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Coronary artery disease is associated with impaired clot structure. The aim of this study was to investigate acute phase myocardial infarction (AMI) and provide detailed quantitative analysis of clot ultrastructure. Clot formation and breakdown, pore size, fiber density, fiber radius and protofibril packing were investigated in plasma clots from AMI patients. These data were compared to those from healthy controls. Analysis on clot formation using turbidity showed increased lag time, suggesting changes in protofibril packing and increased fiber size for AMI patients compared to healthy controls. Additionally, increased average rate of clotting and decreased time to maximum absorbance in AMI patients suggest that clots formed more quickly. Moreover, we observed increased time from max OD to max rate of lysis. Increased fibrinogen and decreased plasminogen in AMI patients were accounted for in represented significant differences. AMI samples showed increased time to 25% and 50% lysis, but no change in 75% lysis, representative of delayed lysis onset, but expediated lysis once initiated. These data suggest that AMI patients formed less porous clots made from more densely packed fibers with decreased numbers of protofibrils, which was confirmed using decreased permeation and increased fiber density, and decreased turbidimetry. AMI plasma formed clots that were denser, less permeable, and lysed more slowly than healthy controls. These findings were confirmed by detailed analysis of clot ultrastructure, fiber size, and protofibril packing. Dense clot structures that are resistant to lysis may contribute to a prothrombotic milieu in AMI. [ABSTRACT FROM AUTHOR]

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]

Enteric (typhoid) fever remains a problem in low- and middle-income countries that lack the infrastructure to maintain sanitation and where inadequate diagnostic methods have restricted our ability to identify and control the disease more effectively. As we move into a period of potential disease elimination through the introduction of typhoid conjugate vaccine (TCV), we again need to reconsider the role of typhoid diagnostics in how they can aid in facilitating disease control. Recent technological advances, including serology, transcriptomics, and metabolomics, have provided new insights into how we can detect signatures of invasive Salmonella organisms interacting with the host during infection. Many of these new techniques exhibit potential that could be further explored with the aim of creating a new enteric fever diagnostic to work in conjunction with TCV. We need a sustained effort within the enteric fever field to accelerate, validate, and ultimately introduce 1 (or more) of these methods to facilitate the disease control initiative. The window of opportunity is still open, but we need to recognize the need for communication with other research areas and commercial organizations to assist in the progression of these diagnostic approaches. The elimination of enteric fever is now becoming a real possibility, but new diagnostics need to be part of the equation and factored into future calculations for disease control. [ABSTRACT FROM AUTHOR]

This article looks at media representations of the projected regeneration of Northern Ireland, paying particular attention to a recent promotional film made to elicit support for the redevelopment of a part of Belfast's city centre. Commissioned by Castlebrooke Investments, 'Tribeca Belfast' offers a future prospectus of the city that is as superficial as it is bland. It is, however, illustrative of two influential ideas and strategies that took flight at the end of the Cold War and the 'triumph of capitalism'. One seeks peace through the application of neo-liberal nostrums; the other combines brand theory with state-craft in pursuit of global competitiveness. Both propose models of citizenship that are politically benign, either preferring middle class solipsism or demanding brand loyalty. In Castlebrooke's projection of a future Belfast, this translates into a city peopled by a mobile professional class, waited upon and entertained by servile locals. But such a sterile vision is inimical to building peace and political progress because it underestimates and downplays the significance of marginalized groups who through their activism and expressions of solidarity can lay better claim to the 'heart and soul' of Belfast evoked by Castlebrooke. [ABSTRACT FROM AUTHOR]

Background Robust household sampling, commonly applied for population-based investigations, requires sampling frames or household lists to minimize selection bias. We have applied Google Earth Pro satellite imagery to constitute structure-based sampling frames at sites in Pikine, Senegal; Pietermaritzburg, South Africa; and Wad-Medani, Sudan. Here we present our experiences in using this approach and findings from assessing its applicability by determining positional accuracy. Methods Printouts of satellite imagery combined with Global Positioning System receivers were used to locate and to verify the locations of sample structures (simple random selection; weighted-stratified sampling). Positional accuracy was assessed by study site and administrative subareas by calculating normalized distances (meters) between coordinates taken from the sampling frame and on the ground using receivers. A higher accuracy in conjunction with smaller distances was assumed. Kruskal-Wallis and Dunn multiple pairwise comparisons were performed to evaluate positional accuracy by setting and by individual surveyor in Pietermaritzburg. Results The median normalized distances and interquartile ranges were 0.05 and 0.03–0.08 in Pikine, 0.09 and 0.05–0.19 in Pietermaritzburg, and 0.05 and 0.00–0.10 in Wad-Medani, respectively. Root mean square errors were 0.08 in Pikine, 0.42 in Pietermaritzburg, and 0.17 in Wad-Medani. Kruskal-Wallis and Dunn comparisons indicated significant differences by low- and high-density setting and interviewers who performed the presented approach with high accuracy compared to interviewers with poor accuracy. Conclusions The geospatial approach presented minimizes systematic errors and increases robustness and representativeness of a sample. However, the findings imply that this approach may not be applicable at all sites and settings; its success also depends on skills of surveyors working with aerial data. Methodological modifications are required, especially for resource-challenged sites that may be affected by constraints in data availability and area size. [ABSTRACT FROM AUTHOR]

The publicly funded screen development agency, Northern Ireland Screen, has been the key institutional actor in the exponential growth of the screen industries in Northern Ireland. The most prominent production to be based in Northern Ireland has been Home Box Office's Game of Thrones, which had much of its eight seasons filmed in the region. Significant amounts of public finance have been offered to the screen industries, with direct funding provided to augment United Kingdom-wide tax breaks. However, there has been a lack of critical analysis of the recipients of this finance, on the precarious nature of many of the jobs that have been created, or on the stated benefits to the economy. This article subjects the role of Northern Ireland Screen to policy analysis to attempt to fill this scholarly gap. Setting the subject into the context of public support for film and television across the United Kingdom, it is argued that the economic argument for providing direct financial support to the screen industries needs to be viewed in the context of the overall impact on society. [ABSTRACT FROM AUTHOR]

Typhoid fever is an acute systemic infectious disease responsible for an estimated 12-20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of typhoid conjugate vaccines in endemic countries. Health economic analyses of typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of typhoid vaccination programmes, because the potential effect of typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of typhoid fever, three to 25 patients without typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive typhoid vaccination programmes-including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings-have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of typhoid conjugate vaccines. [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]

If a radiological incident such as a nuclear power plant accident, a radiological dispersal device, or detonation of an improvised nuclear device occurs, significant areas may be contaminated. Initial cleanup priorities would likely focus on populated areas, leaving the forested areas to pass several seasons where the overhead canopy materials would fall to the forest floor. In the event of a wildfire in a radionuclide-contaminated forest, some radionuclides would be emitted in the air while the rest would remain in the ash. This paper reports on a laboratory simulation study that examines the partitioning of cesium-133 (a nonradioactive isotope of cesium) between airborne particulate matter and residual nonentrained ash when pine needles and peat are doped with cesium. Only 1-2.5% of the doped cesium in pine needles was emitted as particulate matter, and most of the cesium was concentrated in the particulate fraction greater than 10 µm in aerodynamic diameter. For peat fires, virtually all of the cesium remained in the ash. The results from this study will be used for modeling efforts to assess potential exposure risks to firefighters and the surrounding public. Implications: There is a potential for emissions of radionuclides such as cesium-137 from a wildfire over a radionuclide-contaminated forest. This paper reports on a laboratory simulation study of a wildfire with two types of biomass doped with nonradioactive cesium. This simulation suggests that only 1-2.5% of the cesium in the biomass will be emitted from the wildfire, while the rest will reside in the residual ash. In this study, pine needles were the only contributor to the air emissions of cesium; duff was not a source of cesium emissions. In this study, cesium emitted from the simulated wildfire was concentrated in the particle sizes larger than 10 µm. [ABSTRACT FROM AUTHOR]

Whole-genome sequencing (WGS) has been vital for revealing the rapid temporal and spatial evolution of antimicrobial resistance (AMR) in bacterial pathogens. Some antimicrobial- resistant pathogens have outpaced us, with untreatable infections appearing in hospitals and the community. However, WGS has additionally provided us with enough knowledge to initiate countermeasures. Although we cannot stop bacterial adaptation, the predictability of many evolutionary processes in AMR bacteria offers us an opportunity to channel them using new control strategies. Furthermore, by using WGS for coordinating surveillance and to create a more fundamental understanding of the outcome of antimicrobial treatment and AMR mechanisms, we can use current and future antimicrobials more effectively and aim to extend their longevity. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to determine the frequency and outcomes of breast malpractice suits among all enrollees in One Call Medical Inc.'s panel of interpreting radiologists nationally and to evaluate state‐by‐state variations. The 8401 radiologists enrolled had 4764 suits, of which 826 were related to breast disease. In New York and New Jersey, the ratio of breast suits to One Call Radiologists was 0.28 and 0.27, twice as much as in any other state. Breast suits in radiology have a wide variation in frequency across the country with New York and New Jersey far exceeding all others in relative frequency and number of radiologists with multiple breast suits. [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]

Due to its low cost, biocompatibility and slow bioresorption, poly-ε-caprolactone (PCL) continues to be a suitable material for select biomedical engineering applications. We used a combined atomic force microscopy (AFM)/optical microscopy technique to determine key mechanical properties of individual electrospun PCL nanofibers with diameters between 440–1040 nm. Compared to protein nanofibers, PCL nanofibers showed much lower adhesion, as they slipped on the substrate when mechanically manipulated. We, therefore, first developed a novel technique to anchor individual PCL nanofibers to micrometer-sized ridges on a substrate, and then mechanically tested anchored nanofibers. When held at constant strain, tensile stress relaxed with fast and slow relaxation times of 1.0 ± 0.3 s and 8.8 ± 3.1 s, respectively. The total tensile modulus was 62 ± 26 MPa, the elastic (non-relaxing) component of the tensile modulus was 53 ± 36 MPa. Individual PCL fibers could be stretched elastically (without permanent deformation) to strains of 19–23%. PCL nanofibers are rather extensible; they could be stretched to a strain of at least 98%, and a tensile strength of at least 12 MPa, before they slipped off the AFM tip. PCL nanofibers that had aged for over a month at ambient conditions became stiffer and less elastic. Our technique provides accurate nanofiber mechanical data, which are needed to guide construction of scaffolds for cells and other biomedical devices. [ABSTRACT FROM AUTHOR]

Most studies of road dust composition have sampled a very wide range of particle sizes, but from the perspective of respiratory exposure to resuspended dusts, it is the PM 10 fraction which is of most importance. The PM 10 fraction of road dust samples was collected at two sites in Birmingham, UK (major highway and road tunnel) and one site in New Delhi, India. Dust loadings were found to be much higher for New Delhi compared to Birmingham, while concentrations of several species were much higher in the case of Birmingham. Detailed chemical source profiles were prepared for both cities and previously generated empirical factors for source attribution to brake wear, tyre wear, and crustal dust were successfully applied to the UK sites. However, 100% of the mass for the Indian site could not be accounted for using these factors. This study highlights the need for generation of local empirical estimation factors for non-exhaust vehicle emissions. A limited number of bulk road dust and brake pad samples were also characterized. Oxidative potential (OP) was also determined for a limited number of PM 10 and bulk road dust samples, and Cu was found to be a factor significantly associated with OP in PM 10 and bulk road dust. [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]

The purpose of this study is to determine the prevalence, causes, and outcomes of GI malpractice suits in a survey of 8,401 radiologists. The malpractice histories of 8,401 radiologists from 47 states were evaluated from credentialing data of all radiologists participating in the network of One Call Medical Inc. Thirty-two percent of radiologists were defendants in at least one malpractice suit. Of the 4,073 total claims, 346 (8.49 %) were related to the gastrointestinal system. The most frequent primary allegations were failure to diagnose, 65.9 %, and procedural complications, 17.1 %. The commonest missed diagnoses were malignancy, 31.6 %; pneumoperitoneum, 19.3 %; and appendicitis, 14.5 %. Payment to the plaintiff occurred in 75.8 % of claims pertinent to cancer, 73.2 % for missed pneumoperitoneum, and 62.5 % related to appendicitis. Of cases in which a ruling was made in favor of the plaintiff, median payments for pneumoperitoneum was $215,000, for primary cancer $200,000, and for appendicitis $60,000. Among procedurally related errors resulting in judgment against a defending radiologist, 78.6 % of claims regarding retained foreign body, 75 % of barium enema cases, and 62.5 % of liver biopsy resulted in a payment to the plaintiff. Among all resolved cases, the median award was $30,000 for unrecognized foreign body retention, $100,000 for barium enema complications, and $400,000 for liver biopsy complication. Of all GI malpractice claims, failure to diagnose was the most prevalent. Among them, approximately three fourths of claims related to either the diagnosis of primary cancer or for detection of a pneumoperitoneum. [ABSTRACT FROM AUTHOR]

A synthesis of protected homochiral tetrahydropteridines from (2 S )-malic acid has been developed. This presents methodology for the synthesis of reduced pteridine coenzymes and pharmaceuticals. [ABSTRACT FROM AUTHOR]

Salmonella enterica serovar Typhi, the cause of typhoid, is host restricted to humans. S. Typhi has a monophyletic population structure, indicating that typhoid in humans is a relatively new disease. Antimicrobial usage is reshaping the current S. Typhi global population and may be driving the emergence of a specific haplotype, H58, that is well adapted to transmission in modern settings and is able to resist antimicrobial killing more efficiently than other S. Typhi. Evidence gathered through genomics and functional studies using the mouse and in vitro cell systems, together with clinical investigations, has provided insight into the mechanisms that underpin the pathogenesis of human typhoid and host restriction. Here we review the latest scientific advances in typhoid research and discuss how these novel approaches are changing our understanding of the disease. [ABSTRACT FROM AUTHOR]

The Typhoid Fever Surveillance in Africa Program (TSAP) was established in 2009 to fill the data void concerning invasive Salmonella disease in sub-Saharan Africa, and to specifically estimate the burden of bloodstream infections caused by the key pathogen, Salmonella enterica serovar Typhi. TSAP has achieved this ambitious target, finding high incidences of typhoid fever in both rural and urban populations in several countries in sub-Saharan Africa. The results of TSAP will undoubtedly dictate the direction of future typhoid fever research in Africa, and at last provides a key piece of the disease burden jigsaw puzzle. With the dawn of new Vi conjugate vaccines against Salmonella Typhi, the next priority for the typhoid community must be providing the required data on these vaccines so they can be licensed and provided to those in high-risk groups and locations across sub-Saharan Africa. [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]

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]

The author looks at antimicrobial resistance (AMR) in bacteria, saying that the problem is particularly serious in poorer countries and may lead to a return of higher mortality rates from diseases such as typhoid fever. He emphasizes the need for changes in areas including diagnostic testing of infections and veterinary use of human antibiotics. Genetic aspects of AMR are discussed.

Background: Clinical guidelines suggest that patients should be referred to exercise while undergoing cancer treatment. Oncology clinicians report being supportive of exercise referrals but not having the time to make referrals. Toward the goal of making exercise referrals standard of care, we implemented and evaluated a novel clinical workflow. Methods: For this QI project, a rehabilitation navigator was inserted in chemotherapy infusion clinics. Patients were offered a validated electronic triage survey. Exercise or rehabilitation recommendations were communicated to patients during a brief counseling visit by the rehabilitation navigator. The implementation approach was guided by the EPIS framework. Acceptability and feasibility were assessed. Results: Initial meetings with nursing and cancer center leadership ensured buy-in (exploration). The education of medical assistants contributed to the adoption of the triage process (preparation). Audit and feedback ensured leadership was aware of medical assistants’ performance (implementation). 100% of medical assistants participated in implementing the triage tool. A total of 587 patients visited the infusion clinics during the 6-month period when this QI project was conducted. Of these, 501 (85.3%) were offered the triage survey and 391 (78%) completed the survey (acceptability). A total of 176 (45%) of triaged patients accepted a referral to exercise or rehabilitation interventions (feasibility). Conclusions: Implementation of a validated triage tool by medical assistants and brief counseling by a rehabilitation navigator resulted in 45% of infusion patients accepting a referral to exercise or rehabilitation. The triage process showed promise for making exercise referrals standard of care for patients undergoing cancer treatment. [ABSTRACT FROM AUTHOR]

Background Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low- and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures. Methods Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of 3 months, and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs. Results The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE), and the serovar-specific O2 and O9 antigens were greatly elevated over a 3-month follow up period in S. Typhi/ S. Paratyphi A patients compared to controls, suggesting seroconversion. Conclusions We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies. Clinical Trial Registration ISRCTN63006567. [ABSTRACT FROM AUTHOR]

• Several risk factors were associated with polymyxin-resistant strains. • The mortality rate was significantly higher in patients with polymyxin-resistant strains. • Carbapenem exposure was strongly associated with mortality. • Aminoglycoside use was a protection factor against mortality from polymyxin-resistant strains. • Polymyxin resistance occurred through mutational changes in mgrB, phoPQ and soxS genes. This study aimed to assess the clinical impact and potential risk factors associated with polymyxin-resistant Enterobacteriaceae strains isolated from patients hospitalized in adult and neonatal intensive care units. A case–control study was conducted from September 2015 to January 2017. Antimicrobial susceptibility of polymyxin-resistant Enterobacteriaceae strains was determined by broth microdilution. The presence of resistance genes was evaluated by polymerase chain reaction and DNA sequencing. Renal failure [ P =0.02, odds ratio (OR) 11.37, 95% confidence interval (CI) 1.0–128.63], use of a urinary catheter (P <0.01, OR 4.16, 95% CI 38.82–366.07), transfer between hospital units (P =0.03, OR 9.98, 95% CI 1.01–98.42), carbapenem use (P <0.01, OR 45.49, 95% CI 6.93–298.62) and surgical procedure (P <0.01, OR 16.52, 95% CI 2.83–96.32) were found to be risk factors for the acquisition of polymyxin-resistant strains in adult patients. For neonatal patients, use of a central venous catheter (P <0.01, OR 69.59, 95% CI 7.33–660.30) was the only risk factor associated with the acquisition of polymyxin-resistant strains. Analysis of the outcomes revealed that the mortality rate was significantly higher in adult (66.6%) and neonatal (23.5%) patients with polymyxin-resistant strains than in those with polymyxin-susceptible strains. In addition, carbapenem exposure (P <0.01, OR 50.93, 95% CI 2.26–>999.999) was strongly associated with mortality. On the other hand, aminoglycoside use (P <0.03, OR 0.06, 95% CI 0.004–0.97) was a protective factor against mortality from polymyxin-resistant strains. Several risk factors were associated with polymyxin-resistant strains. The high mortality rates showed that acquisition of these strains is a predictor for unfavourable outcomes. Combination treatment with an aminoglycoside and polymyxin might be a better combination to improve patient outcomes. [ABSTRACT FROM AUTHOR]

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]

In Asia, there are an estimated 12 million annual cases of enteric fever, a potentially fatal systemic bacterial infection caused by Salmonella enterica serovars Typhi (STy) and Paratyphi A (SPA). The recent availability of typhoid conjugate vaccines (TCV), an increasing incidence of disease caused by SPA and growing antimicrobial resistance (AMR) across the genus Salmonella makes a bivalent STy/SPA vaccine a useful public health proposition. The uptake of a stand-alone paratyphoid vaccine is likely low thus, there is a pipeline of bivalent STy/SPA candidate vaccines. Several candidates are close to entering clinical trials, which if successful should facilitate a more comprehensive approach for enteric fever control. Additionally, the World Health Organization (WHO) has made advancing the development of vaccines that protect young children and working aged adults against both agents of enteric fever a priority objective. This "Vaccine Value Profile" (VVP) addresses information related predominantly to invasive disease caused by SPA prevalent in Asia. Information is included on stand-alone SPA candidate vaccines and candidate vaccines targeting SPA combined with STy. Out of scope for the first version of this VVP is a wider discussion on the development of a universal Salmonella combination candidate vaccine, addressing both enteric fever and invasive non-typhoidal Salmonella disease, for use globally. This VVP is a detailed, high-level assessment of existing, publicly available information to inform and contextualize the public health, economic, and societal potential of pipeline vaccines and vaccine-like products for SPA. Future versions of this VVP will be updated to reflect ongoing activities such as vaccine development strategies and "Full Vaccine Value Assessment" that will inform the value proposition of an SPA vaccine. This VVP was developed by an expert working group from academia, non-profit organizations, public–private partnerships, and multi-lateral organizations as well as in collaboration with stakeholders from the WHO South-East Asian Region. All contributors have extensive expertise on various elements of the VVP for SPA and collectively aimed to identify current research and knowledge gaps. [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]

Shigella represents a paraphyletic group of enteroinvasive Escherichia coli. More than 40 Shigella serotypes have been reported. However, most cases within the men who have sex with men (MSM) community are attributed to 3 serotypes: Shigella sonnei unique serotype and Shigella flexneri 2a and 3a serotypes. Using the zebrafish model, we demonstrate that Shigella can establish persistent infection in vivo. Bacteria are not cleared by the immune system and become antibiotic tolerant. Establishment of persistent infection depends on the O-antigen, a key constituent of the bacterial surface and a serotype determinant. Representative isolates associated with MSM transmission persist in zebrafish, while representative isolates of a serotype not associated with MSM transmission do not. Isolates of a Shigella serotype establishing persistent infections elicited significantly less macrophage death in vivo than isolates of a serotype unable to persist. We conclude that zebrafish are a valuable platform to illuminate factors underlying establishment of Shigella persistent infection in humans. [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: Blood culture is the standard diagnostic method for typhoid and paratyphoid (enteric) fever in surveillance studies and clinical trials, but sensitivity is widely acknowledged to be suboptimal. We conducted a systematic review and meta-analysis to examine sources of heterogeneity across studies and quantified the effect of blood volume.Methods: We searched the literature to identify all studies that performed blood culture alongside bone marrow culture (a gold standard) to detect cases of enteric fever. We performed a meta-regression analysis to quantify the relationship between blood sample volume and diagnostic sensitivity. Furthermore, we evaluated the impact of patient age, antimicrobial use, and symptom duration on sensitivity.Results: We estimated blood culture diagnostic sensitivity was 0.59 (95% confidence interval [CI], 0.54-0.64) with significant between-study heterogeneity (I2, 76% [95% CI, 68%-82%]; P < .01). Sensitivity ranged from 0.51 (95% CI, 0.44-0.57) for a 2-mL blood specimen to 0.65 (95% CI, 0.58-0.70) for a 10-mL blood specimen, indicative of a relationship between specimen volume and sensitivity. Subgroup analysis showed significant heterogeneity by patient age and a weak trend towards higher sensitivity among more recent studies. Sensitivity was 34% lower (95% CI, 4%-54%) among patients with prior antimicrobial use and 31% lower after the first week of symptoms (95% CI, 19%-41%). There was no evidence of confounding by patient age, antimicrobial use, symptom duration, or study date on the relationship between specimen volume and sensitivity.Conclusions: The relationship between the blood sample volume and culture sensitivity should be accounted for in incidence and next-generation diagnostic studies. [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 article describes the case of a male patient with Salmonella enterica serovar S Typhi. It discusses the symptoms shown by the patient upon admission to Patan Hospital in Kathmandu, Nepal, the patient's diagnosis, and examination of the patient's gallbladder with the use of immunofluorescent labelling.

A correction to the article "Radiology medical malpractice suits in gastrointestinal radiology: prevalence, causes, and outcomes," that was published in the 3 October 2014 issue is presented.

The synthesis of protected homochiral tetrahydropteridines with stereochemistry of natural coenzymes at C-6 from (S)-malic acid is reported. [ABSTRACT FROM AUTHOR]

The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical’s ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical’s potency for a specific MoA—its mechanistic potency—is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ERα agonist potencies with the ability of those chemicals to produce ERα-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ERα agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17β-estradiol or the pharmaceutical estrogen, 17α-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission. [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]