Search

Background: The human gut microbiome harbours diverse species of archaea, bacteria, fungi, protists and viruses. To date, most gut microbiome studies have focused on bacteria, neglecting other microbial communities. Consequently, less is known about the diversity and abundance of the latter. Here, we aimed to characterise the diversity and composition of protists in the gut of preschoolaged children (PSAC) in rural Zimbabwe relative to host age, sex, and schistosome infection status. Methods: The gut protist of 113 PSAC (1-5 years) was examined via shotgun metagenomic sequencing and analysed for diversity. Variation in protist abundance with host and environmental factors was analysed by permutational multivariate analysis of variance (PERMANOVA). To investigate how the composition of specific taxa varies across age, sex, nutritional measures and Schistosoma hematobium infection status, analysis of the composition of microbiomes (ANCOM) was used. Results: Eighty protist genera were identified, and the most abundant genera detected was Blastocystis. The prevalence of pathogenic protists was comparatively low, with 12.4% and 3.4% of the participants' gut colonised by E. histolytica and Cryptosporidium, respectively. Of all the independent variables only S. haematobium infection showed significant relationship with the structure of the gut protist, being associated with increases in Peronospora, Pseudoperonospora, Plasmopara and Blastocystis (FDR= 0.009). Summary: This study provides data on the prevalence and diversity of the gut protists in young Zimbabwean children with an emphasis on the host factors; age, sex and schistosome infection status. Our results showed no association between the host factors investigated, including anthropometric measures adjusted for age and the intestinal protist composition and structure, but S. haematobium infection status was associated with composition of specific taxa. There is a need for more studies determining how pathogenic protist interact with non-pathogenic protist in people exhibiting clinical symptoms to inform therapy and nutraceuticals. [ABSTRACT FROM AUTHOR]

Bacterial infections have been traditionally controlled by antibiotics and vaccines, and these approaches have greatly improved health and longevity. However, multiple stakeholders are declaring that the lack of new interventions is putting our ability to prevent and treat bacterial infections at risk. Vaccine and antibiotic approaches still have the potential to address this threat. Innovative vaccine technologies, such as reverse vaccinology, novel adjuvants, and rationally designed bacterial outer membrane vesicles, together with progress in polysaccharide conjugation and antigen design, have the potential to boost the development of vaccines targeting several classes of multidrug-resistant bacteria. Furthermore, new approaches to deliver small-molecule antibacterials into bacteria, such as hijacking active uptake pathways and potentiator approaches, along with a focus on alternative modalities, such as targeting host factors, blocking bacterial virulence factors, monoclonal antibodies, and microbiome interventions, all have potential. Both vaccines and antibacterial approaches are needed to tackle the global challenge of antimicrobial resistance (AMR), and both areas have the underpinning science to address this need. However, a concerted research agenda and rethinking of the value society puts on interventions that save lives, by preventing or treating life-threatening bacterial infections, are needed to bring these ideas to fruition. [ABSTRACT FROM AUTHOR]

Fiji, an upper-middle income state in the Pacific Ocean, has experienced an increase in confirmed case notifications of enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi). To characterize the epidemiology of typhoid exposure, we conducted a cross-sectional sero-epidemiological survey measuring IgG against the Vi antigen of S. Typhi to estimate the effect of age, ethnicity, and other variables on seroprevalence. Epidemiologically relevant cut-off titres were established using a mixed model analysis of data from recovering culture-confirmed typhoid cases. We enrolled and assayed plasma of 1787 participants for anti-Vi IgG; 1,531 of these were resident in mainland areas that had not been previously vaccinated against S. Typhi (seropositivity 32.3% (95%CI 28.2 to 36.3%)), 256 were resident on Taveuni island, which had been previously vaccinated (seropositivity 71.5% (95%CI 62.1 to 80.9%)). The seroprevalence on the Fijian mainland is one to two orders of magnitude higher than expected from confirmed case surveillance incidence, suggesting substantial subclinical or otherwise unreported typhoid. We found no significant differences in seropositivity prevalences by ethnicity, which is in contrast to disease surveillance data in which the indigenous iTaukei Fijian population are disproportionately affected. Using multivariable logistic regression, seropositivity was associated with increased age (odds ratio 1.3 (95% CI 1.2 to 1.4) per 10 years), the presence of a pit latrine (OR 1.6, 95%CI 1.1 to 2.3) as opposed to a septic tank or piped sewer, and residence in settlements rather than residential housing or villages (OR 1.6, 95% CI 1.0 to 2.7). Increasing seropositivity with age is suggestive of low-level endemic transmission in Fiji. Improved sanitation where pit latrines are used and addressing potential transmission routes in settlements may reduce exposure to S. Typhi. Widespread unreported infection suggests there may be a role for typhoid vaccination in Fiji, in addition to public health management of cases and outbreaks. [ABSTRACT FROM AUTHOR]

A concern for Catholic educators is how to keep Catholic schools viable and healthy in a milieu of diminishing numbers of religious as well as a very complex and changing world. This article addresses the Augustinians' response to the challenge to keep the Order's mission of education alive and thriving in the 21st century. This article hopes to accomplish two goals: first, to articulate the meaning of the three core values of Unitas (Unity), Veritas (Truth), and Caritas (Charity). Secondly, to report the results of a study of the Augustinian Values Institute (AVI), a program that engages participants in reflection on the core values and how they might be applied to their classroom pedagogies. The article concludes with some discussion about future directions for the Institute. [ABSTRACT FROM AUTHOR]

Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular ‘interference’ of fibrin's native polymerization mechanism. We have previously reported that engagement of fibrin's polymerization ‘ hole b ’, also known as ‘b-pockets’, through PEGylated complementary ‘ knob B ’ mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B -fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, K d , increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its K d but increases extensibility of fibers at concentrations above its K d . The data suggest this bimodal behavior is due to the individual contributions knob B , which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics. [ABSTRACT FROM AUTHOR]

Because cerebrospinal fluid (CSF) abnormalities in presymptomatic subjects with PSEN1 (presenilin 1) mutations may be observed 4 to 12 years prior to the estimated age at onset, it is possible to test putative therapies on the CSF analytes that correlate with neurodegeneration during this presymptomatic window of clinical opportunity. It is also possible to test the same therapy on a comparison group with increased risk status conferred by both hyperlipidemia and heterozygosity for apolipoprotein E?4. To our knowledge, the only putative therapy thus far tested in such a common design has been statin therapy. The results of these tests show increases in soluble amyloid precursor protein (sAPP)α correlating with statin-induced decreases in serum cholesterol levels in the non-PSEN1 subjects. This result could be one functional correlate for part of the substantial risk reduction for late onset Alzheimer's disease recently reported in the Rotterdam study, a large, long-term prospective statin trial. Statin therapy significantly decreased both sAPPα and sAPPβ in presymptomatic PSEN1 subjects. Initially, elevated phospho-tau levels in PSEN1 subjects did not further increase during the 2 to 3 years of statin therapy, possibly indicative of a prophylactic effect. These results suggest that large and longer term trials of statin therapy correlating changes in CSF biomarker levels with clinical course may be warranted in both presymptomatic PSEN1 and non-PSEN1 subjects [ABSTRACT FROM AUTHOR]

Background: Salmonella Typhi (S. Typhi) causes typhoid fever, which remains an important public health issue in many developing countries. Kathmandu, the capital of Nepal, is an area of high incidence and the pediatric population appears to be at high risk of exposure and infection. Methods: We recently defined the population structure of S. Typhi, using new sequencing technologies to identify nearly 2,000 single nucleotide polymorphisms (SNPs) that can be used as unequivocal phylogenetic markers. Here we have used the GoldenGate (Illumina) platform to simultaneously type 1,500 of these SNPs in 62 S. Typhi isolates causing severe typhoid in children admitted to Patan Hospital in Kathmandu. Results: Eight distinct S. Typhi haplotypes were identified during the 20-month study period, with 68% of isolates belonging to a subclone of the previously defined H58 S. Typhi. This subclone was closely associated with resistance to nalidixic acid, with all isolates from this group demonstrating a resistant phenotype and harbouring the same resistance-associated SNP in GyrA (Phe83). A secondary clone, comprising 19% of isolates, was observed only during the second half of the study. Conclusions: Our data demonstrate the utility of SNP typing for monitoring bacterial populations over a defined period in a single endemic setting. We provide evidence for genotype introduction and define a nalidixic acid resistant subclone of S. Typhi, which appears to be the dominant cause of severe pediatric typhoid in Kathmandu during the study period. [ABSTRACT FROM AUTHOR]

Typhoid (enteric) fever is still a common disease in many developing countries but current diagnostic tests are inadequate. Studies on pathogenesis and genomics have provided new insight into the organisms that cause enteric fever. Better understanding of the microorganisms explains, in part, why our current typhoid methodologies are limited in their diagnostic information and why developing new strategies may be a considerable challenge. Here we discuss the current position of typhoid diagnostics, highlight the need for technological improvements and suggest potential ways of advancing this area. [ABSTRACT FROM AUTHOR]

Emergency radiology as an academic discipline and practice activity is clearly recognized as a distinct category within the community of radiologists in the USA. But, its place among the other branches of diagnostic imaging is as an outlier. Emergency radiology is not recognized as a separate course of study in the curriculum of training. It is not a component of the qualifying exam of the American Board of Radiology. It has few fellowships. It has not engendered a specific designation of care personnel for trauma centres. Moreover, its situation with respect to emergency physicians is bound, by neither regulation nor tradition, to be intellectually or physically close. Yet, it is recognized as encompassing an established society of teachers, practitioners and investigators. Its journal is a repository of new knowledge. Thus, it occupies a definitive if still anomalous position in American medicine in general and radiology in particular. [ABSTRACT FROM AUTHOR]

Salmonella pathogenicity island 7 (SPI-7) in Salmonella enterica serovar Typhi appears to be related to other genomic islands. Evidence suggests that SPI-7 is susceptible to spontaneous circularization, loss, and transposition. Here, we demonstrate that a region within SPI-7 has the ability to mobilize the small incQ plasmid R300B. [ABSTRACT FROM AUTHOR]

The process by which bacteria regulate flagellar expression is known as phase variation and in Salmonella enterica this process permits the expression of one of two flagellin genes, fliC or fljB, at any one time. Salmonella Typhi ( S. Typhi) is normally not capable of phase variation of flagellar antigen expression as isolates only harbour the fliC gene (H:d) and lacks an equivalent fljB locus. However, some S. Typhi isolates, exclusively from Indonesia, harbour an fljB equivalent encoded on linear plasmid, pBSSB1 that drives the expression of a novel flagellin named H:z66. H:z66+ S. Typhi isolates were stimulated to change flagellar phase and genetically analysed for the mechanism of variation. The phase change was demonstrated to be unidirectional, reverting to expression from the resident chromosomal fliC gene. DNA sequencing demonstrated that pBSSB1 linear DNA was still detectable but that these derivatives had undergone deletion and were lacking fljAz66 (encoding a flagellar repressor) and fljBz66. The deletion end-point was found to involve one of the plasmid termini and a palindromic repeat sequence within fljBz66, distinct to that found at the terminus of pBSSB1. These data demonstrate that, like some Streptomyces linear elements, at least one of the terminal inverted repeats of pBSSB1 is non-essential, but that a palindromic repeat sequence may be necessary for replication. [ABSTRACT FROM AUTHOR]

The generation of complete genome sequences provides a blueprint that facilitates the genetic characterization of pathogens and their hosts. The genome of Salmonella enterica serovar Typhi (S. Typhi) harbors ∼5 million base pairs encoding some 4000 genes, of which >200 are functionally inactive. Comparison of S. Typhi isolates from around the world indicates that they are highly related (clonal) and that they emerged from a single point of origin ∼30,000–50,000 years ago. Evidence suggests that, as well as undergoing gene degradation, S. Typhi has also recently acquired genes, such as those encoding the Vi antigen, by horizontal transfer events. [ABSTRACT FROM AUTHOR]

Unlike the majority of Salmonella enterica serovars, Salmonella Typhi (S. Typhi), the etiological agent of human typhoid, is monophasic. S. Typhi normally harbours only the phase 1 flagellin gene (fliC), which encodes the H:d antigen. However, some S. Typhi strains found in Indonesia express an additional flagellin antigen termed H:z66. Molecular analysis of H:z66+ S. Typhi revealed that the H:z66 flagellin structural gene (fljBz66) is encoded on a linear plasmid that we have named pBSSB1. The DNA sequence of pBSSB1 was determined to be just over 27 kbp, and was predicted to encode 33 coding sequences. To our knowledge, pBSSB1 is the first non-bacteriophage-related linear plasmid to be described in the Enterobacteriaceae. [ABSTRACT FROM AUTHOR]

The divergence of Salmonella enterica and Escherichia coli is estimated to have occurred approximately 140 million years ago. Despite this evolutionary distance, the genomes of these two species still share extensive synteny and homology. However, there are significant differences between the two species in terms of genes putatively acquired via various horizontal transfer events. Here we report on the composition and distribution across the Salmonella genus of a chromosomal region designated SPI-10 in Salmonella enterica serovar Typhi and located adjacent to tRNAleux. We find that across the Salmonella genus the tRNAleux region is a hypervariable hot spot for horizontal gene transfer; different isolates from the same S. enterica serovar can exhibit significant variation in this region. Many P4 phage, plasmid, and transposable element-associated genes are found adjacent to tRNAleux in both Salmonella and E. coli, suggesting that these mobile genetic elements have played a major role in driving the variability of this region. [ABSTRACT FROM AUTHOR]

The genus Salmonella consists of over 2,200 serovars that differ in their host range and ability to cause disease despite their close genetic relatedness. The genetic factors that influence each serovar's level of host adaptation, how they evolved or were acquired, their influence on the evolution of each serovar, and the phylogenic relationships between the serovars are of great interest as they provide insight into the mechanisms behind these differences in host range and disease progression. We have used an Salmonella enterica serovar Typhimurium spotted DNA microarray to perform genomic hybridizations of various serovars and strains of both S. enterica (subspecies I and IIIa) and Salmonella bongori to gain insight into the genetic organization of the serovars. Our results are generally consistent with previously published DNA association and multilocus enzyme electrophoresis data. Our findings also reveal novel information. We observe a more distant relationship of serovar Arizona (subspecies IIIa) from the subspecies I serovars than previously measured. We also observe variability in the Arizona SPI-2 pathogenicity island, indicating that it has evolved in a manner distinct from the other serovars. In addition, we identify shared genetic features of S. enterica serovars Typhi, Paratyphi A, and Sendal that parallel their unique ability to cause enteric fever in humans. Therefore, whereas the taxonomic organization of Salmonella into serogroups provides a good first approximation of genetic relatedness, we show that it does not account for genomic changes that contribute to a serovar's degree of host adaptation. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is commonly associated with the H58 lineage, a lineage that arose comparatively recently before becoming globally disseminated. To better understand when and how H58 emerged and became dominant, we performed detailed phylogenetic analyses on contemporary genome sequences from S. Typhi isolated in the period spanning the emergence. Our dataset, which contains the earliest described H58 S. Typhi organism, indicates that ancestral H58 organisms were already multi-drug resistant (MDR). These organisms emerged spontaneously in India in 1987 and became radially distributed throughout South Asia and then globally in the ensuing years. These early organisms were associated with a single long branch, possessing mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent use of fluoroquinolones led to several independent mutations in gyrA. The ability of H58 to acquire and maintain AMR genes continues to pose a threat, as extensively drug-resistant (XDR; MDR plus resistance to ciprofloxacin and third generation cephalosporins) variants, have emerged recently in this lineage. Understanding where and how H58 S. Typhi originated and became successful is key to understand how AMR drives successful lineages of bacterial pathogens. Additionally, these data can inform optimal targeting of typhoid conjugate vaccines (TCVs) for reducing the potential for emergence and the impact of new drug-resistant variants. Emphasis should also be placed upon the prospective identification and treatment of chronic carriers to prevent the emergence of new drug resistant variants with the ability to spread efficiently. A phylogenetic analysis of Salmonella Typhi isolated from returning travelers to the United Kingdom between 1980 and 1995 suggests that H58 emerged from a chronic carrier in India in 1987 before spreading globally and was already multidrug resistant. [ABSTRACT FROM AUTHOR]

Salmonella Paratyphi A, one of the major etiologic agents of enteric fever, has increased in prevalence in recent decades in certain endemic regions in comparison to S. Typhi, the most prevalent cause of enteric fever. Despite this increase, data on the prevalence and molecular epidemiology of S. Paratyphi A remain generally scarce. Here, we analysed the whole genome sequences of 216 S. Paratyphi A isolates originating from Kathmandu, Nepal between 2005 and 2014, of which 200 were from patients with acute enteric fever and 16 from the gallbladder of people with suspected chronic carriage. By exploiting the recently developed genotyping framework for S. Paratyphi A (Paratype), we identified several genotypes circulating in Kathmandu. Notably, we observed an unusual clonal expansion of genotype 2.4.3 over a four-year period that spread geographically and systematically replaced other genotypes. This rapid genotype replacement is hypothesised to have been driven by both reduced susceptibility to fluoroquinolones and genetic changes to virulence factors, such as functional and structural genes encoding the type 3 secretion systems. Finally, we show that person-to-person is likely the most common mode of transmission and chronic carriers seem to play a limited role in maintaining disease circulation. Author summary: Enteric (typhoid) fever is caused by bacteria of Salmonella enterica species, specifically Salmonella Typhi and Salmonella Paratyphi A. While the former is most commonly identified as the causative agent of enteric fever, S. Paratyphi A is increasing in prevalence in many endemic areas like Nepal. However, the understanding of the phylogenetic structure and population dynamics of this organism, as well as transmission patterns, remains incomplete. Here, we provide a detailed phylogenetic analysis of S. Paratyphi A isolated from enteric fever patients in Nepal through whole genome sequence analysis, combined with epidemiological observations, such as water source use, and chronological and location data. We observed an unusual expansion of a genotype (genetic ID) that replaced other genotypes in the area, indicative of changes in circulating population composition. This expansion is hypothesised to have been driven by reduction in antibiotic susceptibility and changes on bacterial structures that are important for pathogenicity. Our data also suggest person-to-person as the most likely mode of transmission for this pathogen. Understanding of S. Paratyphi A population structure, sources of infection, and transmission will help develop policies for enteric fever management, particularly prior to vaccine introduction, as changes in population composition may affect vaccine efficacy. [ABSTRACT FROM AUTHOR]

Background: Enteric fever is caused by Salmonella enterica serovars Typhi (S. Typhi) and Paratyphi A, B, and C. It continues to be a significant cause of morbidity and mortality worldwide. In highly endemic areas, children are disproportionately affected, and antimicrobial resistance reduces therapeutic options. It is estimated that 2–5% of enteric fever patients develop chronic asymptomatic infection. These carriers may act as reservoirs of infection; therefore, the prospective identification and treatment of carriers are critical for long-term disease control. We aimed to find the frequency of Salmonella Typhi carriers in patients undergoing cholecystectomy. We also compared the detection limit of culturing versus qPCR in detecting S. Typhi, performed a geospatial analysis of the carriers identified using this study, and evaluated the accuracy of anti-Vi and anti-YncE in identifying chronic typhoid carriage. Methods: We performed a cross-sectional study in two centers in Pakistan. Gallbladder specimens were subjected to quantitative PCR (qPCR) and serum samples were analyzed for IgG against YncE and Vi by ELISA. We also mapped the residential location of those with a positive qPCR result. Findings: Out of 988 participants, 3.4% had qPCR-positive gallbladder samples (23 S. Typhi and 11 S. Paratyphi). Gallstones were more likely to be qPCR positive than bile and gallbladder tissue. Anti-Vi and YncE were significantly correlated (r = 0.78 p<0.0001) and elevated among carriers as compared to qPCR negative controls, except for anti-Vi response in Paratyphi A. But the discriminatory values of these antigens in identifying carriers from qPCR negative controls were low. Conclusion: The high prevalence of typhoid carriers observed in this study suggests that further studies are required to gain information that will help in controlling future typhoid outbreaks in a superior manner than they are currently being managed. Author summary: Enteric fever, caused by bacteria Salmonella Typhi or Paratyphi, is a serious global illness particularly affecting children in areas with inadequate hygiene and sanitation facilities. It is transmitted through the oral-fecal route. In Pakistan, prevalence of extensively drug resistant S. Typhi resistant strain further complicates its treatment. Some infected individuals develop chronic infections and become carriers of these pathogens. These asymptomatic carriers may potentially spread the disease by shedding the bacteria in urine or stool. To assess the frequency of the carrier state, we examined gallbladder specimens (bile, stones, and tissue) from patients who underwent gallbladder removal surgeries at Aga Khan University and Jinnah Post-graduate Medical Centre. We demonstrated that PCR had a higher sensitivity in detecting Salmonella carriage with a detection limit of 102 CFU/ml and identified 3.4% of typhoid carriers. Additionally, we investigated whether specific antibodies could identify these carriers using various serological tests. The results underscore the need for further research to promptly detect and appropriately treat this disease, thereby enhancing control and preventing future outbreaks. [ABSTRACT FROM AUTHOR]

Discusses the use of Health Belief Model (HBM) as predictors of screening for the utilization of mammography. Factors affecting the utilization of mammography; Psychometrically validated measure of variables affecting the utilization of mammography; Avoidant behavior among women with history of breast cancer; Recommendations for increasing the use of mammography.

The effect of phospholipid depletion by phospholipases on the properties and formation of monoamine oxidase A and B been investigated. The enzyme was solubilized, partially purified, treated with phospholipases and subjected to gel filtration to reduce the amount of enzyme-associated phospholipids. Phospholipase A treatment of the purified monoamine oxidase fraction had no effect on the deprenil inhibition pattern or the observed transition temperatures in the Arrhenius plots. However, the rate of enzyme inactivation by heat and trypsin were greatly increased but differences in rates of inactivation of monoamine oxidase A and B were still observed. Phospholipase C treatment of the enzyme fraction had no effect on the deprenil inhibition pattern, Arrhenius plots, heat stability or trypsin digestibility. The inhibition pattern of membrane-bound monoamine oxidase and the phospholipase-treated fractions by propargylamine showed a reduced substrate specificity compared to deprenil suggesting a hydrophobic region in the enzyme is a factor involved in the structural differences of monoamine oxidase A and B. [ABSTRACT FROM AUTHOR]

The proteasome is a large multiprotein complex that has a critical role in the degradation of ubiquitylated proteins. A fascinating paper in this issue of Cell () now reveals that the proteasome recruits the SAGA histone acetyltransferase complex to a target promoter during gene activation. This finding adds to the growing body of evidence indicating that the proteasome has nonproteolytic functions. [Copyright &y& Elsevier]

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-sub-regions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis. [ABSTRACT FROM AUTHOR]

Zimbabwe currently faces several healthcare challenges, most notably HIV and associated infections including tuberculosis (TB), malaria and recently outbreaks of cholera, typhoid fever and COVID-19. Fungal infections, which are also a major public health threat, receive considerably less attention. Consequently, there is dearth of data regarding the burden of fungal diseases in the country. We estimated the burden of fungal diseases in Zimbabwe based on published literature and 'at-risk' populations (HIV/AIDS patients, survivors of pulmonary TB, cancer, chronic obstructive pulmonary disease, asthma and patients receiving critical care) using previously described methods. Where there was no data for Zimbabwe, regional, or international data was used. Our study revealed that approximately 14.9% of Zimbabweans suffer from fungal infections annually, with 80% having tinea capitis. The annual incidence of cryptococcal meningitis and Pneumocystis jirovecii pneumonia in HIV/AIDS were estimated at 41/100,000 and 63/100,000, respectively. The estimated prevalence of recurrent vulvovaginal candidiasis (RVVC) was 2,739/100,000. The estimated burden of fungal diseases in Zimbabwe is high in comparison to other African countries, highlighting the urgent need for increased awareness and surveillance to improve diagnosis and management. [ABSTRACT FROM AUTHOR]

Background: Shigella sonnei is a pathogen of growing global importance as a cause of diarrhoeal illness in childhood, particularly in transitional low-middle income countries (LMICs). Here, we sought to determine the incidence of childhood exposure to S. sonnei infection in a contemporary transitional LMIC population, where it represents the dominant Shigella species. Methods: Participants were enrolled between the age of 12–36 months between June and December 2014. Baseline characteristics were obtained through standardized electronic questionnaires, and serum samples were collected at 6-month intervals over two years of follow-up. IgG antibody against S. sonnei O-antigen (anti-O) was measured using an enzyme-linked immunosorbent assay (ELISA). A four-fold increase in ELISA units (EU) with convalescent IgG titre >10.3 EU was taken as evidence of seroconversion between timepoints. Results: A total of 3,498 serum samples were collected from 748 participants; 3,170 from the 634 participants that completed follow-up. Measures of anti-O IgG varied significantly by calendar month (p = 0.03). Estimated S. sonnei seroincidence was 21,451 infections per 100,000 population per year (95% CI 19,307–23,834), with peak incidence occurring at 12–18 months of age. Three baseline factors were independently associated with the likelihood of seroconversion; ever having breastfed (aOR 2.54, CI 1.22–5.26), history of prior hospital admission (aOR 0.57, CI 0.34–0.95), and use of a toilet spray-wash in the household (aOR 0.42, CI 0.20–0.89). Conclusions: Incidence of S. sonnei exposure in Ho Chi Minh City is substantial, with significant reduction in the likelihood of exposure as age increases beyond 2 years. Author summary: Bacteria belonging to the genus Shigella are a leading cause of childhood diarrhea globally. In Vietnam and other transitional low-middle income countries (LMIC), S. sonnei has recently emerged as the dominant Shigella species, displacing S. flexneri, which usually predominates in industrializing regions. Little is known about the epidemiology of S. sonnei and how common infection is amongst children in such settings. In this study, we used regular blood sampling from a large cohort of children in Ho Chi Minh City over a two year period to examine changes in antibody concentrations against S. sonnei, using this to detect evidence of exposure to the bacteria. Importantly, this approach allowed us to identify exposures irrespective of whether the children had experienced symptoms or not. Our findings showed that exposure to S. sonnei was common in this cohort, with the highest incidence of exposure occurring in children observed between the ages of 12 months and 18 months. This is the first study of its kind to describe the epidemiology of S. sonnei infection in a LMIC setting and will be useful in informing future vaccine development and deployment strategies against this important pathogen. [ABSTRACT FROM AUTHOR]

Salmonella enterica serotype 1,4,[5],12:i:- (Typhimurium monophasic variant) of sequence type (ST) 34 has emerged as the predominant pandemic genotype in recent decades. Despite increasing reports of resistance to antimicrobials in Southeast Asia, Salmonella ST34 population structure and evolution remained understudied in the region. Here we performed detailed genomic investigations on 454 ST34 genomes collected from Vietnam and diverse geographical sources to elucidate the pathogen's epidemiology, evolution and antimicrobial resistance. We showed that ST34 has been introduced into Vietnam in at least nine occasions since 2000, forming five co-circulating major clones responsible for paediatric diarrhoea and bloodstream infection. Most expansion events were associated with acquisitions of large multidrug resistance plasmids of IncHI2 or IncA/C2. Particularly, the self-conjugative IncA/C2 pST34VN2 (co-transferring blaCTX-M-55, mcr-3.1, and qnrS1) underlies local expansion and intercontinental spread in two separate ST34 clones. At the global scale, Southeast Asia was identified as a potential hub for the emergence and dissemination of multidrug resistant Salmonella ST34, and mutation analysis suggests of selection in antimicrobial responses and key virulence factors. A genomic epidemiology approach describes the population structure of Salmonella monophasic Typhimurium ST34 from Vietnam, and identifies Southeast Asia as a potential hub for the emergence and international spread of multidrug resistant Salm. ST34. [ABSTRACT FROM AUTHOR]

Background: Salmonella enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. Methods: In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of 'suspected typhoid'). We tested for salmonellae in the Nursing School environment. Results: We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. Conclusion: High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination. [ABSTRACT FROM AUTHOR]

Background: Unregulated antimicrobial use is common in both hospital and community settings of low- and middle-income countries (LMICs). However, discrete data regarding the use/misuse of antimicrobials at pharmacies in LMICs are limited. This study was conducted to understand knowledge, attitude, and practice of pharmacy employees on antimicrobial dispensing in Nepal. Methods: We conducted a cross-sectional survey using a structured questionnaire on 801 pharmacy employees working in community and hospital pharmacies located in Lalitpur metropolitan city (LMC) of Kathmandu, Nepal between April 2017 and March 2019. Results: A majority (92%) of respondents agreed that demand for non-prescription antimicrobials was common. Asking for prescription before dispensing was ranked as the first preference by majority (69%) of participants. Suspected respiratory tract infection was the most common reason demanding for non-prescription antimicrobials with the highest mean rank of 1.5. Azithromycin was the most commonly prescribed and sold antimicrobial, as reported by 46% and 48% of participants respectively. A majority (87%) of respondents agreed on antimicrobial resistance (AMR) to be a global public health threat; and misuse/overuse of antimicrobials was perceived as the most common cause of AMR with a mean rank of 1.93. Conclusion: Our study revealed that unfounded dispensing and use of antimicrobials is prevalent among pharmacies in Kathmandu, Nepal. This over reliance on antimicrobials, notably azithromycin, may escalate burden of AMR. We identified several drivers of inappropriate antimicrobial dispensing practice in pharmacies, which will aid public health authorities in addressing these issues. Further studies considering role of other stakeholders, such as doctors, veterinarians, general public, and policy makers are required to obtain a more holistic perspectives on practices of antimicrobial use so to curb the extant AMR crisis. [ABSTRACT FROM AUTHOR]

Patients with suspected enteric (typhoid and paratyphoid) fever are predominantly managed as outpatients in endemic regions. Nonspecific clinical presentation, lack of accurate diagnostic tools, and widespread antimicrobial resistance makes management challenging. Resistance has been described for all antimicrobials including chloramphenicol, amoxycillin, trimethoprim-sulfamethoxazole, ciprofloxacin, ceftriaxone, and azithromycin. No significant differences have been demonstrated between these antimicrobials in their ability to treat enteric fever in systematic reviews of randomized controlled trials (RCTs). Antimicrobial choice should be guided by local resistance patterns and national guidance. Extensively drug-resistant typhoid isolates require treatment with azithromycin and/or meropenem. Combining antimicrobials that target intracellular and extracellular typhoid bacteria is a strategy being explored in the Azithromycin and Cefixime in Typhoid Fever (ACT-SA) RCT, in progress in South Asia. Alternative antimicrobials, such as the oral carbapenem, tebipenem, need clinical evaluation. There is a paucity of evidence to guide the antimicrobial management of chronic fecal carriers. [ABSTRACT FROM AUTHOR]

Typhoid is an enteric disease caused by Salmonella Typhi. Like many febrile illnesses, typhoid presents with nonspecific symptoms. In routine healthcare settings in low- and middle-income countries, typhoid fever is suspected and treated empirically. Though many diagnostic tests are available for typhoid diagnosis, there are currently no diagnostic tests that meet ideal requirements for sensitivity, specificity, speed, and cost-effectiveness. With introduction of typhoid conjugate vaccine, it is essential to explore the current and future typhoid approach in the context of use case and access to ensure their utilization for disease control. [ABSTRACT FROM AUTHOR]

The global response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic demonstrated the value of timely and open sharing of genomic data with standardized metadata to facilitate monitoring of the emergence and spread of new variants. Here, we make the case for the value of Salmonella Typhi (S. Typhi) genomic data and demonstrate the utility of freely available platforms and services that support the generation, analysis, and visualization of S. Typhi genomic data on the African continent and more broadly by introducing the Africa Centres for Disease Control and Prevention's Pathogen Genomics Initiative, SEQAFRICA, Typhi Pathogenwatch, TyphiNET, and the Global Typhoid Genomics Consortium. [ABSTRACT FROM AUTHOR]

The major structural component of a blood clot is a meshwork of fibrin fibers. It has long been thought that the internal structure of fibrin fibers is homogeneous; that is, the protein density and the bond density between protofibrils are uniform and do not depend on fiber diameter. We performed experiments to investigate the internal structure of fibrin fibers. We formed fibrin fibers with fluorescently labeled fibrinogen and determined the light intensity of a fiber, I, as a function of fiber diameter, D. The intensity and, thus, the total number of fibrin molecules in a cross-section scaled as D1.4. This means that the protein density (fibrin per cross-sectional area), ρp, is not homogeneous but instead strongly decreases with fiber diameter as D-0.6. Thinner fibers are denser than thicker fibers. We also determined Young’s modulus, Y, as a function of fiber diameter. Y decreased strongly with increasing D; Y scaled as D-1.5. This implies that the bond density, ρb, also scales as D-1.5. Thinner fibers are stiffer than thicker fibers. Our data suggest that fibrin fibers have a dense, well-connected core and a sparse, loosely connected periphery. In contrast, electrospun fibrinogen fibers, used as a control, have a homogeneous cross-section. [ABSTRACT FROM AUTHOR]

Louisiana State University Health Sciences Center at Shreveport (LSUHSC-S) serves a largely minority-based, urban population. This study aims to identify trends in urine drug screen (UDS) results among females aged 18–35 visiting State University during 1998–2011 and 2012–2019. Using two databases extracted from the electronic medical record system, we performed statistical analysis of demographics and UDS results. Young females aged 18–35 mostly tested positive for cannabinoids and opiates during both periods, 1998–2011 and 2012–2019. African-American females had a higher percentage of positive UDS for illicit drugs, such as cannabinoids and cocaine, while Caucasian females had a higher rate for prescription drugs such as opiates, benzodiazepines, and amphetamine. Between 1998–2011 and 2012–2019, trends in drug screen results changed in both populations, with Caucasian females showing a drastic increase in amphetamines and African-American females showing increase in opiates and cannabinoids during 2012–2019. GatewayNet analysis (sequential-rule mining for inducing causation) for 2012–2019 indicated that a positive screen for amphetamines is likely preceded by a positive screen for cannabinoids, and benzodiazepines may be preceded by opiates. Our results emphasize the importance of drug use monitoring among young females of childbearing age. GatewayNet analysis implies a sequential nature to drug positivity on urine drug screening in this population. [ABSTRACT FROM AUTHOR]

The article presents the author's insights on the failure of genetic-sequencing in delivering a genomic medicine for the treatment of typhoid fever. He says that the genome sequence of Salmonella enterica Typhi had helped in understanding the microorganism's biology and its effect on human. However, the technological expertise and funding are concentrated in countries that are not affected by typhoid, which makes it useless in public-health context and countries affected by the disease.

Background: We aimed to assess the prevalence of Salmonella Typhi through DNA and IgM-antibody detection methods as a prelude to extended surveillance activities at sites in Ghana, Madagascar, and Ethiopia.Methods: We performed species-specific real-time polymerase reaction (RT-PCR) to identify bacterial nucleic acid, and enzyme-linked immunosorbent assay (ELISA) for detecting HlyE/STY1498-, CdtB/STY1886-, pilL/STY4539- and Vi-antigens in blood and biopsy specimens of febrile and non-febrile subjects. We generated antigen-specific ELISA proxy cut-offs by change-point analyses, and utilized cumulative sum as detection method coupled with 1000 repetitive bootstrap analyses. We computed prevalence rates in addition to odds ratios to assess correlations between ELISA outcomes and participant characteristics.Results: Definitive positive RT-PCR results were obtained from samples of febrile subjects originating from Adama Zuria/Ethiopia (1.9%, 2/104), Wolayita Sodo/Ethiopia (1.0%, 1/100), Diego/Madagascar (1.0%, 1/100), and Kintampo/Ghana (1.0%, 1/100), and from samples of non-febrile subjects from Wolayita Sodo/Ethiopia (1%, 2/201). While IgM antibodies against all antigens were identified across all sites, prevalence rates were highest at all Ethiopian sites, albeit in non-febrile populations. Significant correlations in febrile subjects aged < 15 years versus ≥ 15 years were detected for Vi (Odds Ratio (OR): 8.00, p = 0.034) in Adama Zuria/Ethiopia, STY1498 (OR: 3.21, p = 0.008), STY1886 (OR: 2.31, p = 0.054) and STY4539 (OR: 2.82, p = 0.022) in Diego/Madagascar, and STY1498 (OR: 2.45, p = 0.034) in Kintampo/Ghana. We found statistical significance in non-febrile male versus female subjects for STY1498 (OR: 1.96, p = 0.020) in Adama Zuria/Ethiopia, Vi (OR: 2.84, p = 0.048) in Diego/Madagascar, and STY4539 (OR: 0.46, p = 0.009) in Kintampo/Ghana.Conclusions: Findings indicate non-discriminatory stages of acute infections, though with site-specific differences. Immune responses among non-febrile, presumably healthy participants may mask recall and/or reporting bias leading to misclassification, or asymptomatic, subclinical infection signs induced by suppression of inflammatory responses. As most Ethiopian participants were ≥ 15 years of age and not at high-risk, the true S. Typhi burden was likely missed. Change-point analyses for generating ELISA proxy cut-offs appeared robust, though misclassification is possible. Our findings provided important information that may be useful to assess sites prior to implementing surveillance for febrile illness including Salmonella disease. [ABSTRACT FROM AUTHOR]

Typhoid fever epidemiology was investigated rigorously in Santiago, Chile during the 1980s, when Salmonella enterica serovar Typhi (S. Typhi) caused seasonal, hyperendemic disease. Targeted interventions reduced the annual typhoid incidence rates from 128–220 cases/105 population occurring between 1977–1984 to <8 cases/105 from 1992 onwards. As such, Santiago represents a contemporary example of the epidemiologic transition of an industrialized city from amplified hyperendemic typhoid fever to a period when typhoid is no longer endemic. We used whole genome sequencing (WGS) and phylogenetic analysis to compare the genotypes of S. Typhi cultured from acute cases of typhoid fever occurring in Santiago during the hyperendemic period of the 1980s (n = 74) versus the nonendemic 2010s (n = 80) when typhoid fever was rare. The genotype distribution between "historical" (1980s) isolates and "modern" (2011–2016) isolates was similar, with genotypes 3.5 and 2 comprising the majority of isolations, and 73/80 (91.3%) of modern isolates matching a genotype detected in the 1980s. Additionally, phylogenomically 'ancient' genotypes 1.1 and 1.2.1, uncommon in the global collections, were also detected in both eras, with a notable rise amongst the modern isolates. Thus, genotypes of S. Typhi causing acute illness in the modern nonendemic era match the genotypes circulating during the hyperendemic 1980s. The persistence of historical genotypes may be explained by chronic typhoid carriers originally infected during or before the 1980s. Author summary: Studies of Salmonella Typhi (the cause of typhoid fever) rarely include isolates collected both before and after the interruption of hyperendemic transmission because this typically occurred decades before modern bacteria preservation methods. After interruption, it was assumed that sporadic cases and infrequent outbreaks were due to either chronic biliary carriers or importations, but this was difficult to characterize with low resolution bacterial typing methods. In Santiago, Chile, typhoid fever persisted at hyperendemic levels through the 1980s until organized control efforts in the 1980s and changes to wastewater policy in 1991 caused annual typhoid incidence to plummet. In this study, we used whole genome sequencing (WGS) to investigate whether recent sporadic cases occurring in Santiago in the 2010s were genomically similar to S. Typhi circulating in the 1980s, or dissimilar, possibly representing importations of S. Typhi from outside of Chile. We found concordance amongst S. Typhi genotypes between the 1980s and 2010s, and differences from genotypes circulating in Southeast Asia and Africa where typhoid remains hyperendemic. Our findings suggest that a proportion of modern, rare typhoid cases in Santiago are autochthonous, and that chronic carriers or another unknown reservoir likely contribute. Broadly, our findings corroborate the epidemiologic importance of long-term reservoirs of typhoid fever decades after typhoid elimination. [ABSTRACT FROM AUTHOR]

Broad-spectrum antimicrobial use during the treatment of critical illness influences gastrointestinal fermentation endpoints, host immune response and metabolic activity including the conversion of primary to secondary bile acids. We previously observed reduced fermentation capacity in the faecal microbiota of critically ill children upon hospital admission. Here, we further explore the timecourse of the relationship between the microbiome and bile acid profile in faecal samples collected from critically ill children. The microbiome was assayed by sequencing of the 16S rRNA gene, and faecal water bile acids were measured by liquid chromatography mass spectrometry. In comparison to admission faecal samples, members of the Lachnospiraceae recovered during the late-acute phase (days 8–10) of hospitalisation. Patients with infections had a lower proportion of Lachnospiraceae in their gut microbiota than controls and patients with primary admitting diagnoses. Keystone species linked to ecological recovery were observed to decline with the length of PICU admission. These species were further suppressed in patients with systemic infection, respiratory failure, and undergoing surgery. Bile acid composition recovers quickly after intervention for critical illness which may be aided by the compositional shift in Lachnospiraceae. Our findings suggest gut microbiota recovery can be readily assessed via measurement of faecal bile acids. [ABSTRACT FROM AUTHOR]

Shigellosis is the major global cause of dysentery. Shigella sonnei, which has historically been more commonly isolated in developed countries, is undergoing an unprecedented expansion across industrializing regions in Asia, Latin America, and the Middle East. The precise reasons underpinning the epidemiological distribution of the various Shigella species and this global surge in S. sonnei are unclear but may be due to three major environmental pressures. First, natural passive immunization with the bacterium Plesiomonas shigelloides is hypothesized to protect populations with poor water supplies against S. sonnei. Improving the quality of drinking water supplies would, therefore, result in a reduction in P. shigelloides exposure and a subsequent reduction in environmental immunization against S. sonnei. Secondly, the ubiquitous amoeba species Acanthamoeba castellanii has been shown to phagocytize S. sonnei efficiently and symbiotically, thus allowing the bacteria access to a protected niche in which to withstand chlorination and other harsh environmental conditions in temperate countries. Finally, S. sonnei has emerged from Europe and begun to spread globally only relatively recently. A strong selective pressure from localized antimicrobial use additionally appears to have had a dramatic impact on the evolution of the S. sonnei population. We hypothesize that S. sonnei, which exhibits an exceptional ability to acquire antimicrobial resistance genes from commensal and pathogenic bacteria, has a competitive advantage over S. flexneri, particularly in areas with poorly regulated antimicrobial use. Continuing improvement in the quality of global drinking water supplies alongside the rapid development of antimicrobial resistance predicts the burden and international distribution of S. sonnei will only continue to grow. An effective vaccine against S. sonnei is overdue and may become one of our only weapons against this increasingly dominant and problematic gastrointestinal pathogen. [ABSTRACT FROM AUTHOR]

Shigellosis is the major global cause of dysentery. Shigella sonnei, which has historically been more commonly isolated in developed countries, is undergoing an unprecedented expansion across industrializing regions in Asia, Latin America, and the Middle East. The precise reasons underpinning the epidemiological distribution of the various Shigella species and this global surge in S. sonnei are unclear but may be due to three major environmental pressures. First, natural passive immunization with the bacterium Plesiomonas shigelloides is hypothesized to protect populations with poor water supplies against S. sonnei. Improving the quality of drinking water supplies would, therefore, result in a reduction in P. shigelloides exposure and a subsequent reduction in environmental immunization against S. sonnei. Secondly, the ubiquitous amoeba species Acanthamoeba castellanii has been shown to phagocytize S. sonnei efficiently and symbiotically, thus allowing the bacteria access to a protected niche in which to withstand chlorination and other harsh environmental conditions in temperate countries. Finally, S. sonnei has emerged from Europe and begun to spread globally only relatively recently. A strong selective pressure from localized antimicrobial use additionally appears to have had a dramatic impact on the evolution of the S. sonnei population. We hypothesize that S. sonnei, which exhibits an exceptional ability to acquire antimicrobial resistance genes from commensal and pathogenic bacteria, has a competitive advantage over S. flexneri, particularly in areas with poorly regulated antimicrobial use. Continuing improvement in the quality of global drinking water supplies alongside the rapid development of antimicrobial resistance predicts the burden and international distribution of S. sonnei will only continue to grow. An effective vaccine against S. sonnei is overdue and may become one of our only weapons against this increasingly dominant and problematic gastrointestinal pathogen. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) is a major global public health threat, which has been largely driven by the excessive use of antimicrobials. Control measures are urgently needed to slow the trajectory of AMR but are hampered by an incomplete understanding of the interplay between pathogens, AMR encoding genes, and mobile genetic elements at a microbial level. These factors, combined with the human, animal, and environmental interactions that underlie AMR dissemination at a population level, make for a highly complex landscape. Whole-genome sequencing (WGS) and, more recently, metagenomic analyses have greatly enhanced our understanding of these processes, and these approaches are informing mitigation strategies for how we better understand and control AMR. This review explores how WGS techniques have advanced global, national, and local AMR surveillance, and how this improved understanding is being applied to inform solutions, such as novel diagnostic methods that allow antimicrobial use to be optimised and vaccination strategies for better controlling AMR. We highlight some future opportunities for AMR control informed by genomic sequencing, along with the remaining challenges that must be overcome to fully realise the potential of WGS approaches for international AMR control. [ABSTRACT FROM AUTHOR]

Background: Modeling of the transmission dynamics of typhoid allows for an evaluation of the potential direct and indirect effects of vaccination; however, relevant typhoid models rooted in data have rarely been deployed. Methodology/Principal Findings: We developed a parsimonious age-structured model describing the natural history and immunity to typhoid infection. The model was fit to data on culture-confirmed cases of typhoid fever presenting to Christian Medical College hospital in Vellore, India from 2000–2012. The model was then used to evaluate the potential impact of school-based vaccination strategies using live oral, Vi-polysaccharide, and Vi-conjugate vaccines. The model was able to reproduce the incidence and age distribution of typhoid cases in Vellore. The basic reproductive number (R0) of typhoid was estimated to be 2.8 in this setting. Vaccination was predicted to confer substantial indirect protection leading to a decrease in the incidence of typhoid in the short term, but (intuitively) typhoid incidence was predicted to rebound 5–15 years following a one-time campaign. Conclusions/Significance: We found that model predictions for the overall and indirect effects of vaccination depend strongly on the role of chronic carriers in transmission. Carrier transmissibility was tentatively estimated to be low, consistent with recent studies, but was identified as a pivotal area for future research. It is unlikely that typhoid can be eliminated from endemic settings through vaccination alone. Author Summary: We developed a mathematical model for the transmission dynamics of typhoid in order to evaluate the potential direct and indirect (i.e. herd immunity) effects of vaccination. The model was fit to data from Vellore, India and validated against the results of cluster randomized vaccine trials. We evaluated a variety of school-based vaccination strategies and found that typhoid vaccination is expected to lead to short-term indirect protection and a decrease in typhoid incidence, but vaccination alone is unlikely to lead to elimination. The level of indirect protection was found to depend on assumptions about the role of chronic carriers, identifying an important area for future research. [ABSTRACT FROM AUTHOR]

Background: Modeling of the transmission dynamics of typhoid allows for an evaluation of the potential direct and indirect effects of vaccination; however, relevant typhoid models rooted in data have rarely been deployed. Methodology/Principal Findings: We developed a parsimonious age-structured model describing the natural history and immunity to typhoid infection. The model was fit to data on culture-confirmed cases of typhoid fever presenting to Christian Medical College hospital in Vellore, India from 2000–2012. The model was then used to evaluate the potential impact of school-based vaccination strategies using live oral, Vi-polysaccharide, and Vi-conjugate vaccines. The model was able to reproduce the incidence and age distribution of typhoid cases in Vellore. The basic reproductive number (R0) of typhoid was estimated to be 2.8 in this setting. Vaccination was predicted to confer substantial indirect protection leading to a decrease in the incidence of typhoid in the short term, but (intuitively) typhoid incidence was predicted to rebound 5–15 years following a one-time campaign. Conclusions/Significance: We found that model predictions for the overall and indirect effects of vaccination depend strongly on the role of chronic carriers in transmission. Carrier transmissibility was tentatively estimated to be low, consistent with recent studies, but was identified as a pivotal area for future research. It is unlikely that typhoid can be eliminated from endemic settings through vaccination alone. [ABSTRACT FROM AUTHOR]

The epidemiology of typhoid fever in Lao People's Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p<0.0001 and anti-CdtB; 52.6 vs 12.9 EU; p<0.0001). Conversely, the median anti-Vi IgG titer was significantly higher in adults than children (11.3 vs 3.0 U/ml; p<0.0001). A non-linear trend line fitted to the anti-CdtB and anti-HlyE IgG data identified a peak in antibody concentration in children <5 years of age. We identified elevated titers of anti-HlyE and anti-CdtB IgG in the serum of children residing in Lao PDR in comparison to adults. These antigens are associated with seroconversion after typhoid fever and may be a superior measure of disease burden than anti-Vi IgG. This approach is scalable and may be developed to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines. Author summary: Typhoid fever is a serious bloodstream infection caused by the bacterium Salmonella Typhi. Estimating the burden of typhoid fever is complex due to the limitations, cost, and scalability of current diagnostic surveillance methods. The detection of specific antibody responses against the organism may be a more sustainable manner of measuring exposure and disease burden in endemic location. We measured antibody (IgG) in 937 serum samples (317 children and 620 adults) from across the Lao People's Democratic Republic against a polysaccharide (Vi) and two experimental protein antigens, CdtB and HlyE, that may more appropriate markers of disease exposure. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres against HylE and CdtB were significantly higher in children than adults. Conversely, the median IgG titres against Vi was significantly higher in adults than children. We identified a significant association between a peak in IgG titres against CdtB and HlyE in children aged under 5 years. These data are indicative of high level of typhoid fever exposure in children under 5 years of age in Lao PDR and we surmise that IgG titres against HylE and CdtB may be a superior measure of typhoid disease burden than IgG titres against Vi. Our approach is scalable and can be further validated to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines. [ABSTRACT FROM AUTHOR]

Background: Infection with measles virus (MeV) causes immunosuppression and increased susceptibility to other infectious diseases. Only few studies reported a duration of immunosuppression, with varying results. We investigated the effect of immunosuppression on the incidence of hospital admissions for infectious diseases in Vietnamese children.Methods: We used retrospective data (2005 to 2015; N = 4419) from the two pediatric hospitals in Ho Chi Minh City, Vietnam. We compared the age-specific incidence of hospital admission for infectious diseases before and after hospitalization for measles. We fitted a Poisson regression model that included gender, current age, and time since measles to obtain a multiplicative effect measure. Estimates were transformed to the additive scale.Results: We observed two phases in the incidence of hospital admission after measles. The first phase started with a fourfold increased rate of admissions during the first month after measles, dropping to a level quite comparable to children of the same age before measles. In the second phase, lasting until at least 6 years after measles, the admission rate decreased further, with values up to 20 times lower than in children of the same age before measles. However, on the additive scale the effect size in the second phase was much smaller than in the first phase.Conclusion: The first phase highlights the public health benefits of measles vaccination by preventing measles and immune amnesia. The beneficial second phase is interesting, but its strength strongly depends on the scale. It suggests a complicated interaction between MeV infection and the host immunity. [ABSTRACT FROM AUTHOR]

Epidemiologic data regarding health care acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) from Nepal are negligible. We conducted a prospective observational cohort study in the intensive care unit (ICU) of a major tertiary hospital in Nepal between April 2016 and March 2018, to calculate the incidence of VAP, and to describe clinical variables, microbiological etiology, and outcomes. Four hundred and thirty-eight patients were enrolled in the study. Demographic data, medical history, antimicrobial administration record, chest X-ray, biochemical, microbiological and haematological results, acute physiology and chronic health evaluation II score and the sequential organ failure assessment scores were recorded. Categorical variables were expressed as count and percentage and analyzed using the Fisher's exact test. Continuous variables were expressed as median and interquartile range and analyzed using Kruskal-Wallis rank sum test and the pairwise Wilcoxon rank—sum test. 46.8% (205/438) of the patients required intubation. Pneumonia was common in both intubated (94.14%; 193/205) and non-intubated (52.36%; 122/233) patients. Pneumonia developed among intubated patients in the ICU had longer days of stay in the ICU (median of 10, IQR 5–15, P< 0.001) when compared to non-intubated patients with pneumonia (median of 4, IQR 3–6, P< 0.001). The incidence rate of VAP was 20% (41/205) and incidence density was 16.45 cases per 1,000ventilator days. Mortality was significantly higher in patients with pneumonia requiring intubation (44.6%, 86/193) than patients with pneumonia not requiring intubation (10.7%, 13/122, p<0.001, Fisher's exact test). Gram negative bacteria such as Klebsiella and Acinetobacter species were the dominant organisms from both VAP and non-VAP categories. Multi-drug resistance was highly prevalent in bacterial isolates associated with VAP (90%; 99/110) and non-VAP categories (81.5%; 106/130). HAP including VAP remains to be the most prevalent hospital-acquired infections (HAIs) at Patan hospital. A local study of etiological agents and outcomes of HAP and VAP are required for setting more appropriate guidelines for management of such diseases. [ABSTRACT FROM AUTHOR]

Background: The proportion of enteric fever cases caused by Salmonella Paratyphi A is increasing and may increase further as we begin to introduce typhoid conjugate vaccines (TCVs). While numerous epidemiological and genomic studies have been conducted for S. Typhi, there are limited data describing the genomic epidemiology of S. Paratyphi A in especially in endemic settings, such as Bangladesh. Principal findings: We conducted whole genome sequencing (WGS) of 67 S. Paratyphi A isolated between 2008 and 2018 from eight enteric disease surveillance sites across Bangladesh. We performed a detailed phylogenetic analysis of these sequence data incorporating sequences from 242 previously sequenced S. Paratyphi A isolates from a global collection and provided evidence of lineage migration from neighboring countries in South Asia. The data revealed that the majority of the Bangladeshi S. Paratyphi A isolates belonged to the dominant global lineage A (67.2%), while the remainder were either lineage C (19.4%) or F (13.4%). The population structure was relatively homogenous across the country as we did not find any significant lineage distributions between study sites inside or outside Dhaka. Our genomic data showed presence of single point mutations in gyrA gene either at codon 83 or 87 associated with decreased fluoroquinolone susceptibility in all Bangladeshi S. Paratyphi A isolates. Notably, we identified the pHCM2- like cryptic plasmid which was highly similar to S. Typhi plasmids circulating in Bangladesh and has not been previously identified in S. Paratyphi A organisms. Significance: This study demonstrates the utility of WGS to monitor the ongoing evolution of this emerging enteric pathogen. Novel insights into the genetic structure of S. Paratyphi A will aid the understanding of both regional and global circulation patterns of this emerging pathogen and provide a framework for future genomic surveillance studies. Author summary: Salmonella enterica serovar Paratyphi A is an understudied cause of enteric fever which has started replacing Salmonella Typhi in some endemic regions. Currently, there are limited genomic epidemiology data to understand the true disease burden of disease caused by S. Paratyphi A in poor resource settings like Bangladesh. Our genomic data revealed that the population structure of S. Paratyphi A in Bangladesh comprised of only previously defined lineages A, C and F and carried single point mutation in gyrA gene associated with decreased fluoroquinolone susceptibility with no evidence of multi-drug resistance. Additionally, the global context revealed the clustering of organisms associated with neighboring countries in South Asia. We identified the pHCM2-like cryptic plasmid among our collection, which was not found in any S. Paratyphi A isolates previously. A comparative plasmid analysis showed that S. Paratyphi A pHCM2-like plasmid was highly similar to the plasmid found in S. Typhi but significantly different to a similar plasmid from non-invasive Salmonella Paratyphi B variant Java isolate from Bangladesh. This present study highlights the importance of sustained genomic surveillance to monitor the ongoing evolution of antimicrobial resistant determinants and plasmids in Bangladesh and transmission between different countries. [ABSTRACT FROM AUTHOR]

Little is known about the genetic diversity of Salmonella enterica serovar Typhi (S. Typhi) circulating in Latin America. It has been observed that typhoid fever is still endemic in this part of the world; however, a lack of standardized blood culture surveillance across Latin American makes estimating the true disease burden problematic. The Colombian National Health Service established a surveillance system for tracking bacterial pathogens, including S. Typhi, in 2006. Here, we characterized 77 representative Colombian S. Typhi isolates collected between 1997 and 2018 using pulse field gel electrophoresis (PFGE; the accepted genotyping method in Latin America) and whole genome sequencing (WGS). We found that the main S. Typhi clades circulating in Colombia were clades 2.5 and 3.5. Notably, the sequenced S. Typhi isolates from Colombia were closely related in a global phylogeny. Consequently, these data suggest that these are endemic clades circulating in Colombia. We found that AMR in S. Typhi in Colombia was uncommon, with a small subset of organisms exhibiting mutations associated with reduced susceptibility to fluoroquinolones. This is the first time that S. Typhi isolated from Colombia have been characterized by WGS, and after comparing these data with those generated using PFGE, we conclude that PFGE is unsuitable for tracking S. Typhi clones and mapping transmission. The genetic diversity of pathogens such as S. Typhi is limited in Latin America and should be targeted for future surveillance studies incorporating WGS. Author summary: Salmonella Typhi is the causative agent of typhoid fever, with between 9–13 million cases and 116,800 associated deaths annually. Typhoid fever is still a public health problem mainly in low and middle-income countries (LMICs), including in Latin America, which has a modelled incidence of up to 169 (32–642) cases per 100,000 person-years. Several international studies have aimed to fill data gaps regarding the global distribution and genetic landscape of typhoid; however, in spite of these efforts Latin America is still underrepresented. The globally dominant lineages of S. Typhi (e.g., H58), which often carry multi-drug resistance (MDR) plasmids, decreased fluoroquinolone susceptibility, and now azithromycin resistance, are not detectable by the accepted method (PFGE) used to track outbreaks of typhoid in Latin America. We compared PFGE with whole genome sequence (WGS) and found it correlated poorly, resulting in the over clustering of cases. We additionally found that unlike in most endemic countries, S. Typhi in Colombia are highly antimicrobial susceptible and restricted to a limited number of genotypes that are not as commonly identified in other S. Typhi endemic countries. Our study provides the first enhanced insights into the molecular epidemiology of S. Typhi in Colombia, using WGS data for the first time to investigate the population structure in Colombia and identifying predominant circulating genotypes. Our work demonstrates that routine surveillance with the integration of WGS is necessary not only to improve disease burden estimates, but also to track the national and regional transmission dynamics of S. Typhi. [ABSTRACT FROM AUTHOR]