and that there are notable differences in illness reduction according to the type of improved water and sanitation implemented.

Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries.

OBJECTIVE: To estimate the burden of diarrhoeal diseases from exposure to inadequate water, sanitation and hand hygiene in low- and middle-income settings and provide an overview of the impact on other diseases. METHODS: For estimating the impact of water, sanitation and hygiene on diarrhoea, we selected exposure levels with both sufficient global exposure data and a matching exposure-risk relationship. Global exposure data were estimated for the year 2012, and risk estimates were taken from the most recent systematic analyses. We estimated attributable deaths and disability-adjusted life years (DALYs) by country, age and sex for inadequate water, sanitation and hand hygiene separately, and as a cluster of risk factors. Uncertainty estimates were computed on the basis of uncertainty surrounding exposure estimates and relative risks. RESULTS: In 2012, 502,000 diarrhoea deaths were estimated to be caused by inadequate drinking water and 280,000 deaths by inadequate sanitation. The most likely estimate of disease burden from inadequate hand hygiene amounts to 297,000 deaths. In total, 842,000 diarrhoea deaths are estimated to be caused by this cluster of risk factors, which amounts to 1.5% of the total disease burden and 58% of diarrhoeal diseases. In children under 5 years old, 361,000 deaths could be prevented, representing 5.5% of deaths in that age group. CONCLUSIONS: This estimate confirms the importance of improving water and sanitation in low- and middle-income settings for the prevention of diarrhoeal disease burden. It also underscores the need for better data on exposure and risk reductions that can be achieved with provision of reliable piped water, community sewage with treatment and hand hygiene.

Cytosine arabinoside and mitoxantrone followed by second allogeneic transplant for the treatment of children with refractory juvenile myelomonocytic leukemia.

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for most patients with juvenile myelomonocytic leukemia (JMML). However, persistent disease and relapse rates after transplant range from 26% to 58%. We report the successful use of second HSCT after preparation with mitoxantrone and cytosine arabinoside (Ara-C) for patients with refractory or recurrent disease. Between 1993 and 2006, 5 children who underwent HSCT at our institution as initial therapy for JMML had persistent disease or relapsed. Pre-HSCT conditioning varied and donors were either HLA-matched siblings (n=2) or matched unrelated donors (n=3). After initial HSCT, they subsequently received high-dose Ara-C (3 g/m IV) every 12 hours on days -8 through -3 and mitoxantrone (10 mg/m/d IV) on days -8, -7, -6 followed by second HSCT from their original donors. All 5 patients are alive at 88, 179, 199, 234, and 246 months with no evidence of JMML, no significant toxicity, and 100% donor chimera as determined by PCR short-tandem repeat analysis. Our experience supports second transplant utilizing high-dose Ara-C and mitoxantrone in children with JMML who do not respond or relapse after first transplant.

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.

How do we improve patient compliance and adherence to long-term statin therapy?

Statins are highly effective drugs prescribed to millions of people to lower LDL-cholesterol and decrease cardiovascular risk. The benefits of statin therapy seen in randomized clinical trials will only be replicated in real-life if patients adhere to the prescribed treatment regimen. But, about half of patients discontinue statin therapy within the first year, and adherence decreases with time. Patient, physician and healthcare system-related factors play a role in this problem. Recent studies have focused more on the patients' perspectives on non-adherence. Adverse events are cited as the most common cause of statin discontinuation; thus, the healthcare provider must be willing to ally and dialogue with patients to address concerns and assess the risks and benefits of continued statin therapy.

Gene expression signatures: a new approach to understanding the pathophysiology of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex inflammatory disease with variable disease manifestation. Though external risk factors are associated with development and/or persistence of CRS, the host mucosal response is also important, as nasal epithelium acts as a physical and immune barrier. Under inflammatory stress, the nasal epithelium can undergo injury, followed by a rapid remodeling response ranging from epithelial hyperplasia, to goblet-cell metaplasia, to denudation, loss of cilia, fibrosis, and basement membrane thickening. Identification of gene expression signatures and molecular pathways in CRS pathogenesis have now begun to contribute significantly to a better understanding of the genetic and molecular alterations underlying CRS development and progression. Genetic studies are especially illuminating when multiple gene variants synergize within a permissive environmental context, and are expected to guide development of more effective therapeutic targets for CRS treatment.

Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours.

1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V(d)) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V(d)). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V(d) were 2.31 L/hr and 17.5 L, respectively. The CL and V(d) allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V(d) increased with increasing weight similar to BSA.

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.

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.

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.