Reassessing potential economic value and health impact of effective Shigella vaccines.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.

La bactérie à Gram négatif Shigella est l'une des principales causes de morbidité et de mortalité diarrhéiques chez les enfants des pays à revenu faible et intermédiaire. Plusieurs candidats vaccins prometteurs sont en phase avancée de conception clinique contre cet agent pathogène qui connaît une antibiorésistance croissante. Toutefois, compte tenu du calendrier de vaccination pédiatrique de plus en plus chargé et coûteux et de l'arrivée probable d'autres nouveaux vaccins importants, il n'est pas certain que la mise sur le marché d'un vaccin contre Shigella constitue une priorité élevée pour les agences internationales ou les ministères de la Santé des pays à revenu faible ou intermédiaire. Pour déterminer l'existence d'un intérêt convaincant en matière de santé publique pour un vaccin contre Shigella, nous avons utilisé le cadre analytique du cadre d'évaluation de la valeur totale des vaccins de l'Organisation mondiale de la santé et formulé cinq propositions scientifiques, politiques, économiques et commerciales générales concernant la conception d'un vaccin contre Shigella. Nous avons également étudié les défis en matière réglementaire, clinique, politique et commerciale qui se posent actuellement à la mise au point et à l'adoption d'un vaccin combiné contenant des Shigella. Nous avons abordé chacune de ces propositions au moyen d'une série d'analyses documentaires, de consultations d'experts, d'études de terrain en sciences sociales et d'analyses basées sur des modèles. Comme décrit dans une série de publications distinctes résumées ici, nous avons conclu que la valeur économique et sur le plan de la santé publique d'un vaccin contre Shigella pourrait être plus importante que ce qui était considéré précédemment, en particulier s'il s'avère que ce vaccin s'avère également efficace contre les formes moins sévères de maladies diarrhéiques et de retard de croissance chez l'enfant. La décision d'entreprises pharmaceutiques de mettre au point un vaccin autonome ou une combinaison de plusieurs agents pathogènes sera un facteur clé dans la détermination de sa priorité relative par les différentes parties prenantes dans les pays à revenu faible et intermédiaire.

La bacteria gramnegativa Shigella es una de las principales causas de morbilidad y mortalidad por diarrea en niños de países de ingresos bajos y medios. Varias vacunas candidatas y prometedoras se encuentran en las últimas fases de desarrollo clínico contra este patógeno cada vez más resistente a los antibióticos. Sin embargo, teniendo en cuenta el esquema de inmunización pediátrica, cada vez más saturado y costoso, y la probable llegada de otras vacunas nuevas importantes, no está claro si la introducción de una vacuna contra la Shigella representaría una alta prioridad para los organismos internacionales o los ministerios de salud de los países de ingresos bajos y medios. Para determinar si existe una propuesta de valor de salud pública convincente para una vacuna contra la Shigella, utilizamos el marco de análisis Full Value of Vaccine Assessment de la Organización Mundial de la Salud y formulamos cinco amplias propuestas científicas, políticas, económicas y comerciales relacionadas con el desarrollo de una vacuna contra la Shigella. También exploramos los actuales desafíos reglamentarios, clínicos, políticos y comerciales para el desarrollo y la adopción de una vacuna combinada que contenga Shigella. Mediante una serie de revisiones bibliográficas, consultas a expertos, estudios de campo de ciencias sociales y análisis basados en modelos, abordamos cada una de estas proposiciones. Como se describe en una serie de publicaciones separadas que se sintetizan aquí, llegamos a la conclusión de que el valor económico y de salud pública de una vacuna contra la Shigella puede ser mayor de lo que se reconocía anteriormente, en particular si se descubre que también es eficaz contra formas menos graves de enfermedad diarreica y retraso del crecimiento infantil. La decisión de las empresas farmacéuticas de desarrollar una vacuna independiente o una combinación multipatógena será un factor clave a la hora de determinar su prioridad relativa por parte de las diversas partes interesadas en los países de ingresos bajos y medios.

Vaccine value profile for enterotoxigenic Escherichia coli (ETEC).

Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO's primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens. The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5-8 years. Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers' diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines. This 'Vaccine Value Profile' (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Vaccine value profile for Shigella.

Shigella is the leading bacterial cause of diarrhoea and the second leading cause of diarrhoeal mortality among all ages. It also exhibits increasing levels of antibiotic resistance. The greatest burden is among children under five in low- and middle-income countries (LMICs). As such, a priority strategic goal of the World Health Organization (WHO) is the development of a safe, effective and affordable vaccine to reduce morbidity and mortality from Shigella-attributable dysentery and diarrhea, including long term outcomes associated with chronic inflammation and growth faltering, in children under 5 years of age in LMICs. In addition, a safe and effective Shigella vaccine is of potential interest to travellers and military both to prevent acute disease and rarer, long-term sequelae. An effective Shigella vaccine is also anticipated to reduce antibiotic use and thereby help diminish further emergence of enteric pathogens resistant to antimicrobials. The most advanced vaccine candidates are multivalent, parenteral formulations in Phase 2 and Phase 3 clinical studies. They rely on O-antigen-polysaccharide protein conjugate technologies or, alternatively, outer membrane vesicles expressing penta-acylated lipopolysaccharide that has been detoxified. Other parenteral and oral formulations, many delivering a broader array of Shigella antigens, are at earlier stages of clinical development. These formulations are being assessed in alignment with the WHO Preferred Product Characteristics, which call for a 1 to 2 dose primary immunization series given during the first 12 months of life, ideally starting at 6 months of age. This 'Vaccine Value Profile' (VVP) for Shigella is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the Shigella VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Graph-based analysis of EEG for schizotypy classification applying flicker Ganzfeld stimulation.

Ganzfeld conditions induce alterations in brain function and pseudo-hallucinatory experiences, particularly in people with high positive schizotypy. The current study uses graph-based parameters to investigate and classify brain networks under Ganzfeld conditions as a function of positive schizotypy. Participants from the general population (14 high schizotypy (HS), 29 low schizotypy (LS)) had an electroencephalography assessment during Ganzfeld conditions, with varying visual activation (8 frequencies of random light flicker) and soundscape-induced mood (neutral, serenity, and anxiety). Weighted functional networks were computed in six frequency sub-bands (delta, theta, alpha-low, alpha-high, beta, and gamma) as a function of light-flicker frequency and mood. The brain network was analyzed using graph theory parameters, including clustering coefficient (CC), strength, and global efficiency (GE). It was found that the LS groups had higher CC and strength than the HS groups, especially in bilateral temporal and frontotemporal brain regions. Moreover, some decreases in CC and strength measures were found in LS groups among occipital and parieto-occipital brain regions. LS groups also had significantly higher GE in all Ganzfeld conditions compared to the HS groups. The random under-sampling boosting (RUSBoost) algorithm achieved the best classification performance with an accuracy of 95.34%, specificity of 96.55%, and sensitivity of 92.85% during an anxiety-induction Ganzfeld condition. This is the first exploration of the relationship between brain functional state changes under Ganzfeld conditions in individuals who vary in positive schizotypy. The accuracy of graph-based parameters in classifying brain states as a function of schizotypy is shown, particularly for brain activity during anxiety induction, and should be investigated in psychosis.

Potential impact and cost-effectiveness of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 years or younger: a modelling study.

BACKGROUND: Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea. METHODS: We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes. FINDINGS: We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions. INTERPRETATION: Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis. FUNDING: Bill & Melinda Gates Foundation and Wellcome Trust.

Projecting the long-term economic benefits of reducing Shigella-attributable linear growth faltering with a potential vaccine: a modelling study.

BACKGROUND: Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to linear growth faltering (LGF). However, benefits from potential reductions in LGF are rarely included in economic analyses of enteric infections. We aimed to quantify the economic benefits of vaccination related to reduced Shigella-attributable disease and associated LGF compared with the net costs of a vaccine programme. METHODS: In this benefit-cost analysis, we modelled productivity benefits in 102 low-income and middle-income countries that had recent stunting estimates available, at least one Shigella-attributable death annually, and available economic data, particularly on gross national income and growth rate projections. We modelled benefits strictly related to linear growth improvements and no other benefits associated with reducing diarrhoeal burden. The effect size in each country was calculated as shifts in height-for-age Z score (HAZ), representing population average changes for preventing Shigella-attributable less-severe diarrhoea and moderate-to-severe diarrhoea separately for children younger than 5 years. Benefits data were calculated per country and combined with estimated net costs of the vaccine programme in the form of benefit-cost ratios (BCRs); BCRs above parity, or $1 in benefits per $1 in costs (with a 10% margin representing borderline results: 1·10:1), were considered cost-beneficial. Countries were aggregated for analysis by WHO region, World Bank income category, and eligibility for support from Gavi, the Vaccine Alliance. FINDINGS: In the base-case scenario, all regions exhibited cost-beneficial results, with the South-East Asia region and Gavi-eligible countries exhibiting the highest BCRs (21·67 for the South-East Asia region and 14·45 for Gavi-eligible countries), and the Eastern Mediterranean region yielding the lowest BCRs (2·90). All regions exhibited cost-beneficial results from vaccination, except in more conservative scenarios (eg, those assuming early retirement ages and higher discount rates). Our findings were sensitive to assumed returns for increased height, assumptions about vaccine efficacy against linear growth detriments, the anticipated shift in HAZ, and discount rate. Incorporating the productivity benefits of LGF reduction into existing cost-effectiveness estimates resulted in longer-term cost-savings in nearly all regions. INTERPRETATION: LGF is a secondary outcome of Shigella infection and reduction in LGF is not often quantified as a health or economic benefit of vaccination. However, even under conservative assumptions, a Shigella vaccine only moderately effective against LGF could pay for itself from productivity gains alone in some regions. We recommend that LGF be considered in future models assessing the economic and health impacts of interventions preventing enteric infections. Further research is needed on vaccine efficacy against LGF to inform such models. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust.

Could a Shigella vaccine impact long-term health outcomes?: Summary report of an expert meeting to inform a Shigella vaccine public health value proposition, March 24 and 29, 2021.

Shigellosis is a leading cause of diarrhea and dysentery in young children from low to middle-income countries and adults experiencing traveler's diarrhea worldwide. In addition to acute illness, infection by Shigella bacteria is associated with stunted growth among children, which has been linked to detrimental long-term health, developmental, and economic outcomes. On March 24 and 29, 2021, PATH convened an expert panel to discuss the potential impact of Shigella vaccines on these long-term outcomes. Based on current empirical evidence, this discussion focused on whether Shigella vaccines could potentially alleviate the long-term burden associated with Shigella infections. Also, the experts provided recommendations about how to best model the burden, health and vaccine impact, and economic consequences of Shigella infections. This international multidisciplinary panel included 13 scientists, physicians, and economists from multiple relevant specialties. According to the panel, while the relationship between Shigella infections and childhood growth deficits is complex, this relationship likely exists. Vaccine probe studies are the crucial next step to determine whether vaccination could ameliorate Shigella infection-related long-term impacts. Infants should be vaccinated during their first year of life to maximize their protection from severe acute health outcomes and ideally reduce stunting risk and subsequent negative long-term developmental and health impacts. With vaccine schedule crowding, targeted or combination vaccination approaches would likely increase vaccine uptake in high-burden areas. Shigella impact and economic assessment models should include a wider range of linear growth outcomes. Also, these models should produce a spectrum of results-ones addressing immediate benefits for usual health care decision-makers and others that include broader health impacts, providing a more comprehensive picture of vaccination benefits. While many of the underlying mechanisms of this relationship need better characterization, the remaining gaps can be best addressed by collecting data post-vaccine introduction or through large trials.

Effects of geographic and economic heterogeneity on the burden of rotavirus diarrhea and the impact and cost-effectiveness of vaccination in Nigeria.

Child mortality from rotavirus gastroenteritis remains high in Nigeria, representing 14% of all rotavirus deaths worldwide. Here, we examine the potential impact and cost-effectiveness of national rotavirus vaccine introduction in geographic and economic subpopulations of Nigeria. We projected the health and economic outcomes of rotavirus vaccination in children over the first five years of life using a spreadsheet-based model. We modeled child populations using national survey data on rotavirus mortality risk factors and vaccination coverage to predict burden and impact across regional and wealth quintile subpopulations within Nigeria. Our base case considered introduction of a general rotavirus vaccine, modeled to encompass characteristics of existing vaccines, versus no vaccine. Base case costs were estimated from the government perspective, assuming Gavi subsidies, over the first five years. We also present estimates from the cost of vaccination from the perspective of Gavi. We explored uncertainty in model parameters through probabilistic uncertainty, one-way sensitivity, and scenario analyses. According to our estimates, rotavirus enteritis was responsible for 47,898 [95% Uncertainty Limits: 35,361; 63,703] child deaths per year, with approximately 80% of the national burden concentrated in the three northern regions of Nigeria. Rotavirus vaccination was estimated to prevent 6,454 [3,960; 9,721] deaths, 13% [9%; 18%] of the national annual RV burden. National ICERs for rotavirus vaccination from the Nigerian government and Gavi perspectives were US$47 [$18; $105] and $62 [$29; $130] per DALY averted, respectively. General rotavirus vaccination was projected to reduce rotavirus mortality by only 6% [4%; 9%] in the North West region compared to 35% [24%; 47%] in the South East region. Base case ICERs ranged from US$25 [10; 56] per DALY averted in North West to US$64 [18; 157] per DALY averted in South South. Gavi perspective ICERs ranged from US$33 [$15; $68] in North West to US$88 [35; 191] per DALY averted in South South. According to one-way sensitivity analyses, ICERs were most sensitive to vaccine efficacy, followed by estimated administrative costs and rotavirus mortality. Disparities in mortality reduction were largely driven by inequality in vaccination coverage across regions and between socioeconomic subpopulations. Due to high, persistent, and inequitable burden of rotavirus in Nigeria, routine vaccination with any of these rotavirus vaccines would be an high impact and cost-effective strategy in reducing child mortality.

Heterogeneity in enterotoxigenic Escherichia coli and shigella infections in children under 5 years of age from 11 African countries: a subnational approach quantifying risk, mortality, morbidity, and stunting.

BACKGROUND: Diarrhoea, a global cause of child mortality and morbidity, is linked to adverse consequences including childhood stunting and death from other diseases. Few studies explore how diarrhoeal mortality varies subnationally, especially by cause, which is important for targeting investments. Even fewer examine indirect effects of diarrhoeal morbidity on child mortality. We estimated the subnational distribution of mortality, morbidity, and childhood stunting attributable to enterotoxigenic Escherichia coli (ETEC) and shigella infection in children younger than 5 years from 11 eastern and central African countries. These pathogens are leading causes of diarrhoea in young children and have been linked to increased childhood stunting. METHODS: We combined proxy indicators of morbidity and mortality risk from the most recent Demographic and Health Surveys with published relative risks to estimate the potential distribution of diarrhoeal disease risk. To estimate subnational burden, we used country-specific or WHO region-specific morbidity and mortality estimates and distributed them subnationally by three indices that integrate relevant individual characteristics (ie, underweight, probability of receiving oral rehydration treatment of diarrhoea, and receiving vitamin A supplementation) and household characteristics (ie, type of drinking water and sanitation facilities). FINDINGS: Characterising ETEC and shigella subnational estimates of indirect morbidity (infection-attributable stunting) and indirect mortality (stunting-related deaths from other infectious diseases) identified high-risk areas that could be missed by traditional metrics. Burundi and Democratic Republic of the Congo had the highest ETEC-associated and shigella-associated mortality and stunting rates. Mozambique, Democratic Republic of the Congo, and Zimbabwe had the greatest subnational heterogeneity in most ETEC and shigella mortality measures. Inclusion of indirect ETEC and shigella mortality in burden estimates resulted in a 20-30% increase in total ETEC and shigella mortality rates in some subnational areas. INTERPRETATION: Understanding the indirect mortality and morbidity of diarrhoeal pathogens on a subnational level will strengthen disease control strategies and could have important implications for the relative impact and cost-effectiveness of new enteric vaccines. Because our methods rely on publicly available data, they could be employed for national planning. FUNDING: Bill & Melinda Gates Foundation.

Heterogeneity in potential impact and cost-effectiveness of ETEC and Shigella vaccination in four sub-Saharan African countries.

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.

Potential impact and cost-effectiveness of future ETEC and Shigella vaccines in 79 low- and lower middle-income countries.

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.

Burden of enterotoxigenic Escherichia coli and shigella non-fatal diarrhoeal infections in 79 low-income and lower middle-income countries: a modelling analysis.

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.

Reduction in lower-alpha power during Ganzfeld flicker stimulation is associated with the production of imagery and trait positive schizotypy.

Light-flicker Ganzfeld (LFG) induces a lower to upper-alpha frequency shift. However, it is unclear how this neurophysiological response might relate to LFG-induced pseudo-hallucinatory phenomena. It is also unknown whether emotional states (e.g., fear) or traits associated with risk for psychosis (e.g., proneness to perceptual anomalies, ability to produce vivid mental imagery) affect such neurophysiological and/or perceptual responses to LFG. The present study investigated alpha sub-bands during LFG across several flicker frequencies, in relation to individual differences in propensity for Ganzfeld-induced imagery (GI), positive schizotypy and trait mental imagery, and in relation to manipulations of affective state. Given previously reported sex differences in risk for psychosis and response to Ganzfeld, the effect of sex on GI was also studied. Forty-six healthy adults (16 men) completed psychometric measures of trait mental imagery and positive schizotypy before undergoing three LFG (20 min each) conditions. In each condition, participants wore white-out goggles and listened to either mood-inducing soundscapes (fear, serenity) or pink noise (control) through headphones. Greatest propensity for GI arose between 13.1 and 16.0 Hz flicker, with a peak at 16.0 Hz flicker. Occipital lower-alpha was reduced for lower flicker frequencies (13.1-16.0 Hz) and was inversely associated with GI. Upper-alpha power was not significantly related to GI or to other measures. Fear-induction was associated with reduction in alpha power, but did not significantly affect GI. Men reported more GI than women. Findings support a role for cortical destabilisation, as reflected in reduced lower-alpha, in perceptual anomalies; and, by extension, LFG as an experimental model of liability for psychosis.

Origin of Jupiter's cloud-level zonal winds remains a puzzle even after Juno.

How far Jupiter's cloud-level zonal winds penetrate into its interior, a question related to the origin of the winds, has long been a major puzzle about Jupiter. There exist two different views: the shallow scenario in which the cloud-level winds are confined within the thin weather layer at cloud top and the deep scenario in which the cloud-level winds manifest thermal convection in the deep interior. We interpret, using two different models corresponding to the two scenarios, the high-precision measurements of Jupiter's equatorially antisymmetric gravitational field by the Juno spacecraft. We demonstrate, based on the thermal-gravitational wind equation, that both the shallow and deep cloud-level winds models are capable of explaining the measured odd gravitational coefficients within the measured uncertainties, reflecting the nonunique nature of the gravity inverse problem. We conclude that the high-precision Juno gravity measurements cannot provide an answer to the long-standing question about the origin of Jupiter's cloud-level zonal winds.

Effects of geographic and economic heterogeneity on the burden of rotavirus diarrhea and the impact and cost-effectiveness of vaccination in Pakistan.

Globally, rotavirus is a leading cause of childhood diarrhea and related mortality. Although rotavirus vaccination has been introduced in many countries worldwide, there are numerous low- to middle-income countries that have not yet introduced. Pakistan is one of the countries with the highest number of rotavirus deaths in children under five years. Although rotavirus infection is almost universal among children, mortality is often a result of poor nutrition and lack of access to health care and other aspects of poverty. We assess the impact and cost-effectiveness of introducing childhood rotavirus vaccination in Pakistan. We use household data from the 2012-2013 Demographic Health survey in Pakistan to estimate heterogeneity in rotavirus mortality risk, vaccination benefits, and cost-effectiveness across geographic and economic groups. We estimate two-dose rotavirus vaccination coverage that would be distributed through a routine vaccination program. In addition, we estimate rotavirus mortality (burden), and other measures of vaccine cost-effectiveness and impact by subpopulations of children aggregated by region and economic status. Results indicate that the highest estimated regional rotavirus burden is in Sindh (3.3 rotavirus deaths/1000 births) and Balochistan (3.1 rotavirus deaths/1000 births), which also have the lowest estimated vaccination coverage, particularly for children living in the poorest households. In Pakistan, introduction could prevent 3061 deaths per year with current routine immunization patterns at an estimated $279/DALY averted. Increases in coverage to match the region with highest coverage (Islamabad) could prevent an additional 1648 deaths per year. Vaccination of children in the highest risk regions could result in a fourfold mortality reduction as compared to low risk children, and children in the poorest households have a three to four times greater mortality reduction benefit than the richest. Based on the analysis presented here, the benefits and cost-effectiveness of rotavirus vaccination can be maximized by reaching economically and geographically vulnerable children.