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Abstract We employed a leave-one-out cross validation to determine optimally sized neighborhood. Variations between a single point and the other points within each filter size for all the points in the study area were evaluated, and the mean squared error (MSE) for each filter was calculated. The filter with the lowest MSE was considered as the optimal neighborhood. The method is useful in determining the optimal neighborhood for both geographic and population filters.

Abstract Background Entering data on case report forms and subsequently digitizing them in electronic media is the traditional way to maintain a record keeping system in field studies. Direct data entry using an electronic device avoids this two-step process. It is gaining in popularity and has replaced the paper-based data entry system in many studies. We report our experiences with paper- and PDA-based data collection during a fever surveillance study in Pemba Island, Zanzibar, Tanzania. Methods Data were collected on a 14-page case report paper form in the first period of the study. The case report paper forms were then replaced with handheld computers (personal digital assistants or PDAs). The PDAs were used for screening and clinical data collection, including a rapid assessment of patient eligibility, real time errors, and inconsistency checking. Results A comparison of paper-based data collection with PDA data collection showed that direct data entry via PDA was faster and 25% cheaper. Data was more accurate (7% versus 1% erroneous data) and omission did not occur with electronic data collection. Delayed data turnaround times and late error detections in the paper-based system which made error corrections difficult were avoided using electronic data collection. Conclusions Electronic data collection offers direct data entry at the initial point of contact. It has numerous advantages and has the potential to replace paper-based data collection in the field. The availability of information and communication technologies for direct data transfer has the potential to improve the conduct of public health research in resource-poor settings.

Abstract Background Influenza-like illness (ILI) is often defined as fever (>38.0°C) with cough or sore throat. In this study, we tested the sensitivity, specificity, and positive and negative predictive values of this case definition in a Cambodia patient population. Methods Passive clinic-based surveillance was established at nine healthcare centers to identify the causes of acute undifferentiated fever in patients aged two years and older seeking treatment. Fever was defined as tympanic membrane temperature >38°C lasting more than 24 hours and less than 10 days. Influenza virus infections were identified by polymerase chain reaction. Results From July 2008 to December 2008, 2,639 patients were enrolled. From 884 (33%) patients positive for influenza, 652 presented with ILI and 232 acute fever patients presented without ILI. Analysis by age group identified no significant differences between influenza positive patients from the two groups. Positive predictive values (PPVs) varied during the course of the influenza season and among age groups. Conclusion The ILI case definition can be used to identify a significant percentage of patients with influenza infection during the influenza season in Cambodia, assisting healthcare providers in its diagnosis and treatment. However, testing samples based on the criteria of fever alone increased our case detection by 34%.

Antimicrobial susceptibility testing was performed on 3627 isolates ofEscherichia coliand 180 isolates ofShigellaspp. collected in rural locations from 875 Egyptian children with diarrhoea between 1995 and 2000. The cumulative rates of resistance forE. coliandShigellaspp. were high (respectively, 68.2% and 54.8% for ampicillin, 24.2% and 23.5% for ampicillin–sulbactam, 57.2% and 42.5% for trimethoprim–sulphamethoxazole, and 50.9% and 75.4% for tetracycline). Non-enterotoxigenicE. coli(NETEC) isolates had a consistently higher level of antimicrobial resistance than did enterotoxigenicE. coli(ETEC) isolates. Trend testing showed significant decreases in resistance to ampicillin, ampicillin–sulbactam and tetracycline among allE. coliisolates. Increasing rates of resistance were observed for trimethoprim–sulphamethoxazole in ETEC isolates andShigellaspp., but not in NETEC isolates. Low levels of resistance were observed for all other antimicrobial agents tested. Overall, high levels, but decreasing trends, of resistance to commonly used antimicrobial agents were detected among isolates ofE. coliandShigellaspp. from children in rural Egypt. [ABSTRACT FROM AUTHOR]

Background: Household sampling is used for cost-efficient, in-depth population-based investigations, including the assessment of healthcare utilization. Probability sampling requires a comprehensive sampling frame (household list), which did not exist at sites of the Typhoid Fever Surveillance in Africa Program (TSAP) in Pikine/Senegal, Pietermaritzburg/South Africa, and Wad Medani/Sudan. Here we describe the methodology of constructing a geospatial sampling frame. Methods & Materials: Sites were diverse in population size, population density, area size, and administratively-identified subareas. They varied in topography, vegetation, and composition of formal/informal settlements and single-/multi-story structures. We used high-resolution GoogleEarthPro® satellite imageries for manually enumerating (pinpointing) structures to construct a sampling frame at each site. Hand-held satellite maps and global positioning system (GPS) devices were utilized by interviewers for rapidly, precisely locating structures (households); structures were selected randomly and weighted proportional to the population size of each subarea (weighted-stratified sampling). The methodology was evaluated for accuracy by calculating ranges and quartiles of distances between GPS coordinates of original (as per sampling frame) and enrolled structures. Results: A total of 46510, 63008, and 32794 structures were enumerated at sites in Senegal, South Africa, and Sudan, respectively. The fabrication of satellite maps, including the selection and pictorialization of structures, took approximately two to three weeks by site. We found that 87% (517/592), 56% (1,098/1,963) and 86% (471/549) of distances were <2.5 meters at the site in Senegal, South Africa, and Sudan, respectively. Calculations revealed furthermore that 59% of distances in rural, 57% in semi-urban and 50% in urban subareas of South Africa were <2.5 meters. Conclusion: We have demonstrated that satellite imageries are a simple, precise instrument for creating a sampling frame at certain TSAP-sites. Hand-held satellite maps and GPS devices allowed for the rapid, accurate location of selected structures. Some limitations remain. Correctly locating structures can be challenging for clustered, interlaced structures since interfering factors (obstructive/reflective structures, multi-story buildings, environmental diversity) may impact on the precision of GPS readings. Geospatial frames require constant updating, but could provide an approach for population-based investigations at probability samples of households in settings that are uncensused and lack longitudinal recording of socio-demographic and vital statistics. [ABSTRACT FROM AUTHOR]

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of lower urinary tract infection (UTI). UTI presents a serious health risk and has considerable secondary implications including economic burden, recurring episodes, and overuse of antibiotics. A safe and effective vaccine would address this widespread health problem and emerging antibiotic resistance. Killed, whole-cell vaccines have shown limited efficacy to prevent recurrent UTI in human trials. We explored photochemical inactivation with psoralen drugs and UVA light (PUVA), which crosslinks nucleic acid, as an alternative to protein-damaging methods of inactivation to improve whole-cell UTI vaccines. Exposure of UPEC to the psoralen drug AMT and UVA light resulted in a killed but metabolically active (KBMA) state, as reported previously for other PUVA-inactivated bacteria. The immunogenicity of PUVA-UPEC as compared to formalin-inactivated UPEC was compared in mice. Both generated high UPEC-specific serum IgG titers after intramuscular delivery. However, using functional adherence as a measure of surface protein integrity, we found differences in the properties of PUVA- and formalin-inactivated UPEC. Adhesion mediated by Type-1 and P-fimbriae was severely compromised by formalin but was unaffected by PUVA, indicating that PUVA preserved the functional conformation of fimbrial proteins, which are targets of protective immune responses. In vitro assays indicated that although they retained metabolic activity, PUVA-UPEC lost virulence properties that could negatively impact vaccine safety. Our results imply the potential for PUVA to improve killed, whole-cell UTI vaccines by generating bacteria that more closely resemble their live, infectious counterparts relative to vaccines generated with protein-damaging methods., Importance: Lower urinary tract infection (UTI), caused primarily by uropathogenic Escherichia coli , represents a significant health burden, accounting for 7 million primary care and 1 million emergency room visits annually in the United States. Women and the elderly are especially susceptible and recurrent infection (rUTI) is common in those populations. Lower UTI can lead to life-threatening systemic infection. UTI burden is manifested by healthcare dollars spent (1.5 billion annually), quality of life impact, and resistant strains emerging from antibiotic overuse. A safe and effective vaccine to prevent rUTI would address a substantial healthcare issue. Vaccines comprised of inactivated uropathogenic bacteria have yielded encouraging results in clinical trials but improvements that enhance vaccine performance are needed. To that end, we focused on inactivation methodology and provided data to support photochemical inactivation, which targets nucleic acid, as a promising alternative to conventional protein-damaging inactivation methods to improve whole-cell UTI vaccines., Competing Interests: The authors declare no conflict of interest.

Diarrhoeal disease attributable to enterotoxigenic Escherichia coli (ETEC) causes substantial morbidity and mortality predominantly in paediatric populations in low- and middle-income countries. In addition to acute illness, there is an increasing appreciation of the long-term consequences of enteric infections, including ETEC, on childhood growth and development. Provision of potable water and sanitation and appropriate clinical care for acute illness are critical to reduce the ETEC burden. However, these interventions are not always practical and may not achieve equitable and sustainable coverage. Vaccination may be the most cost-effective and equitable means of primary prevention; however, additional data are needed to accelerate the investment and guide the decision-making process for ETEC vaccines. First, to understand and quantify the ETEC disease burden, additional data are needed on the association between ETEC infection and physical and cognitive stunting as well as delayed educational attainment. Furthermore, the role of inappropriate or inadequate antibiotic treatment of ETEC-attributable diarrhoea may contribute to the development of antimicrobial resistance (AMR) and needs further elucidation. An ETEC vaccine that mitigates acute diarrhoeal illness and minimizes the longer-term disease manifestations could have significant public health impact and be a cost-effective countermeasure. Herein we review the ETEC vaccine pipeline, led by candidates compatible with the general parameters of the Preferred Product Characteristics (PPC) recently developed by the World Health Organization. Additionally, we have developed an ETEC Vaccine Development Strategy to provide a framework to underpin priority activities for researchers, funders and vaccine manufacturers, with the goal of addressing globally unmet data needs in the areas of research, product development, and policy, as well as commercialization and delivery. The strategy also aims to guide prioritization and co-ordination of the priority activities needed to minimize the timeline to licensure and use of ETEC vaccines, especially in in low- and middle-income countries, where they are most urgently needed., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children., Methods: We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5·5 × 10 10 cells], quarter [2·5 × 10 10 cells], or eighth [1·25 × 10 10 cells] adult dose), with or without dmLT adjuvant (2·5 μg, 5·0 μg, or 10·0 μg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802., Findings: Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24-59 months, 100 aged 12-23 months, and 200 aged 6-11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten [8%] of 130 patients aged 24-59 months, 13 [13%] of 100 aged 12-23 months, and 29 [15%] of 200 aged 6-11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6-11 months. 78 (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants., Interpretation: The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas., Funding: PATH (Bill & Melinda Gates Foundation and the UK's Department for International Development), the Swedish Research Council, and The Swedish Foundation for Strategic Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Diarrheal disease burden has become more heterogenous in low- and lower middle-income countries as access to clean water, sanitation and health care has increased in wealthier urban populations. Enterotoxigenic Escherichia coli (ETEC) and Shigella are among the top five causes of diarrheal mortality in children living in sub-Saharan Africa. Here, we explored how accounting for subnational and economic heterogeneity in ETEC and Shigella disease burden affects projected vaccine impact and cost-effectiveness of standalone ETEC and Shigella vaccines during the first decade after introduction in four sub-Saharan African countries. We developed dynamic models for provincial areas and socioeconomic subpopulations of children in the Democratic Republic of Congo (DRC), Kenya, Zambia, and Zimbabwe. We estimated deaths and morbidity due to ETEC and Shigella diarrhea plus additional deaths from other infectious diseases attributable to ETEC- and Shigella -induced stunting. We analyzed cost-effectiveness using Incremental Cost-Effectiveness Ratios (ICERs) with Disability-Adjusted Life Years (DALYs) and Moderate-and-Severe Diarrheal episodes (MSD) averted as denominators. Other infectious disease deaths due to induced stunting accounted for 9-28% and 9-32% of the total provincial level ETEC and Shigella disease burden, respectively, across these four countries from years 2025 to 2034. Our results indicated that the lowest and most cost-effective provincial DALYs averted ICERs were below $600 and $500/DALY averted for ETEC and Shigella vaccination, respectively in Zimbabwe. ICERs were the highest in Zambia and Kenya, where all provincial ICERs where above $2000/DALY. The highest national and provincial MSD averted ICERs were in DRC, while the lowest were in Kenya and Zimbabwe. Vaccinations were most cost-effective in averting DALYs in lower wealth subpopulations living in the highest burden provincial areas. Our approach focused on subnational heterogeneity in ETEC and Shigella burden and vaccination access found that impact and cost-effectiveness were more favorable if vaccinations reach the most vulnerable children in underserved provinces., (© 2019 The Author(s).)

PATH hosted the second Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Mexico City in June 2018, again providing experts from around the world an opportunity to participate in a highly collaborative forum to discuss progress in the development of new enteric vaccines. Through a combination of plenary sessions and posters, keynote presentations, and workshops, the 2018 VASE Conference aimed to accelerate communication and progress among those working to achieve the goal of licensed vaccines against these two bacterial pathogens. Many presentations recognized the importance of diarrheal disease and long-term sequelae caused by infections with Shigella and enterotoxigenic E. coli (ETEC). Other presentations explored new strategies for vaccine development, including the search for novel, possibly conserved, antigens for more effective vaccines. Much progress is being made as some vaccine candidates are now moving through clinical trials. Research presented in oral and poster presentations at the VASE Conference covered a range of topics, including: the global burden of disease, epidemiology, and health economics; host parameters and genomics that predict responses to infection and disease; preclinical evaluations of vaccine antigens and models of enteric diseases; and vaccine candidates in clinical trials and human challenge studies. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2018 VASE Conference., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While diarrhea mortality in children has declined over the last two decades, there has been a slower decline in diarrheal episodes. Repeated diarrheal episodes are associated with childhood stunting, which leads to increased mortality risk from infectious diseases. Vaccine candidates are under development for enterotoxigenic Escherichia coli [ETEC] and Shigella , important enteric pathogens in children in low income countries. These future vaccines could significantly reduce diarrheal burden, prevent ETEC- and Shigella -induced stunting, and stunting-associated mortality. We developed a cost-effectiveness model for two putative standalone ETEC and Shigella vaccine candidates to evaluate vaccine impact on mortality, morbidity, stunting, and stunting-associated deaths from other infectious diseases. We modeled impact over the first ten years after vaccine introduction in children under five years old living in 79 low and low-middle income countries. ETEC and Shigella diarrhea would cause an estimated 239,300 [95% UL: 179,700-309,800] and 340,300 [256,500-440,800] child deaths, respectively, from years 2025 to 2034. Most of these deaths would occur in AFRO countries. ETEC and Shigella moderate-to-severe diarrheal episodes would result in over 13.7 [8.4-19.0] and 21.4 [13.1-29.8] million stunted children, respectively. Introducing ETEC or Shigella vaccine each with 60% efficacy could prevent 92,000 [61,000-129,000] ETEC and 126,600 [84,000-179,000] Shigella direct deaths and 21,400 [11,300-34,800] ETEC- and 34,200 [18,000-56,000] Shigella -induced stunting deaths. ETEC ICERs ranged from $2172/DALY [1457-4369] in AFRO to $19,172/DALY [12,665-39,503] in EURO. Shigella ICERs ranged from $952/DALY [632-2001] in EMRO to $640,316/DALY [434,311-1,297,192] in EURO. Limitations of this analysis include uncertainty of vaccine efficacy, duration of protection, and vaccine price. Inclusion of other infectious disease mortality due to stunting provides a more accurate assessment of total ETEC and Shigella disease burden and increased the projected impact and cost-effectiveness of vaccination. Introducing vaccines only in high burden countries and regions could substantially reduce cost without substantially reducing impact.

Background: Enterotoxigenic Escherichia coli (ETEC) and shigella are two major pathogens that cause moderate-to-severe diarrhoea in children younger than 5 years. Diarrhoea is associated with an increased risk of stunting, which puts children at risk of death due to other infectious diseases., Methods: We modelled ETEC-related and shigella-related mortality and the effect of moderate-to-severe diarrhoea episodes to determine the number of children with stunting due to these infections in 79 low-income and lower middle-income countries. We applied population attributable risk for increased number of deaths due to other infectious diseases in children who are stunted. We calculated 95% uncertainty intervals (UIs) for the point estimates., Findings: In children younger than 5 years, we estimate 196 million (95% UI 135-269) episodes of ETEC and shigella diarrhoea occur annually, resulting in 3·5 million (0·8-5·4) cases of moderate-to-severe stunting and 44 400 (29 400-59 800) total ETEC deaths and 63 100 (44 000-81 900) total shigella deaths in 2015. Additional infectious disease mortality due to stunting resulted in increases of 24% (8-34; for ETEC) and 28% (10-39; for shigella) over direct deaths due to diarrhoeal episodes. The distribution of mortality and morbidity varied geographically, with African Region and Eastern Mediterranean Region countries bearing the greatest burden., Interpretation: The expanded effects of non-fatal ETEC and shigella-related diarrhoeal episodes can have lasting consequences. Prevention of these infections could reduce the risk of direct death and stunting and deaths due to other infectious diseases. Understanding the countries and populations with the highest disease risk helps to target interventions for the most vulnerable populations., Funding: The Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The study involved preparing and implementation a model of complex screening programme for adolescents and comparison of anthropometric examinations between the population of the SOPKARD-Junior programme and representative sample of Polish children in the same age., Material and Methods: The screening programme in 14-15 year old pupils ( n = 282) included: anthropometric, blood pressure, echocardiographic, electrocardiographic, carotid arteries, kidney and thyroid ultrasound examinations, as well as respiratory, dental and masticatory system, orthopaedic, psychological and psychiatric assessment. Blood and urine tests were also performed. The results of anthropometric examinations from the SOPKARD-Junior and OLAF programmes were used for comparative analysis., Results: Statistically significant ( p < 0.001) differences between young people from Sopot and their peers in the general Polish population were found in height (+3.61 cm for boys), body mass (+5.19 kg for boys and +3.99 kg for girls), body mass index (+0.99 kg/m 2 for boys and +1.33 kg/m 2 for girls), waist circumference (+4.52 cm for boys and +4.52 cm for girls) and hip circumference (+2.51 cm for boys). The highest attendance rate was achieved for examinations performed in school (e.g. anthropometric and blood pressure measurements - n = 268; 95%) and the lowest for the echocardiograpy performed in local hospital ( n = 133; 47%). The mean score of the programme quality (scale 1-6) assessed by children was 4.63., Conclusions: The SOPKARD-Junior programme represents an attempt to develop a model of screening assessments for teenagers in Poland. Preliminary results of the SOPKARD-Junior programme indicate small differences in the biological development of Sopot youth in comparison with their peers from Polish population of the OLAF programme. The high attendance rate on research conducted at the school indicate that proposed health examinations in adolescents are acceptable and feasible., Competing Interests: The authors declare no conflict of interest.

Shigella are gram-negative bacteria that cause severe diarrhea and dysentery. In 2013, Shigella infections caused an estimated 34,400 deaths in children less than five years old and, in 2010, an estimated 40,000 deaths in persons older than five years globally. New disease burden estimates from newly deployed molecular diagnostic assays with increased sensitivity suggest that Shigella-associated morbidity may be much greater than previous disease estimates from culture-based methods. Primary prevention of this disease should be based on universal provision of potable water and sanitation methods and improved personal and food hygiene. However, an efficacious and low-cost vaccine would complement and accelerate disease reduction while waiting for universal access to water, sanitation, and hygiene improvements. This review article provides a landscape of Shigella vaccine development efforts. No vaccine is yet available, but human and animal challenge-rechallenge trials with virulent Shigella as well as observational studies in Shigella-endemic areas have shown that the incidence of disease decreases following Shigella infection, pointing to biological feasibility of a vaccine. Immunity to Shigella appears to be strain-specific, so a vaccine that covers the most commonly detected strains (i.e., S. flexneri 2a, 3a, 6, and S. sonnei) or a vaccine using cross-species conserved antigens would likely be most effective. Vaccine development and testing may be accelerated by use of animal models, such as the guinea pig keratoconjunctivitis or murine pneumonia models. Because there is no correlate of protection, however, human studies will be necessary to evaluate vaccine efficacy prior to deployment. A diversity of Shigella vaccine constructs are under development, including live attenuated, formalin-killed whole-cell, glycoconjugate, subunit, and novel antigen vaccines (e.g., Type III secretion system and outer membrane proteins)., (Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)