A mitochondrial-targeted activity-based sensing probe for ratiometric imaging of formaldehyde reveals key regulators of the mitochondrial one-carbon pool.

Formaldehyde (FA) is both a highly reactive environmental genotoxin and an endogenously produced metabolite that functions as a signaling molecule and one-carbon (1C) store to regulate 1C metabolism and epigenetics in the cell. Owing to its signal-stress duality, cells have evolved multiple clearance mechanisms to maintain FA homeostasis, acting to avoid the established genotoxicity of FA while also redirecting FA-derived carbon units into the biosynthesis of essential nucleobases and amino acids. The highly compartmentalized nature of FA exposure, production, and regulation motivates the development of chemical tools that enable monitoring of transient FA fluxes with subcellular resolution. Here we report a mitochondrial-targeted, activity-based sensing probe for ratiometric FA detection, MitoRFAP-2, and apply this reagent to monitor endogenous mitochondrial sources and sinks of this 1C unit. We establish the utility of subcellular localization by showing that MitoRFAP-2 is sensitive enough to detect changes in mitochondrial FA pools with genetic and pharmacological modulation of enzymes involved in 1C and amino acid metabolism, including the pervasive, less active genetic mutant aldehyde dehydrogenase 2*2 (ALDH2*2), where previous, non-targeted versions of FA sensors are not. Finally, we used MitoRFAP-2 to comparatively profile basal levels of FA across a panel of breast cancer cell lines, finding that FA-dependent fluorescence correlates with expression levels of enzymes involved in 1C metabolism. By showcasing the ability of MitoRFAP-2 to identify new information on mitochondrial FA homeostasis, this work provides a starting point for the design of a broader range of chemical probes for detecting physiologically important aldehydes with subcellular resolution and a useful reagent for further studies of 1C biology.

Foot and Ankle Care by Podiatrists and Amputations in Patients With Diabetes and Kidney Failure.

Importance: Patients with kidney failure have an increased risk of diabetes-related foot complications. The benefit of regular foot and ankle care in this at-risk population is unknown. Objective: To investigate foot and ankle care by podiatrists and the outcomes of diabetic foot ulcers (DFUs) in patients with kidney failure. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries with type 2 diabetes receiving dialysis who had a new DFU diagnosis. The analysis of the calendar year 2016 to 2019 data from the United States Renal Data System was performed on June 15, 2023, with subsequent updates on December 11, 2023. Exposures: Foot and ankle care by podiatrists during 3 months prior to DFU diagnosis. Main Outcomes and Measures: The outcomes were a composite of death and/or major amputation, as well as major amputation alone. Kaplan-Meier analysis was used to estimate 2 to 3 years of amputation-free survival. Foot and ankle care by podiatrists and the composite outcome was examined using inverse probability-weighted Cox regression, while competing risk regression models were used for the analysis of amputation alone. Results: Among the 14 935 adult patients with kidney failure and a new DFU (mean [SD] age, 59.3 [12.7] years; 35.4% aged ≥65 years; 8284 men [55.4%]; Asian, 2.7%; Black/African American, 35.0%; Hispanic, 17.7%; White, 58.5%), 18.4% (n = 2736) received care by podiatrists in the 3 months before index DFU diagnosis. These patients were older, more likely to be male, and have more comorbidities than those without prior podiatrist visits. Over a mean (SD) 13.5 (12.0)-month follow-up, 70% of those with podiatric care experienced death and/or major amputation, compared with 74% in the nonpodiatric group. Survival probabilities at 36 months were 26.3% vs 22.8% (P < .001, unadjusted Kaplan-Meier survival analysis). In multivariate regression analysis, foot and ankle care was associated with an 11% lower likelihood of death and/or amputation (hazard ratio [HR], 0.89 95% CI, 0.84-0.93) and a 9% lower likelihood of major amputation (above or below knee) (HR, 0.91; 95% CI, 0.84-0.99) than those who did not. Conclusions and Relevance: The findings of this study suggest that patients with kidney failure at risk for DFUs who receive foot and ankle care from podiatrists may be associated with a reduced likelihood of diabetes-related amputations.

Marine Protected Area Expansion and Country-Level Age-Standardized Adult Mortality.

Many countries have adopted targets to increase marine protected areas (MPAs) to limit the degradation of water bodies. Although there is evidence that MPAs can conserve marine life and promote biodiversity, there are limited data on the human health implications of MPAs. Using panel data from 1990, 2000, and 2014, we estimated the country-level associations between MPAs (i.e., percentage of territorial waters designated as marine reserves) and age-standardized mortality (i.e., age-standardized probability of dying between 15 and 60 years from all-causes among ages 15-60/100,000 population) by sex, among 110 countries. We fit mixed-effects linear regression models of mortality as a function of current MPA coverage, gross domestic product growth, year, the prior extent of MPA, electricity coverage, governance, and country-level random effects. We observed a significant inverse association between current MPA coverage and adult mortality. For each 5-percentage-point increase in current MPA coverage, a country had 0.982 times the geometric means of female and male mortality [geometric mean ratio: 0.982 (95% CI 0·976, 0·988)] conditional on past %MPA coverage and other modeled variables. The model showed no significant residual association of mortality with past %MPA conditional on current %MPA and other modeled variables. This is one of the first studies to show a positive association between increasing marine conservation and human health. This macro-level study suggests there may be important co-benefits for human health from expanding MPAs that merit further investigation.

Medicaid Coverage for Routine Foot Care.

BACKGROUND: Despite national and international guidelines supporting podiatric services as a means of prevention for lower-extremity complications, especially in at-risk individuals, current coverage for these services under the US Medicaid program is not universal. The vast differences between state Medicaid programs regarding reimbursable foot care services is confusing and potentially serves as a barrier for the most vulnerable populations to receive preventative services. This article provides a brief discussion of "routine" podiatric services from a clinical perspective and provides a review of state Medicaid programs including optional services (eg, podiatric coverage). METHODS: Using data from a national survey of state Medicaid programs, we present and discuss common Medicaid coverage schemes for routine foot care provided by podiatric physicians. RESULTS: Analysis demonstrated that states vary dramatically in basic descriptions of preventive foot care, levels of coverage, eligibility, and methods of documenting coverage details. CONCLUSIONS: The authors recommend bringing Medicaid in line with other federal health programs and including podiatric physicians in the definition of "physician" for coverage purposes. States should move away from describing preventative services as "routine" and choose language that more accurately reflects the true nature and purpose of the care.

The Effects of the COVID-19 Economic Downturn on Medicaid Coverage for Podiatry Services.

As of 2016, Medicaid accounted for nearly 20% of state general fund budgets. Optional Medicaid services such as podiatry are often subject to cost-cutting measures in periods of economic downturn, as was the case in the wake of the 2007 financial crisis. Although the cuts were intended as a cost-saving measure, research indicates that they had the opposite effect. The restriction and limitation of these services during the Great Recession resulted in both poorer health outcomes for beneficiaries, and poorer financial outcomes for state Medicaid programs. With states citing record levels of unemployment as of April of 2020 and projecting significant declines in annual revenue in 2021, the economic conditions resulting from the coronavirus disease of 2019 pandemic are likely to rival those of the Great Recession. Given the historical precedent for restricting or eliminating optional Medicaid services as a cost-saving measure, it is likely that podiatric services will once again come under scrutiny. Previous efforts by state-level podiatric societies have proven successful in lobbying for the reinstatement of coverage under Medicaid by conveying evidence of the negative outcomes associated with elimination to stakeholders. The specialty must once again engage policymakers by drawing on evidence gleaned and lessons learned from past cuts of optional Medicaid services to avert counterproductive coverage restrictions intended to mitigate the financial impact of the coronavirus disease of 2019 pandemic.

Medicaid Coverage for Podiatric Care: A National Survey.

OBJECTIVES: Medicaid provides health insurance for low-income people meeting specific eligibility requirements. It is funded and administered by both the federal and state governments; this decentralization leads to vastly different programs across the country. The objective of this legal surveillance project was to describe state-by-state differences in podiatric care coverage for nonelderly adults across Medicaid programs. METHODS: We used policy surveillance, a form of advanced legal mapping. It is the systematic collection and analysis of written policies across jurisdictions. Policy surveillance captures the important features of law through a rigorous scientific process to turn these policies into structured, quantitative legal data that are suitable for further evaluation or modeling. Data for the 51 jurisdictions were current as of September 1, 2020. RESULTS: The vast majority of jurisdictions (82%) covered podiatric services for all classes of Medicaid beneficiaries, but the rules, restrictions, and limitations around coverage differed. Twenty-five jurisdictions had no limits on the number of podiatric visits during a specified period; 26 jurisdictions indicated a cap. Ten jurisdictions had no explicit limitations on coverage of routine foot care, whereas 33 jurisdictions covered routine foot care only when medically necessary or with a triggering condition. Eight jurisdictions did not cover routine foot care at all, and 28 jurisdictions required prior authorizations. CONCLUSIONS: Podiatric care coverage, which is often preventive, varies greatly by state. This variability in coverage, which has not been previously tracked at the level of detail provided in our study, has implications for cost and health outcomes. The value of podiatric care is especially apparent in Medicaid populations. The compilation of these data can serve as a valuable resource for clinicians, researchers, and policy makers.

Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.

Influenza forecasting for French regions combining EHR, web and climatic data sources with a machine learning ensemble approach.

Effective and timely disease surveillance systems have the potential to help public health officials design interventions to mitigate the effects of disease outbreaks. Currently, healthcare-based disease monitoring systems in France offer influenza activity information that lags real-time by one to three weeks. This temporal data gap introduces uncertainty that prevents public health officials from having a timely perspective on the population-level disease activity. Here, we present a machine-learning modeling approach that produces real-time estimates and short-term forecasts of influenza activity for the twelve continental regions of France by leveraging multiple disparate data sources that include, Google search activity, real-time and local weather information, flu-related Twitter micro-blogs, electronic health records data, and historical disease activity synchronicities across regions. Our results show that all data sources contribute to improving influenza surveillance and that machine-learning ensembles that combine all data sources lead to accurate and timely predictions.

A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Ligand-Directed Approach to Activity-Based Sensing: Developing Palladacycle Fluorescent Probes That Enable Endogenous Carbon Monoxide Detection.

Carbon monoxide (CO) is an emerging gasotransmitter and reactive carbon species with broad anti-inflammatory, cytoprotective, and neurotransmitter functions along with therapeutic potential for the treatment of cardiovascular diseases. The study of CO chemistry in biology and medicine relative to other prominent gasotransmitters such as NO and H2S remains challenging, in large part due to limitations in available tools for the direct visualization of this transient and freely diffusing small molecule in complex living systems. Here we report a ligand-directed activity-based sensing (ABS) approach to CO detection through palladium-mediated carbonylation chemistry. Specifically, the design and synthesis of a series of ABS probes with systematic alterations in the palladium-ligand environment (e.g., sp3-S, sp3-N, sp2-N) establish structure-activity relationships for palladacycles to confer selective reactivity with CO under physiological conditions. These fundamental studies led to the development of an optimized probe, termed Carbon Monoxide Probe-3 Ester Pyridine (COP-3E-Py), which enables imaging of CO release in live cell and brain settings, including monitoring of endogenous CO production that triggers presynaptic dopamine release in fly brains. This work provides a unique tool for studying CO in living systems and establishes the utility of a synthetic methods approach to activity-based sensing using principles of organometallic chemistry.

Use of Twitter social media activity as a proxy for human mobility to predict the spatiotemporal spread of COVID-19 at global scale.

As of February 27, 2020, 82,294 confirmed cases of coronavirus disease (COVID-19) have been reported since December 2019, including 2,804 deaths, with cases reported throughout China, as well as in 45 international locations outside of mainland China. We predict the spatiotemporal spread of reported COVID- 19 cases at the global level during the first few weeks of the current outbreak by analyzing openly available geolocated Twitter social media data. Human mobility patterns were estimated by analyzing geolocated 2013-2015 Twitter data from users who had: i) tweeted at least twice on consecutive days from Wuhan, China, between November 1, 2013, and January 28, 2014, and November 1, 2014, and January 28, 2015; and ii) left Wuhan following their second tweet during the time period under investigation. Publicly available COVID-19 case data were used to investigate the correlation among cases reported during the current outbreak, locations visited by the study cohort of Twitter users, and airports with scheduled flights from Wuhan. Infectious Disease Vulnerability Index (IDVI) data were obtained to identify the capacity of countries receiving travellers from Wuhan to respond to COVID-19. Our study cohort comprised 161 users. Of these users, 133 (82.6%) posted tweets from 157 Chinese cities (1,344 tweets) during the 30 days after leaving Wuhan following their second tweet, with a median of 2 (IQR= 1-3) locations visited and a mean distance of 601 km (IQR= 295.2-834.7 km) traveled. Of our user cohort, 60 (37.2%) traveled abroad to 119 locations in 28 countries. Of the 82 COVID-19 cases reported outside China as of January 30, 2020, 54 cases had known geolocation coordinates and 74.1% (40 cases) were reported less than 15 km (median = 7.4 km, IQR= 2.9-285.5 km) from a location visited by at least one of our study cohort's users. Countries visited by the cohort's users and which have cases reported by January 30, 2020, had a median IDVI equal to 0.74. We show that social media data can be used to predict the spatiotemporal spread of infectious diseases such as COVID-19. Based on our analyses, we anticipate cases to be reported in Saudi Arabia and Indonesia; additionally, countries with a moderate to low IDVI (i.e. ≤0.7) such as Indonesia, Pakistan, and Turkey should be on high alert and develop COVID- 19 response plans as soon as permitting.

Enteral baclofen withdrawal managed with intravenous dexmedetomidine: A case report.

PURPOSE: Acute enteral baclofen withdrawal can be clinically severe if not identified and managed appropriately. Treatment of baclofen withdrawal includes supportive care and reinitiation of baclofen. There are limited pharmacotherapeutic interventions available to manage symptoms of acute enteral baclofen withdrawal, especially in nonintubated patients. SUMMARY: We describe a 61-year-old Caucasian male with a past medical history of chronic back pain and spinal stenosis who was admitted to the medical intensive care unit with confusion, insomnia, agitation, delirium, and auditory and visual hallucinations. For control of agitation, the patient was administered 10 mg of i.v. haloperidol, 1 mg of i.v. lorazepam, and 14 mg of i.v. midazolam, with minimal improvement noted; therefore, dexmedetomidine was initiated, which led to clinical resolution of his symptoms. Upon further investigation it was determined that the patient was taking approximately 10 baclofen 20-mg tablets a day. According to his pharmacy records, he had filled prescriptions for a total of 738 baclofen tablets in the previous 12 weeks. The patient's presentation and sudden discontinuation of high-dose baclofen led to a diagnosis of baclofen withdrawal. Baclofen was subsequently restarted, and dexmedetomidine was weaned over 36 hours. CONCLUSION: Dexmedetomidine controlled this patient's agitation and delirium without suppressing his respiratory drive and should be considered for management of acute enteral baclofen withdrawal.

TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease.

Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990-2016.

BACKGROUND: Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016. METHODS: We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates. FINDINGS: Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979-326 913) and about 13·2% (9·2-17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191-93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757-83 064) and about 3·2% (1·8-4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2-6·8) of diarrhoea deaths in children younger than 5 years. INTERPRETATION: The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden. FUNDING: Bill & Melinda Gates Foundation.

Rotavirus Vaccination and the Global Burden of Rotavirus Diarrhea Among Children Younger Than 5 Years.

Importance: Rotavirus infection is the global leading cause of diarrhea-associated morbidity and mortality among children younger than 5 years. Objectives: To examine the extent of rotavirus infection among children younger than 5 years by country and the number of deaths averted because of the rotavirus vaccine. Design, Setting, and Participants: This report builds on findings from the Global Burden of Disease Study 2016, a cross-sectional study that measured diarrheal diseases and their etiologic agents. Models were used to estimate burden in data-sparse locations. Exposure: Diarrhea due to rotavirus infection. Main Outcomes and Measures: Rotavirus-associated mortality and morbidity by country and year and averted deaths attributable to the rotavirus vaccine by country. Results: Rotavirus infection was responsible for an estimated 128 500 deaths (95% uncertainty interval [UI], 104 500-155 600) among children younger than 5 years throughout the world in 2016, with 104 733 deaths occurring in sub-Saharan Africa (95% UI, 83 406-128 842). Rotavirus infection was responsible for more than 258 million episodes of diarrhea among children younger than 5 years in 2016 (95% UI, 193 million to 341 million), an incidence of 0.42 cases per child-year (95% UI, 0.30-0.53). Vaccine use is estimated to have averted more than 28 000 deaths (95% UI, 14 600-46 700) among children younger than 5 years, and expanded use of the rotavirus vaccine, particularly in sub-Saharan Africa, could have prevented approximately 20% of all deaths attributable to diarrhea among children younger than 5 years. Conclusions and Relevance: Rotavirus-associated mortality has decreased markedly over time in part because of the introduction of the rotavirus vaccine. This study suggests that prioritizing vaccine introduction and interventions to reduce diarrhea-associated morbidity and mortality is necessary in the continued global reduction of rotavirus infection.

Direct arylation of strong aliphatic C-H bonds.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)-heteroatom bonds from strong C-H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp3)-H bonds via substrate-directed transition-metal C-H insertion8, undirected C-H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)-C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study.

BACKGROUND: The protozoan Cryptosporidium is a leading cause of diarrhoea morbidity and mortality in children younger than 5 years. However, the true global burden of Cryptosporidium infection in children younger than 5 years might have been underestimated in previous quantifications because it only took account of the acute effects of diarrhoea. We aimed to demonstrate whether there is a causal relation between Cryptosporidium and childhood growth and, if so, to quantify the associated additional burden. METHODS: The Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2016 was a systematic and scientific effort to quantify the morbidity and mortality associated with more than 300 causes of death and disability, including diarrhoea caused by Cryptosporidium infection. We supplemented estimates on the burden of Cryptosporidium in GBD 2016 with findings from a systematic review of published and unpublished cohort studies and a meta-analysis of the effect of childhood diarrhoea caused by Cryptosporidium infection on physical growth. FINDINGS: In 2016, Cryptosporidium infection was the fifth leading diarrhoeal aetiology in children younger than 5 years, and acute infection caused more than 48 000 deaths (95% uncertainty interval [UI] 24 600-81 900) and more than 4·2 million disability-adjusted life-years lost (95% UI 2·2 million-7·2 million). We identified seven data sources from the scientific literature and six individual-level data sources describing the relation between Cryptosporidium and childhood growth. Each episode of diarrhoea caused by Cryptosporidium infection was associated with a decrease in height-for-age Z score (0·049, 95% CI 0·014-0·080), weight-for-age Z score (0·095, 0·055-0·134), and weight-for-height Z score (0·126, 0·057-0·194). We estimated that diarrhoea from Cryptosporidium infection caused an additional 7·85 million disability-adjusted life-years (95% UI 5·42 million-10·11 million) after we accounted for its effect on growth faltering-153% more than that estimated from acute effects alone. INTERPRETATION: Our findings show that the substantial short-term burden of diarrhoea from Cryptosporidium infection on childhood growth and wellbeing is an underestimate of the true burden. Interventions designed to prevent and effectively treat infection in children younger than 5 years will have enormous public health and social development impacts. FUNDING: The Bill & Melinda Gates Foundation.

Global disability-adjusted life-year estimates of long-term health burden and undernutrition attributable to diarrhoeal diseases in children younger than 5 years.

BACKGROUND: Diarrhoea is a leading cause of death and illness globally among children younger than 5 years. Mortality and short-term morbidity cause substantial burden of disease but probably underestimate the true effect of diarrhoea on population health. This underestimation is because diarrhoeal diseases can negatively affect early childhood growth, probably through enteric dysfunction and impaired uptake of macronutrients and micronutrients. We attempt to quantify the long-term sequelae associated with childhood growth impairment due to diarrhoea. METHODS: We used the Global Burden of Diseases, Injuries, and Risk Factors Study framework and leveraged existing estimates of diarrhoea incidence, childhood undernutrition, and infectious disease burden to estimate the effect of diarrhoeal diseases on physical growth, including weight and height, and subsequent disease among children younger than 5 years. The burden of diarrhoea was measured in disability-adjusted life-years (DALYs), a composite metric of mortality and morbidity. We hypothesised that diarrhoea is negatively associated with three common markers of growth: weight-for-age, weight-for-height, and height-for-age Z-scores. On the basis of these undernutrition exposures, we applied a counterfactual approach to quantify the relative risk of infectious disease (subsequent diarrhoea, lower respiratory infection, and measles) and protein energy malnutrition morbidity and mortality per day of diarrhoea and quantified the burden of diarrhoeal disease due to these outcomes caused by undernutrition. FINDINGS: Diarrhoea episodes are significantly associated with childhood growth faltering. We found that each day of diarrhoea was associated with height-for-age Z-score (-0·0033 [95% CI -0·0024 to -0·0041]; p=4·43 × 10-14), weight-for-age Z-score (-0·0077 [-0·0058 to -0·0097]; p=3·19â€ˆ× 10-15), and weight-for-height Z-score (-0·0096 [-0·0067 to -0·0125]; p=7·78 × 10-11). After addition of the DALYs due to the long-term sequelae as a consequence of undernutrition, the burden of diarrhoeal diseases increased by 39·0% (95% uncertainty interval [UI] 33·0-46·6) and was responsible for 55 778 000 DALYs (95% UI 49 125 400-62 396 200) among children younger than 5 years in 2016. Among the 15 652 300 DALYs (95% UI 12 951 300-18 806 100) associated with undernutrition due to diarrhoeal episodes, more than 84·7% are due to increased risk of infectious disease, whereas the remaining 15·3% of long-term DALYs are due to increased prevalence of protein energy malnutrition. The burden of diarrhoea has decreased substantially since 1990, but progress has been greater in long-term (78·7% reduction [95% UI 69·3-85·5]) than in acute (70·4% reduction [95% UI 61·7-76·5]) DALYs. INTERPRETATION: Diarrhoea represents an even larger burden of disease than was estimated in the Global Burden of Disease Study. In order to adequately address the burden of its long-term sequelae, a renewed emphasis on controlling the risk of diarrhoea incidence may be required. This renewed effort can help further prevent the potential lifelong cost on child health, growth, and overall potential. FUNDING: Bill & Melinda Gates Foundation.