Gut microbiota dysbiosis and its impact on asthma and other lung diseases: potential therapeutic approaches.

The emerging field of gut-lung axis research has revealed a complex interplay between the gut microbiota and respiratory health, particularly in asthma. This review comprehensively explored the intricate relationship between these two systems, focusing on their influence on immune responses, inflammation, and the pathogenesis of respiratory diseases. Recent studies have demonstrated that gut microbiota dysbiosis can contribute to asthma onset and exacerbation, prompting investigations into therapeutic strategies to correct this imbalance. Probiotics and prebiotics, known for their ability to modulate gut microbial compositions, were discussed as potential interventions to restore immune homeostasis. The impact of antibiotics and metabolites, including short-chain fatty acids produced by the gut microbiota, on immune regulation was examined. Fecal microbiota transplantation has shown promise in various diseases, but its role in respiratory disorders is not established. Innovative approaches, including mucus transplants, inhaled probiotics, and microencapsulation strategies, have been proposed as novel therapeutic avenues. Despite challenges, including the sophisticated adaptability of microbial communities and the need for mechanistic clarity, the potential for microbiota-based interventions is considerable. Collaboration between researchers, clinicians, and other experts is essential to unravel the complexities of the gut-lung axis, paving a way for innovative strategies that could transform the management of respiratory diseases.

The use of controlled human infection models to identify correlates of protection for invasive Salmonella vaccines.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S. Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S. Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Obstructive Sleep Apnea and Medical Comorbidities in the Asian Population: Evidence From a Nationwide Healthcare System Data in South Korea.

OBJECTIVE: Obstructive sleep apnea (OSA) is a breathing disorder characterized by recurrent airway obstruction during sleep. Previous western studies have investigated the link between medical disorders and the pathophysiology of OSA. The prevalence and comorbidity rates of OSA; however, vary across different countries and racial groups. This study aimed to delve into medical comorbidities in patients with OSA using a large nationwide healthcare database in Korea. METHODS: This nationwide study used the Korean National Health Insurance claims database (2010-2019). The effect of OSA on the incidence of medical disorders was estimated using the Cox proportional hazard ratio (HR) model. The results were reported as crude and adjusted HRs with 95% confidence intervals (CI). Subgroup analysis was conducted by sex and age. RESULTS: In total, 103,785 patients with OSA and 207,570 patients without OSA were included. OSA group had significantly higher HRs for ischemic heart disease and stroke even after adjusting for hypertension, dyslipidemia, and diabetes. The OSA group also showed an increased risk of metabolic syndrome-related diseases, chronic kidney disease, and gastroesophageal reflux disease. Female patients with OSA exhibited notably higher rates of comorbid liver cirrhosis, chronic obstructive pulmonary disease, and asthma. The cardiovascular burden of patients increased in accordance with the patients' age. CONCLUSION: Korean patients with OSA have a significantly increased risk of cardio-cerebrovascular diseases, which aligns with the previous studies conducted in the western countries. This result holds particular significance as it represents the first nationwide, population-based study conducted in Asia.

Mayaro Virus: An Emerging Alphavirus in the Americas.

Mayaro virus (MAYV) is an arbovirus first isolated in Trinidad and Tobago in 1954. MAYV is the causative agent of Mayaro fever, which is characterised by high fever, maculopapular rash, myalgia and arthralgia. The potential for chronic arthralgia is of particular clinical concern. Currently, MAYV outbreaks are restricted to South and Central America, with some cases reported in Africa as well as several imported cases in Europe. However, in recent years, MAYV has become a growing global concern due to its potential to emerge into urban transmission cycles. Challenges faced with diagnostics, as well as a lack of specific antivirals or licensed vaccines further exacerbate the potential global health threat posed by MAYV. In this review, we discuss this emerging arboviral threat with a particular focus on the current treatment and vaccine development efforts. Overall, MAYV remains a neglected arbovirus due to its limited area of transmission. However, with the potential of its urbanisation and expanding circulation, the threat MAYV poses to global health cannot be overlooked. Further research into the improvement of current diagnostics, as well as the development of efficacious antivirals and vaccines will be crucial to help prevent and manage potential MAYV outbreaks.

Advances in Alphavirus and Flavivirus Research.

Newly emerging viruses, primarily zoonotic or vector-borne, pose a persistent threat to public health and have led to outbreaks of global concern [...].

Association Between Hypnotics and Dementia: A Mini Narrative Review.

OBJECTIVE: This narrative review aims to provide a comprehensive assessment of the existing literature on the relationship between hypnotics and dementia, considering both potential link and inconclusive or lack of association. METHODS: Data from studies that investigate the association between hypnotic medications and dementia were reviewed. Studies included both cohort studies and systematic reviews, participants with various type of dementia and hypnotics including benzodiazepines (BZDs) and Z-drugs (ZDs). RESULTS: The existing literatures presents conflicting evidence regarding the association between hypnotics, including BZDs and ZDs, and the risk of dementia. Some studies suggest a potential link between prolonged use of hypnotics and an increased risk of dementia. However, other studies indicate inconclusive or lacking evidence regarding this association. Factors such as study design, sample characteristics, and control of confounding variables contribute to the variability in findings. CONCLUSION: The relationship between hypnotics and dementia remains complex and controversial. While some studies suggest a potential association, others find inconclusive or conflicting evidence. Future research should focus on addressing methodological limitations, considering classifying dementia subtypes, and try to adjust medication lag time.

Bipolar Disorder, Circadian Rhythm and Clock Genes.

Sleep disturbance and abnormal circadian rhythm might be closely related to bipolar disorder. Several studies involving disturbed sleep/wake cycle, changes in rhythms such as melatonin and cortisol, clock genes, and circadian preference have shown the relationship between bipolar disorder and circadian rhythm. The results differed across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was observed during the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes. Accordingly, circadian rhythm disorder was proposed as a trait marker for bipolar disorder. The altered circadian rhythm may represent a pathological mechanism that contributes to the mood episodes. However, a prospective cohort study is needed for further clarification.

The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial.

BACKGROUND: Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). METHODS: In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry-India (CTRI/2022/06/043608) and is completed. FINDINGS: 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8-99·9) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9-99·2) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4-100·0) with Sii-PTCV and 3·3% (0·1-17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9-99·2) with Sii-PTCV and 0% (0·0-11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. INTERPRETATION: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. FUNDING: Serum Institute of India.

Immune responses to typhoid conjugate vaccine in a two dose schedule among Nepalese children <2 years of age.

BACKGROUND: Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. METHODS: Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FINDINGS: Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). INTERPRETATION: Vi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses.

Human papillomavirus detection rates in Bowen disease: correlation with pelvic and digital region involvement and specific p53 immunostaining patterns.

BACKGROUND: The relationship between human papillomavirus (HPV) and Bowen disease (BD) is not fully understood. OBJECTIVES: To investigate the differences in HPV detection rates in BD samples across various body regions and analyse the expression patterns of p53, p16 and Ki-67 in relation to HPV presence. METHODS: Tissue samples from patients diagnosed with BD, confirmed through histopathology, were retrospectively collected. Next-generation sequencing was used for HPV DNA detection. Immunohistochemistry (IHC) for p16, p53 and Ki-67 was performed. RESULTS: Out of 109 patients with BD, 21 (19.3%) were HPV-positive. All identified types were α-HPVs, with HPV-16 being the most common. The HPV detection rate was significantly higher in the pelvic (9/13, 69%, P < 0.001) and digital (5/10, 50%, P = 0.02) areas compared with those in the other regions. HPV presence was significantly correlated with p53 negativity (P = 0.002), the p53 'non-overexpression' IHC pattern (P < 0.001) and p16-p53 immunostain pattern discordance (P < 0.001). Conversely, there was no notable association between HPV presence and p16 positivity, the p16 IHC pattern or Ki-67 expression. CONCLUSIONS: Our findings suggest the oncogenic role of sexually transmitted and genito-digitally transmitted α-HPVs in the pathogenesis of BD in pelvic and digital regions.

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Association between weekend catch-up sleep and the risk of prediabetes and diabetes: A cross-sectional study using KNHANES.

BACKGROUND: The objectives of this cross-sectional study were to explore the relationship between weekend catch-up sleep (WCUS) and the risk of prediabetes/diabetes and to assess how this risk varies based on WCUS duration, using a large population sample in South Korea. METHODS: Data were sourced from the 2021 Korea National Health and Nutrition Examination Survey, involving 2472 subjects aged 30 years and above, employed, and not using blood glucose-lowering medications. Prediabetes/diabetes risk was examined based on the presence of WCUS. Participants were categorized into four groups by WCUS duration (< 1, ≥ 1 and < 2, ≥ 2 and < 3, and ≥ 3 h) to evaluate the prediabetes/diabetes risk across varying WCUS durations. RESULTS: No significant difference in prediabetes/diabetes risk was observed between the WCUS and non-WCUS groups. In subgroup analysis, a WCUS duration of 1 to 2 h was related to a lower odds ratio of prediabetes (aOR = 0.618, 95% CI = 0.382-0.999), while 3 h or more was associated with a higher odds ratio of diabetes (aOR = 3.098, 95% CI = 1.561-6.149). CONCLUSIONS: In individuals who experience insufficient sleep during weekdays and manage to achieve the optimal average sleep duration of 1 to 2 h of WCUS, WCUS was associated with improved blood glucose regulation. However, compensating for excessive weekday sleep deprivation with WCUS of 3 h or more was associated with impaired blood glucose regulation.

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Immaturity of immune cells around the dural venous sinuses contributes to viral meningoencephalitis in neonates.

High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection. Virus propagated extensively from the perivenous sinus region of the dura mater to the leptomeninges, choroid plexus, and cerebral cortex. Although the structural barrier of CNS border tissues is comparable between neonates and adults, immunofluorescence staining and single-cell RNA sequencing analyses revealed that the neonatal dural immune cells are immature and predominantly composed of CD206hi macrophages, with major histocompatibility complex class II (MHCII)hi macrophages being rare. In adults, however, perivenous sinus immune cells were enriched in MHCIIhi macrophages that are specialized for producing antiviral molecules and chemokines compared with CD206hi macrophages and protected the CNS against systemic virus invasion. Our findings clarify how systemic pathogens enter the CNS through its border tissues and how the immune barrier at the perivenous sinus region of the dura blocks pathogen access to the CNS.

Recent Advances in Nutraceuticals for the Treatment of Sarcopenic Obesity.

Sarcopenic obesity, low muscle mass, and high body fat are growing health concerns in the aging population. This review highlights the need for standardized criteria and explores nutraceuticals as potential therapeutic agents. Sarcopenic obesity is associated with insulin resistance, inflammation, hormonal changes, and reduced physical activity. These factors lead to impaired muscle activity, intramuscular fat accumulation, and reduced protein synthesis, resulting in muscle catabolism and increased fat mass. Myostatin and irisin are myokines that regulate muscle synthesis and energy expenditure, respectively. Nutritional supplementation with vitamin D and calcium is recommended for increasing muscle mass and reducing body fat content. Testosterone therapy decreases fat mass and improves muscle strength. Vitamin K, specifically menaquinone-4 (MK-4), improves mitochondrial function and reduces muscle damage. Irisin is a hormone secreted during exercise that enhances oxidative metabolism, prevents insulin resistance and obesity, and improves bone quality. Low-glycemic-index diets and green cardamom are potential methods for managing sarcopenic obesity. In conclusion, along with exercise and dietary support, nutraceuticals, such as vitamin D, calcium, vitamin K, and natural agonists of irisin or testosterone, can serve as promising future therapeutic alternatives.

Thermal Behavior of Carbon-Phenolic/Silica Phenolic Dual-Layer Ablator Specimens through Arc-Jet Tests.

We studied the behavioral characteristics of a newly developed dual-layer ablator, which uses carbon-phenolic as a recession layer and silica-phenolic as an insulating layer. The ablator specimens were tested in a 0.4 MW supersonic arc-jet plasma wind tunnel, employing two different shapes (flat-faced and hemispherical-faced) and varying thicknesses of the carbon-phenolic recession layer. The specimens underwent two test conditions, namely, stationary tests (7.5 MW/m2, ~40 s) and transient tests simulating an interplanetary spacecraft re-entry heat flux trajectory (6.25↔9.4 MW/m2, ~108 s). During the stationary tests, stagnation point temperatures of the specimens were measured. Additionally, internal temperatures of the specimens were measured at three locations for both stationary and transient tests: inside the carbon-phenolic recession layer, inside the silica-phenolic insulating layer, and at the recession layer-insulating layer intersection. The hemispherical-faced specimen surface temperatures were about 3000 K, which is about 350 K higher than those of flat-faced specimens, resulting in higher internal temperatures. The recession layer internal temperatures rose more exponentially when moved closer to the specimen stagnation point. Layer interaction and insulating layer internal temperatures were found to be dependent on both the recession layer thickness and the exposed surface shape. The change in exposed surface shape increased mass loss and recession, with hemispherical-faced specimens showing ~1.4-fold higher values than the flat-faced specimens.

Ultrasonographic analysis of facial skin thickness in relation to age, site, sex, and body mass index.

BACKGROUND: Numerous nonsurgical but invasive cosmetic procedures are performed blindly in the dermis or subcutaneous fat layer of the facial skin. OBJECTIVES: To measure the numerical skin thickness of the facial areas where dermatological procedures are performed by applying ultrasound techniques, and to make it possible to estimate the skin thickness by investigating the influence of several individual constitutional factors such as age, sex, and body mass index (BMI), so that these variables can be applied to estimate skin thickness. MATERIALS AND METHODS: Skin thickness was measured at eight different facial points using an ultrasound machine (Affiniti 50; Philips Inc.). Demographic data were gathered using questionnaires. Manual BMI was calculated from the weight and height of each participant, and individual BMI measurements were performed using a body composition analyzer. RESULTS: In terms of whole skin thickness, the thickest point was the mouth corner, and the thinnest point was the lateral forehead. The thickest point in the epidermis was the chin, and the thinnest point was the nasolabial fold. The thickest point in the dermis was the corner of the mouth, and the thinnest was the lateral forehead. Full skin thickness and dermal thickness were mostly lower in females. Skin thickness was not significantly correlated with BMI. CONCLUSION: The skin thickness at different points on the face was variable, and realistic data about skin thickness can be obtained by in vivo ultrasonographic analysis of the skin.

Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.

Arc-Jet Tests of Carbon-Phenolic-Based Ablative Materials for Spacecraft Heat Shield Applications.

We developed and tested two carbon-phenolic-based ablators for future Korean spacecraft heat shield applications. The ablators are developed with two layers: an outer recession layer, fabricated from carbon-phenolic material, and an inner insulating layer, fabricated either from cork or silica-phenolic material. The ablator specimens were tested in a 0.4 MW supersonic arc-jet plasma wind tunnel at heat flux conditions ranging from 6.25 MW/m2 to 9.4 MW/m2, with either specimen being stationary or transient. Stationary tests were conducted for 50 s each as a preliminary investigation, and the transient tests were conducted for ~110 s each to stimulate a spacecraft's atmospheric re-entry heat flux trajectory. During the tests, each specimen's internal temperatures were measured at three locations: 25 mm, 35 mm, and 45 mm from the specimen stagnation point. During the stationary tests, a two-color pyrometer was used to measure specimen stagnation-point temperatures. During the preliminary stationary tests, the silica-phenolic-insulated specimen's reaction was normal compared to the cork-insulated specimen; hence, only the silica-phenolic-insulated specimens were further subjected to the transient tests. During the transient tests, the silica-phenolic-insulated specimens were stable, and the internal temperatures were lower than 450 K (~180 °C), achieving the main objective of this study.

Accelerating clinical development of a live attenuated vaccine against Salmonella Paratyphi A (VASP): study protocol for an observer-participant-blind randomised control trial of a novel oral vaccine using a human challenge model of Salmonella Paratyphi A infection in healthy adult volunteers.

INTRODUCTION: This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. METHODS AND ANALYSIS: This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN15485902.