A Half Century of Oral Rehydration Therapy in Childhood Gastroenteritis: Toward Increasing Uptake and Improving Coverage.

Termed by the Lancet, as "potentially the most important medical advance of the twentieth century," therapy with oral rehydration solutions (ORSs) has been essential to reducing mortality in children less than 5 years (under five) with infectious gastroenteritis and diarrhea. The target of the diarrhea-control programs in the 1990s was to achieve ORS use in 80% of diarrhea cases by the year 2000. Nevertheless, nearly 20 years later, global uptake remains limited to only a third of the cases. Our analysis shows that from 1990 to 2017, mean ORS coverage in Countdown countries [the 81 Countdown-to-2030 priority countries, which together account for 95% of maternal deaths and 90% of under-five deaths] increased from ~ 30% to nearly 40%. Flawed government policies, inadequate supplies, and lack of awareness among health workers and communities all contributed to this shortfall in coverage. Moreover, imperfect measurement methodology is implicated in questionable coverage data. A multipronged approach focusing on the manufacture, supply, training, and behavioral change is essential to ensure that ORS is used in all epidemic diarrhea cases globally, especially in the under-five population.

Trends and determinants of newborn mortality in Kyrgyzstan: a Countdown country case study.

BACKGROUND: Kyrgyzstan has made considerable progress in reducing child mortality compared with other countries in the region, despite a comparatively low economic standing. However, maternal mortality is still high. Given the availability of an established birth registration system, we aimed to comprehensively assess the trends and determinants of reproductive, maternal, newborn, and child health in Kyrgyzstan. METHODS: For this Countdown to 2030 country case study, we used publicly available data repositories and the national birth registry of Kyrgyzstan to examine trends and inequalities of reproductive, maternal, and newborn health and mortality between 1990 and 2018, at a national and subnational level. Coverage of newborn and maternal health interventions was assessed and disaggregated by equity dimensions. We did Oaxaca-Blinder decomposition to determine the contextual factors associated with the observed decline in newborn mortality rates. We also undertook a comprehensive review of national policies and programmes, as well as a prospective Lives Saved Tool analysis, to highlight interventions that have the potential to avert the most maternal, neonatal, and child deaths. FINDINGS: Over the past two decades, Kyrgyzstan reduced newborn mortality rates by 46% and mortality rates of children younger than 5 years by 69%, whereas maternal mortality rates were reduced by 7% and stillbirth rates by 29%. The leading causes of neonatal deaths were prematurity and asphyxia or hypoxia, and preterm small-for-gestational-age infants were more than 80 times more likely to die in their first month of life compared with those born appropriate-for-gestational age at term. Except for contraceptive use, coverage of essential interventions has increased and is generally high, with limited sociodemographic inequities. With scale-up of a few essential neonatal and maternal interventions, 39% of neonatal deaths, 11% of stillbirths, and 19% of maternal deaths could be prevented by 2030. INTERPRETATION: Kyrgyzstan has reduced newborn mortality rates considerably, with the potential for further reduction. To achieve and exceed the Sustainable Development Goal 3 targets for newborn survival and reducing stillbirths, Kyrgyzstan needs to scale up packages of interventions for the care of small and sick babies, assure quality of care in all health-care facilities with regionalised perinatal care, and create a linked national registry for mothers and neonates with rapid feedback and accountability. FUNDING: US Fund for UNICEF under the Countdown to 2015, UNICEF Kyrgyzstan Office.

A sub-national real-time epidemiological and vaccination database for the COVID-19 pandemic in Canada.

The COVID-19 pandemic has demonstrated the need for real-time, open-access epidemiological information to inform public health decision-making and outbreak control efforts. In Canada, authority for healthcare delivery primarily lies at the provincial and territorial level; however, at the outset of the pandemic no definitive pan-Canadian COVID-19 datasets were available. The COVID-19 Canada Open Data Working Group was created to fill this crucial data gap. As a team of volunteer contributors, we collect daily COVID-19 data from a variety of governmental and non-governmental sources and curate a line-list of cases and mortality for all provinces and territories of Canada, including information on location, age, sex, travel history, and exposure, where available. We also curate time series of COVID-19 recoveries, testing, and vaccine doses administered and distributed. Data are recorded systematically at a fine sub-national scale, which can be used to support robust understanding of COVID-19 hotspots. We continue to maintain this dataset, and an accompanying online dashboard, to provide a reliable pan-Canadian COVID-19 resource to researchers, journalists, and the general public.

Social Equity and COVID-19: The Case of African Americans.

Emerging statistics demonstrate that COVID-19 disproportionately affects African Americans. The effects of COVID-19 for this population are inextricably linked to areas of systemic oppression and disenfranchisement, which are exacerbated by COVID-19: (1) health care inequality; (2) segregation, overall health, and food insecurity; (3) underrepresentation in government and the medical profession; and (4) inequalities in participatory democracy and public engagement. Following a discussion of these issues, this essay shares early and preliminary lessons and strategies on how public administration scholars and practitioners can lead in crafting equitable responses to this global pandemic to uplift the African American community.

Contemporary Management of Bulbar Urethral Strictures.

Urethral stricture disease (USD) is a progressive scar-forming disease commonly encountered by urologists and is challenging to manage. USD most frequently occurs in the bulbar urethra. Patients typically present with chronic obstructive voiding symptoms but may develop recurrent urinary tract infections, detrusor failure, or renal disease. The authors review the pathophysiology, diagnostic workup, and evidence-based management of bulbar urethral strictures (BUS). There are multiple surgical options to treat BUS. Endoscopic techniques (eg, dilation and urethrotomy) are suitable for the initial management of short strictures but new evidence-based guidelines recommend against repeated endoscopic treatment. Urethroplasty is the gold standard treatment for BUS of all lengths, with anastomotic techniques appropriate for strictures <2 cm and tissue substitution performed for longer strictures. New techniques, such as non-transecting urethroplasty, lack long-term data but may represent a paradigm shift in the field. Future treatments may utilize tissue-engineered grafts and agents that inhibit inflammation and scar formation.

The impact of community-wide, mass drug administration on aggregation of soil-transmitted helminth infection in human host populations.

BACKGROUND: Soil-transmitted helminths (STH) are intestinal parasites estimated to infect over 1.5 billion people. Current treatment programmes are aimed at morbidity control through school-based deworming programmes (targeting school-aged children, SAC) and treating women of reproductive age (WRA), as these two groups are believed to record the highest morbidity. More recently, however, the potential for interrupting transmission by treating entire communities has been receiving greater emphasis and the feasibility of such programmes are now under investigation in randomised clinical trials through the Bill & Melinda Gates Foundation funded DeWorm3 studies. Helminth parasites are known to be highly aggregated within human populations, with a small minority of individuals harbouring most worms. Empirical evidence from the TUMIKIA project in Kenya suggests that aggregation may increase significantly after anthelminthic treatment. METHODS: A stochastic, age-structured, individual-based simulation model of parasite transmission is employed to better understand the factors that might induce this pattern. A simple probabilistic model based on compounded negative binomial distributions caused by age-dependencies in both treatment coverage and exposure to infection is also employed to further this understanding. RESULTS: Both approaches confirm helminth aggregation is likely to increase post-mass drug administration as measured by a decrease in the value of the negative binomial aggregation parameter, k. Simple analytical models of distribution compounding describe the observed patterns well. CONCLUSIONS: The helminth aggregation that was observed in the field was replicated with our stochastic individual-based model. Further work is required to generalise the probabilistic model to take account of the respective sensitivities of different diagnostics on the presence or absence of infection.

Current epidemiological evidence for predisposition to high or low intensity human helminth infection: a systematic review.

BACKGROUND: The human helminth infections include ascariasis, trichuriasis, hookworm infections, schistosomiasis, lymphatic filariasis (LF) and onchocerciasis. It is estimated that almost 2 billion people worldwide are infected with helminths. Whilst the WHO treatment guidelines for helminth infections are mostly aimed at controlling morbidity, there has been a recent shift with some countries moving towards goals of disease elimination through mass drug administration, especially for LF and onchocerciasis. However, as prevalence is driven lower, treating entire populations may no longer be the most efficient or cost-effective strategy. Instead, it may be beneficial to identify individuals or demographic groups who are persistently infected, often termed as being "predisposed" to infection, and target treatment at them. METHODS: The authors searched Embase, MEDLINE, Global Health, and Web of Science for all English language, human-based papers investigating predisposition to helminth infections published up to October 31st, 2017. The varying definitions used to describe predisposition, and the statistical tests used to determine its presence, are summarised. Evidence for predisposition is presented, stratified by helminth species, and risk factors for predisposition to infection are identified and discussed. RESULTS: In total, 43 papers were identified, summarising results from 34 different studies in 23 countries. Consistent evidence of predisposition to infection with certain species of human helminth was identified. Children were regularly found to experience greater predisposition to Ascaris lumbricoides, Schistosoma mansoni and S. haematobium than adults. Females were found to be more predisposed to A. lumbricoides infection than were males. Household clustering of infection was identified for A. lumbricoides, T. trichiura and S. japonicum. Ascaris lumbricoides and T. trichiura also showed evidence of familial predisposition. Whilst strong evidence for predisposition to hookworm infection was identified, findings with regards to which groups were affected were considerably more varied than for other helminth species. CONCLUSION: This review has found consistent evidence of predisposition to heavy (and light) infection for certain human helminth species. However, further research is needed to identify reasons for the reported differences between demographic groups. Molecular epidemiological methods associated with whole genome sequencing to determine 'who infects whom' may shed more light on the factors generating predisposition.

Defining stopping criteria for ending randomized clinical trials that investigate the interruption of transmission of soil-transmitted helminths employing mass drug administration.

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage-indicated by mathematical models as necessary for breaking transmission-will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences measured at six months after the last round of MDA and the impact of MDA coverage levels were evaluated to see if the likelihood of bounce-back or elimination could reliably be assessed at that point, rather than after two years of subsequent surveillance. The analyses suggest that all clusters should be assessed for transmission interruption after two years of surveillance, unless transmission interruption can be effectively ruled out through evidence of low treatment coverage. Models suggest a tight range of homogenous prevalence estimates following high coverage MDA across clusters which do not allow for discrimination between bounce back or transmission interruption within 24 months following cessation of MDA.

Testing for soil-transmitted helminth transmission elimination: Analysing the impact of the sensitivity of different diagnostic tools.

In recent years, an increased focus has been placed upon the possibility of the elimination of soil-transmitted helminth (STH) transmission using various interventions including mass drug administration. The primary diagnostic tool recommended by the WHO is the detection of STH eggs in stool using the Kato-Katz (KK) method. However, detecting infected individuals using this method becomes increasingly difficult as the intensity of infection decreases. Newer techniques, such as qPCR, have been shown to have greater sensitivity than KK, especially at low prevalence. However, the impact of using qPCR on elimination thresholds is yet to be investigated. In this paper, we aim to quantify how the sensitivity of these two diagnostic tools affects the optimal prevalence threshold at which to declare the interruption of transmission with a defined level of confidence. A stochastic, individual-based STH transmission model was used in this study to simulate the transmission dynamics of Ascaris and hookworm. Data from a Kenyan deworming study were used to parameterize the diagnostic model which was based on egg detection probabilities. The positive and negative predictive values (PPV and NPV) were calculated to assess the quality of any given threshold, with the optimal threshold value taken to be that at which both were maximised. The threshold prevalence of infection values for declaring elimination of Ascaris transmission were 6% and 12% for KK and qPCR respectively. For hookworm, these threshold values are lower at 0.5% and 2% respectively. Diagnostic tests with greater sensitivity are becoming increasingly important as we approach the elimination of STH transmission in some regions of the world. For declaring the elimination of transmission, using qPCR to diagnose STH infection results in the definition of a higher prevalence, than when KK is used.

The past matters: estimating intrinsic hookworm transmission intensity in areas with past mass drug administration to control lymphatic filariasis.

BACKGROUND: Current WHO guidelines for soil-transmitted helminth (STH) control focus on mass drug administration (MDA) targeting preschool-aged (pre-SAC) and school-aged children (SAC), with the goal of eliminating STH as a public health problem amongst children. Recently, attention and funding has turned towards the question whether MDA alone can result in the interruption of transmission for STH. The lymphatic filariasis (LF) elimination programme, have been successful in reaching whole communities. There is the possibility of building upon the infrastructure created for these LF-programmes to enhance the control of STH. Using hookworm as an example, we explore what further MDA coverage might be required to induce interruption of transmission for hookworm in the wake of a successful LF programme. RESULTS: Analyses based on the model of STH transmission and MDA impact predict the effects of previous LF control by MDA over five years, on a defined baseline prevalence of STH in an area with a defined transmission intensity (the basic reproductive number R0). If the LF MDA programme achieved a high coverage (70, 70 and 60% for pre-SAC, SAC and adults, respectively) we expect that in communities with a hookworm prevalence of 15%, after 5 years of LF control, the intrinsic R0 value in that setting is 2.47. By contrast, if lower LF coverages were achieved (40, 40 and 30% for pre-SAC, SAC and adults, respectively), with the same prevalence of 15% at baseline (after 5 years of LF MDA), the intrinsic hookworm R0 value is predicted to be 1.67. The intrinsic R0 value has a large effect on the expected successes of follow-up STH programmes post LF MDA. Consequently, the outcomes of identical programmes may differ between these communities. CONCLUSION: To design the optimal MDA intervention to eliminate STH infections, it is vital to have information on historical MDA programmes and baseline prevalence to estimate the intrinsic transmission intensity for the defined setting (R0). The baseline prevalence alone is not sufficient to inform policy for the control of STH, post cessation of LF MDA, since this will be highly dependent on the intensity and effectiveness of past programmes and the intrinsic transmission intensity of the dominant STH species in any given setting.

Identifying optimal threshold statistics for elimination of hookworm using a stochastic simulation model.

BACKGROUND: There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH). Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design. One key factor is the choice of threshold for detecting elimination. However, there are currently no thresholds defined for STH regarding breaking transmission. METHODS: We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters. The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model. We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed. RESULTS: End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value. Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad. For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities. Number of communities in a cluster is a key indicator of probability of elimination and PPV. Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back. CONCLUSIONS: The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities. However, most studies and programmes are constructed on the basis of clusters. Since elimination occurs within smaller population sub-units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure. Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions.

Research Needs for Effective Transition in Lifelong Care of Congenital Genitourinary Conditions: A Workshop Sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.

Over the last 5 decades, health-care advances have yielded quantum improvements in the life expectancy of individuals with congenital genitourinary conditions (CGCs), leading to a crisis of care. Many individuals with CGC enter adulthood unprepared to manage their condition. Pediatric CGC specialists lack training to manage adulthood-related health-care issues, whereas adult genitourinary specialists lack training within the context of CGCs. To address these challenges, the National Institutes of Diabetes and Digestive and Kidney Diseases convened individuals with CGCs and experts from a variety of fields to identify research needs to improve transitional urology care. This paper outlines identified research needs.

Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non-CB1/CB2 G(i/o) linked receptor.

1 Noladin ether has recently been reported to be an endocannabinoid, with selectivity for the cannabinoid (CB) CB1 receptor. In the present study, we investigated the effects of noladin ether in the rat isolated mesenteric arterial bed, cultured dorsal root ganglia (DRG) cells and human vanilloid (TRPV1)-receptor-expressing HEK293 cells (TRPV1-HEK293 cells). 2 Electrical field stimulation of the mesenteric bed evoked frequency-dependent vasorelaxation due to the action of calcitonin gene-related peptide (CGRP) released from sensory nerves. Noladin ether (0.1-3 microm) attenuated sensory neurogenic relaxation in a concentration-dependent manner. Noladin ether (1 microm) reduced vasorelaxation at a submaximal frequency (8 Hz), from 57.3+/-6.8 to 23.3+/-3.8% (P<0.05, n=4). 3 The inhibitory effects of noladin ether were unaffected by the CB1 antagonists SR141716A and LY320135, and the CB2 antagonist SR144528 (1 microm). 4 Noladin ether had no effect on vasorelaxation elicited by exogenous CGRP or capsaicin. These data suggest that noladin ether is acting at a prejunctional site and no interaction with TRPV1 is involved. 5 In mesenteric beds from pertussis toxin (PTX)-pretreated rats, the inhibitory actions of noladin ether on sensory neurotransmission were abolished, indicating the involvement of G(i/o) protein-coupled receptors. 6 Noladin ether evoked a concentration-dependent increase in intracellular Ca2+ concentration in TRPV1-HEK293 cells at 10 microm (36.5+/-3.2% of maximal capsaicin-induced response), but it was a less potent agonist than both capsaicin and anandamide and at 1 microm it was essentially inactive. Noladin ether (1 microm) had no effect on capsaicin-evoked Ca2+ responses in DRG cells, and produced no response alone, indicating it neither modulates nor acts directly on TRPV1 receptors. 7 These data demonstrate that noladin ether attenuates sensory neurotransmission in rat mesenteric arteries via a non-CB1 non-CB2 PTX-sensitive prejunctional site, independently of TRPV1 receptors.