Safety and immunogenicity of a 4-component GMMA-based Shigella vaccine in healthy European adults: Stage 1 of a randomized, controlled phase I/II clinical trial.

BACKGROUND: We report data from Stage 1 of an ongoing two-staged, phase I/II randomized clinical trial (NCT05073003) with a 4-component Generalized Modules for Membrane Antigens-based vaccine against Shigella sonnei and S. flexneri 1b, 2a and 3a (altSonflex1-2-3, GSK). METHODS: 18-50-year-old Europeans (N=102) were randomized (2:1) to receive two injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at pre-specified timepoints. RESULTS: The most common solicited administration-site event (until 7 days post-each injection) and unsolicited adverse event (until 28 days post-each injection) were pain (altSonflex1-2-3: 97.1%; Placebo: 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days post-injection 1 and remained substantially higher than pre-vaccination at 3 or 6 months post-vaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (ELISA: post-injection 1: 91.0%; post-injection 2 [Day {D}113; D197]: 100%; 97.0%; serum bactericidal activity (SBA): post-injection 1: 94.4%; post-injection 2: 85.7%; 88.9%) followed by S. sonnei (ELISA: post-injection 1: 77.6%; post-injection 2: 84.6%; 78.8%; SBA: post-injection 1: 83.3%; post-injection 2: 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a. CONCLUSIONS: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population.

What is the context? Shigella bacteria cause severe and often bloody diarrhea, called shigellosis, that affects mostly young children and can be life-threatening. Shigellosis is particularly common in low- and middle-income countries due to inadequate sanitation and limited access to healthcare. Since the immune response to Shigella is serotype-specific, an ideal vaccine should include multiple Shigella serotypes to ensure broad protection. What is new? We developed a novel vaccine against Shigella that includes Shigella sonnei and three prevalent Shigella flexneri serotypes. In Stage 1 (phase I) of the study, healthy European adults received two vaccine injections given 3 or 6 months apart. We found that: The vaccine was well tolerated, and no safety signals or concerns were identified.Regardless of the interval between injections, specific antibodies were elicited against all four Shigella serotypes, with highest levels against Shigella flexneri 2a and Shigella sonnei.Functional antibody levels peaked after the first injection, remaining higher than the baseline up to 6 months. A second injection did not boost responses but restored functional antibody levels to those after the first injection. What is the impact? The vaccine can now be tested in Stage 2 (phase II) of the study in Africa, a region highly affected by shigellosis.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4ß7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in The Gambia.

Background: The Gambia, located in West Africa, is one of 7 country sites conducting the Enterics for Global Health (EFGH) Shigella Surveillance Study to establish incidence and consequence of Shigella-associated medically attended diarrhea among children 6-35 months old. Methods: Here we describe the study site and research experience, sociodemographic characteristics of the study catchment area, facilities of recruitment for diarrhea case surveillance, and known care-seeking behavior for diarrheal illness. We also describe The Gambia's healthcare system and financing, current vaccine schedule and Shigella vaccine adaptation, local diarrhea management guidelines and challenges, and antibiotic resistance patterns in the region. Conclusions: The EFGH study in The Gambia will contribute to the multisite network of Shigella surveillance study and prepare the site for future vaccine trials. In addition, the data produced will inform policy makers about prevention strategies and upcoming Shigella vaccine studies among children in this setting.

Microbiological Methods Used in the Enterics for Global Health Shigella Surveillance Study.

Background: Shigella is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting Shigella are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study is designed to determine the incidence of medically attended shigellosis in 6- to 35-month-old children in 7 resource-limited settings. Here, we describe the microbiological methods used to isolate and identify Shigella. We developed a standardized laboratory protocol for isolation and identification of Shigella by culture. This protocol was implemented across all 7 sites, ensuring consistency and comparability of results. Secondary objectives of the study are to determine the antibiotic resistance profiles of Shigella, compare isolation of Shigella from rectal swabs versus whole stool, and compare isolation of Shigella following transport of rectal swabs in Cary-Blair versus a modified buffered glycerol saline transport medium. Conclusions: Data generated from EFGH using culture methods described herein can potentially be used for microbiological endpoints in future phase 3 clinical trials to evaluate vaccines against shigellosis and for other clinical and public health studies focused on these organisms.

Evaluation of Fecal Inflammatory Biomarkers to Identify Bacterial Diarrhea Episodes: Systematic Review and Protocol for the Enterics for Global Health Shigella Surveillance Study.

Background: The measurement of fecal inflammatory biomarkers among individuals presenting to care with diarrhea could improve the identification of bacterial diarrheal episodes that would benefit from antibiotic therapy. We reviewed prior literature in this area and describe our proposed methods to evaluate 4 biomarkers in the Enterics for Global Health (EFGH) Shigella surveillance study. Methods: We systematically reviewed studies since 1970 from PubMed and Embase that assessed the diagnostic characteristics of inflammatory biomarkers to identify bacterial diarrhea episodes. We extracted sensitivity and specificity and summarized the evidence by biomarker and diarrhea etiology. In EFGH, we propose using commercial enzyme-linked immunosorbent assays to test for myeloperoxidase, calprotectin, lipocalin-2, and hemoglobin in stored whole stool samples collected within 24 hours of enrollment from participants in the Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia sites. We will develop clinical prediction scores that incorporate the inflammatory biomarkers and evaluate their ability to identify Shigella and other bacterial etiologies of diarrhea as determined by quantitative polymerase chain reaction (qPCR). Results: Forty-nine studies that assessed fecal leukocytes (n = 39), red blood cells (n = 26), lactoferrin (n = 13), calprotectin (n = 8), and myeloperoxidase (n = 1) were included in the systematic review. Sensitivities were high for identifying Shigella, moderate for identifying any bacteria, and comparable across biomarkers. Specificities varied depending on the outcomes assessed. Prior studies were generally small, identified red and white blood cells by microscopy, and used insensitive gold standard diagnostics, such as conventional bacteriological culture for pathogen detection. Conclusions: Our evaluation of inflammatory biomarkers to distinguish diarrhea etiologies as determined by qPCR will provide an important addition to the prior literature, which was likely biased by the limited sensitivity of the gold standard diagnostics used. We will determine whether point-of-care biomarker tests could be a viable strategy to inform treatment decision making and increase appropriate targeting of antibiotic treatment to bacterial diarrhea episodes.

Assessment of particulate matter (PM) in ambient air of different settings and its associated health risk in Haripur city, Pakistan / Avaliação de material particulado (MP) no ar ambiente de diferentes configurações e sua associação com o risco à saúde na cidade de Haripur, Paquistão

Particulate matter (PM) is a major air pollutant causing serious health problems. The aim of the present study was to find out concentration of PM in ambient air and its associated health risk in Haripur city, Pakistan. Twenty-three samples were taken at various educational institutes, hospitals, recreational areas and industries in Haripur city. Concentration of PM2.5 (µg/m3) and PM10 (µg/m3) was measured with Youngteng YT-HPC 3000A portable PM counter. The results revealed that values of both PM2.5 and PM10 were above the permissible limits (35 µg/m3 for PM2.5 and 150 µg/m3 for PM10) set by Environmental Protection Agency Pakistan (Pak-EPA) in all the educational institutes, hospitals, recreational areas and industries investigated. Furthermore, significant (p<0.05) variation was found in the concentration of both PM2.5 and PM10 in all the educational institutes, hospitals, recreational areas, and industries studied. The concentration of PM2.5 was positively correlated with the concentration of PM10 in all the sampling sites. Therefore, from 1-14 scale standard of health index, the values of PM2.5 and PM10 exhibited that the ambient air quality of Haripur city Pakistan is under high risk. If the regulatory authorities such as Environmental Protection Agency, Health Department and Local Government monitor PM pollution in different settings of Haripur city, then a decrease can be possible in the pollution level. The remedies that can be taken to overcome the problem of ambient air pollution such as PM are plantation of trees at the sites where there are higher levels of air pollutants and use of masks on personal protection basis along with implementation of pollution control system in industries of Hattar Industrial Estate Haripur city, Pakistan.

O material particulado (MP) é um importante poluente do ar que causa sérios problemas de saúde. O objetivo do presente estudo foi descobrir a concentração de MP no ar ambiente e sua associação com o risco à saúde na cidade de Haripur, Paquistão. Vinte e três amostras foram coletadas em várias instituições de ensino, hospitais, áreas recreativas e indústrias na cidade de Haripur. A concentração de MP2,5 (µg/m3) e MP10 (µg/m3) foi medida por meio do contador de MP portátil Youngteng YT-HPC 3000A. Os resultados revelaram que os valores de MP2,5 e MP10 estavam acima dos limites permitidos (35 µg/m3 para MP2,5 e 150 µg/m3 para MP10) estabelecidos pela Agência de Proteção Ambiental do Paquistão (Pak-EPA) em todas as instituições de ensino, hospitais, áreas recreativas e indústrias investigadas. Além disso, foi encontrada variação significativa (p < 0,05) na concentração de MP2,5 e MP10 em todos os locais estudados. A concentração de MP2,5 correlacionou-se positivamente com a concentração de MP10 em todos os locais de amostragem. Portanto, a partir da escala padrão 1-14 do índice de saúde, os valores de MP2,5 e MP10 mostraram que a qualidade do ar ambiente na cidade de Haripur, Paquistão, está sob alto risco. Se as autoridades reguladoras, como a Pak-EPA, o Departamento de Saúde e o governo local, monitorarem a poluição por MP em diferentes configurações da cidade de Haripur, pode ser que haja uma diminuição no nível de poluição. As medidas que podem ser tomadas para superar o problema da poluição do ar ambiente, como o MP, são o plantio de árvores nos locais onde há maiores níveis de poluentes atmosféricos, o uso de máscaras e a implantação de sistema de controle de poluição nas propriedades industriais de Hattar, na cidade Haripur, Paquistão.

Assessment of particulate matter (PM) in ambient air of different settings and its associated health risk in Haripur city, Pakistan

Abstract Particulate matter (PM) is a major air pollutant causing serious health problems. The aim of the present study was to find out concentration of PM in ambient air and its associated health risk in Haripur city, Pakistan. Twenty-three samples were taken at various educational institutes, hospitals, recreational areas and industries in Haripur city. Concentration of PM2.5 (µg/m3) and PM10 (µg/m3) was measured with Youngteng YT-HPC 3000A portable PM counter. The results revealed that values of both PM2.5 and PM10 were above the permissible limits (35 µg/m3 for PM2.5 and 150 µg/m3 for PM10) set by Environmental Protection Agency Pakistan (Pak-EPA) in all the educational institutes, hospitals, recreational areas and industries investigated. Furthermore, significant (p 0.05) variation was found in the concentration of both PM2.5 and PM10 in all the educational institutes, hospitals, recreational areas, and industries studied. The concentration of PM2.5 was positively correlated with the concentration of PM10 in all the sampling sites. Therefore, from 1-14 scale standard of health index, the values of PM2.5 and PM10 exhibited that the ambient air quality of Haripur city Pakistan is under high risk. If the regulatory authorities such as Environmental Protection Agency, Health Department and Local Government monitor PM pollution in different settings of Haripur city, then a decrease can be possible in the pollution level. The remedies that can be taken to overcome the problem of ambient air pollution such as PM are plantation of trees at the sites where there are higher levels of air pollutants and use of masks on personal protection basis along with implementation of pollution control system in industries of Hattar Industrial Estate Haripur city, Pakistan.

Resumo O material particulado (MP) é um importante poluente do ar que causa sérios problemas de saúde. O objetivo do presente estudo foi descobrir a concentração de MP no ar ambiente e sua associação com o risco à saúde na cidade de Haripur, Paquistão. Vinte e três amostras foram coletadas em várias instituições de ensino, hospitais, áreas recreativas e indústrias na cidade de Haripur. A concentração de MP2,5 (µg/m3) e MP10 (µg/m3) foi medida por meio do contador de MP portátil Youngteng YT-HPC 3000A. Os resultados revelaram que os valores de MP2,5 e MP10 estavam acima dos limites permitidos (35 µg/m3 para MP2,5 e 150 µg/m3 para MP10) estabelecidos pela Agência de Proteção Ambiental do Paquistão (Pak-EPA) em todas as instituições de ensino, hospitais, áreas recreativas e indústrias investigadas. Além disso, foi encontrada variação significativa (p 0,05) na concentração de MP2,5 e MP10 em todos os locais estudados. A concentração de MP2,5 correlacionou-se positivamente com a concentração de MP10 em todos os locais de amostragem. Portanto, a partir da escala padrão 1-14 do índice de saúde, os valores de MP2,5 e MP10 mostraram que a qualidade do ar ambiente na cidade de Haripur, Paquistão, está sob alto risco. Se as autoridades reguladoras, como a Pak-EPA, o Departamento de Saúde e o governo local, monitorarem a poluição por MP em diferentes configurações da cidade de Haripur, pode ser que haja uma diminuição no nível de poluição. As medidas que podem ser tomadas para superar o problema da poluição do ar ambiente, como o MP, são o plantio de árvores nos locais onde há maiores níveis de poluentes atmosféricos, o uso de máscaras e a implantação de sistema de controle de poluição nas propriedades industriais de Hattar, na cidade Haripur, Paquistão.

Subarachnoid lavage following inadvertent intrathecal injection of tranexamic acid

Tranexamic acid (TXA) is a commonly used antifibrinolytic drug during surgical procedures to reduce blood loss. An Inadvertent intrathecal injection of TXAmay lead to serious side effects including seizures and ventricular fibrillation with reported fatalities. We report a case of an inadvertentintrathecal injection of TXAwhich occurred as a result of similarities in appearance between TXAand heavy bupivacaine ampoules. The patient had subarachnoid lavage after experiencing back pain, systemic hypertension followed by generalized tonic clonic seizures

Clinical practice guidelines in complicated intra-abdominal infection 2018: an Indonesian perspective

BACKGROUND: The occurrence of complicated intra-abdominal infections (cIAI) remains high despite system improvement in accordance with Joint Commission International because of heterogeneity of management. However, published clinical practice guidelines (CPGs) were not feasible to be implemented because these guidelines were not specific to Indonesian characteristics. Thus, a national CPG should be developed to minimize heterogeneity in the management of cIAI in Indonesia. METHODS: We developed a CPG on cIAI through the adaptation of published CPGs. The process proceeded in steps recommended by ADAPTE. Published CPGs were critically appraised using Appraisal of Guidelines for Research and Evaluation (AGREE) II critical appraisal tools. For a specific updated CPG, the analysis was performed using Checklist for the Reporting of Updated Guidelines (CheckUp). Appropriate statements and recommendations in selected CPGs were adapted into our CPG with consideration of Indonesian characteristics. The recommendations were established by the hierarchy of evidence on Grading of Recommendations Assessment, Development and Evaluation (GRADE). The approval of the recommendation draft was performed using the Delphi method. RESULTS: Sixty-eight full-text guidelines were downloaded from several sites. Thirty-three CPGs were related to intra-abdominal infection and 18 others were specific on CPG on intra-abdominal infection and cIAI. On review of these 18 CPGs, 13 were strongly recommended, three were recommended, and two were not recommended. On review updated CPGs, five updated CPGs were found, all with the same score. Two of the strongly recommended updated CPGs had been published in 2016 and 2017, i.e. recommendations by the World Society of Emergency Surgery 2016 consensus conference and revised CPG of the Surgical Site Infection Society. There were a total of 84 statements and recommendations developed and approved by the task force through using the Delphi method. CONCLUSIONS: This guideline summarizes the definition, classification, pathophysiology, etiology, risk factors, assessments, and management of cIAI. Evidence-based recommendations have been developed with consideration of Indonesian-specific characteristics.

Factors influencing health seeking behaviour among residents of Basawa community, Sabon Gari l.G.A. Kaduna State, Nigeria

Background: The health of the citizenry is crucial to the growth and development of any nation. Nigeria is riddled with poor health indices ranging from maternal mortality to infant mortality rates. It has been established that health-seeking behaviour has a strong influence on health status, morbidity and mortality indices of a society. It also drives utilisation of health services and is affected by predisposing, enabling and need factors. This study assessed the factors influencing health-seeking behaviour among residents of Basawa community, Sabon Gari LGA, Kaduna State, Nigeria. Method: This was a descriptive cross-sectional study carried out in September 2017 among 125 residents of Basawa community selected by systematic sampling technique. Data was collected using asemi-structured interviewer-administered questionnaire and analysed with SPSS version 21. The results were presented as tables and charts among others. Level of statistical significance was set at p <0.05. Results: The mean age of the respondents was 42±10 years. Majority of the respondents were male (60.8%) and married (90.4%). About two-thirds of the respondents delayed for more than 24 hours before seeking healthcare. Long waiting time (55.2%), the attitude of health workers (22.4%) and the high cost of drugs (22.4%) were given as barriers to health care utilisation. High cost of services, type and severity of illness and attitude of health care workers are the main determinants of health-seeking behaviour. There was a statistically significant relationship between education, monthly income and delay in seeking health care. Conclusion: The study showed several factors that influence health care seeking behaviour. In view of the multifactorial determinants of health-care seeking behaviour, there is need for health workers to be trained and retrained to improve on their attitude, and the provision of community-based social health insurance scheme by the government among others