Retrospective Review of Blood Culture-Confirmed Cases of Enteric Fever in Navi Mumbai, India: 2014-2018.

India has one of the highest estimated burdens of enteric fever globally. Prior to the implementation of Typbar-TCV typhoid conjugate vaccine (TCV) in a public sector pediatric immunization campaign in Navi Mumbai, India, we conducted a retrospective review of blood culture-confirmed cases of typhoid and paratyphoid fevers to estimate the local burden of disease. This review included all blood cultures processed at a central microbiology laboratory, serving multiple hospitals, in Navi Mumbai (January 2014-May 2018) that tested positive for either Salmonella Typhi or Salmonella Paratyphi A. Of 40,670 blood cultures analyzed, 1,309 (3.2%) were positive for S. Typhi (1,201 [92%]) or S. Paratyphi A (108 [8%]). Culture positivity was highest in the last months of the dry season (April-June). Our findings indicate a substantial burden of enteric fever in Navi Mumbai and support the importance of TCV immunization campaigns and improved water, sanitation, and hygiene.

Population structure and antimicrobial resistance patterns of Salmonella Typhi and Paratyphi A amid a phased municipal vaccination campaign in Navi Mumbai, India.

We performed whole-genome sequencing of 174 Salmonella Typhi and 54 Salmonella Paratyphi A isolates collected through prospective surveillance in the context of a phased typhoid conjugate vaccine introduction in Navi Mumbai, India. We investigate the temporal and geographical patterns of emergence and spread of antimicrobial resistance. We evaluated the relationship between the spatial distance between households and genetic clustering of isolates. Most isolates were non-susceptible to fluoroquinolones, with nearly 20% containing ≥3 quinolone resistance-determining region mutations. Two H58 isolates carried an IncX3 plasmid containing blaSHV-12, associated with ceftriaxone resistance, suggesting that the ceftriaxone-resistant isolates from India independently evolved on multiple occasions. Among S. Typhi, we identified two main clades circulating (2.2 and 4.3.1 [H58]); 2.2 isolates were closely related following a single introduction around 2007, whereas H58 isolates had been introduced multiple times to the city. Increasing geographic distance between isolates was strongly associated with genetic clustering (odds ratio [OR] = 0.72 per km; 95% credible interval [CrI]: 0.66-0.79). This effect was seen for distances up to 5 km (OR = 0.65 per km; 95% CrI: 0.59-0.73) but not seen for distances beyond 5 km (OR = 1.02 per km; 95% CrI: 0.83-1.26). There was a non-significant reduction in odds of clustering for pairs of isolates in vaccination communities compared with non-vaccination communities or mixed pairs compared with non-vaccination communities. Our findings indicate that S. Typhi was repeatedly introduced into Navi Mumbai and then spread locally, with strong evidence of spatial genetic clustering. In addition to vaccination, local interventions to improve water and sanitation will be critical to interrupt transmission. IMPORTANCE Enteric fever remains a major public health concern in many low- and middle-income countries, as antimicrobial resistance (AMR) continues to emerge. Geographical patterns of typhoidal Salmonella spread, critical to monitoring AMR and planning interventions, are poorly understood. We performed whole-genome sequencing of S. Typhi and S. Paratyphi A isolates collected in Navi Mumbai, India before and after a typhoid conjugate vaccine introduction. From timed phylogenies, we found two dominant circulating lineages of S. Typhi in Navi Mumbai-lineage 2.2, which expanded following a single introduction a decade prior, and 4.3.1 (H58), which had been introduced repeatedly from other parts of India, frequently containing "triple mutations" conferring high-level ciprofloxacin resistance. Using Bayesian hierarchical statistical models, we found that spatial distance between cases was strongly associated with genetic clustering at a fine scale (<5 km). Together, these findings suggest that antimicrobial-resistant S. Typhi frequently flows between cities and then spreads highly locally, which may inform surveillance and prevention strategies.

Programmatic Effectiveness of a Pediatric Typhoid Conjugate Vaccine Campaign in Navi Mumbai, India.

BACKGROUND: The World Health Organization recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018, the Navi Mumbai Municipal Corporation (NMMC) implemented a typhoid conjugate vaccine (TCV) campaign. The campaign targeted all children aged 9 months through 14 years within NMMC boundaries (approximately 320 000 children) over 2 vaccination phases. The phase 1 campaign occurred from 14 July 2018 through 25 August 2018 (71% coverage, approximately 113 420 children). We evaluated the phase 1 campaign's programmatic effectiveness in reducing typhoid cases at the community level. METHODS: We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai and offered blood cultures to children who presented with fever ≥3 days. We used a cluster-randomized (by administrative boundary) test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched test-positive, culture-confirmed typhoid cases with up to 3 test-negative, culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression. RESULTS: Between 1 September 2018 and 31 March 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (programmatic effectiveness, 56%; 95% confidence interval [CI], 25% to 74%; P = .002). Cases aged ≥5 years were 0.37 times as likely (95% CI, .19 to .70; P = .002) and cases during the first year of surveillance were 0.30 times as likely (95% CI, .14 to .64; P = .002) to live in vaccine campaign communities. CONCLUSIONS: Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.

Phase prediction and experimental realisation of a new high entropy alloy using machine learning.

Nearly ~ 108 types of High entropy alloys (HEAs) can be developed from about 64 elements in the periodic table. A major challenge for materials scientists and metallurgists at this stage is to predict their crystal structure and, therefore, their mechanical properties to reduce experimental efforts, which are energy and time intensive. Through this paper, we show that it is possible to use machine learning (ML) in this arena for phase prediction to develop novel HEAs. We tested five robust algorithms namely, K-nearest neighbours (KNN), support vector machine (SVM), decision tree classifier (DTC), random forest classifier (RFC) and XGBoost (XGB) in their vanilla form (base models) on a large dataset screened specifically from experimental data concerning HEA fabrication using melting and casting manufacturing methods. This was necessary to avoid the discrepancy inherent with comparing HEAs obtained from different synthesis routes as it causes spurious effects while treating an imbalanced data-an erroneous practice we observed in the reported literature. We found that (i) RFC model predictions were more reliable in contrast to other models and (ii) the synthetic data augmentation is not a neat practice in materials science specially to develop HEAs, where it cannot assure phase information reliably. To substantiate our claim, we compared the vanilla RFC (V-RFC) model for original data (1200 datasets) with SMOTE-Tomek links augmented RFC (ST-RFC) model for the new datasets (1200 original + 192 generated = 1392 datasets). We found that although the ST-RFC model showed a higher average test accuracy of 92%, no significant breakthroughs were observed, when testing the number of correct and incorrect predictions using confusion matrix and ROC-AUC scores for individual phases. Based on our RFC model, we report the development of a new HEA (Ni25Cu18.75Fe25Co25Al6.25) exhibiting an FCC phase proving the robustness of our predictions.

Challenges and issues in continuum modelling of tribology, wear, cutting and other processes involving high-strain rate plastic deformation of metals.

Contribution of finite element method (FEM) as a modelling and simulation technique to represent complex tribological processes has improved our understanding about various biomaterials. This paper presents a review of the advances in the domain of finite element (FE) modelling for simulating tribology, wear, cutting and other processes involving high-strain rate plastic deformation of metals used in bio tribology and machining. Although the study is largely focused on material removal cases in metals, the modelling strategies can be applied to a wide range of other materials. This study discusses the development of friction models, meshing and remeshing strategies, and constitutive material models. The mesh-based and meshless formulations employed for bio tribological simulations with their advantages and limitations are also discussed. The output solution variables including scratch forces, local temperature, residual stresses are analyzed as a function of input variables.

Activity of novel lactone ketolide nafithromycin against multicentric invasive and non-invasive pneumococcal isolates collected in India.

BACKGROUND: India is among the nations reporting substantial healthcare burden linked to pneumococcal infections. Nafithromycin is a novel lactone ketolide antibiotic, which recently entered Phase 3 development in India for the indication of community-acquired bacterial pneumonia (CABP). OBJECTIVES: To assess the in vitro activity of nafithromycin against serotyped invasive and non-invasive Streptococcus pneumoniae isolates, collected from nine medical centres across India. METHODS: A total of 534 isolates of S. pneumoniae were collected during 2015-20 and serotyped as per CDC protocol. A subset of erythromycin-non-susceptible S. pneumoniae (n = 200) was screened for the presence of erm(B) and mef(A/E) genes. A subset of MDR isolates (n = 54) were also subjected to MLST. The MICs of antibiotics were determined by the reference agar-dilution method (CLSI). Susceptibilities of the comparators were interpreted as per CLSI criteria. RESULTS: Fifty-nine distinct serotypes were identified among the 534 isolates. Among erythromycin-non-susceptible isolates, erm(B) and mef(A/E) genes were found in 49% and 59% strains respectively, while MLST showed clonal diversity. Azithromycin (67.6% non-susceptible) and clindamycin (31.8% non-susceptible) showed limited activity. Penicillin (for non-meningitis) or quinolone non-susceptibility was low (<11% and <6%, respectively). Nafithromycin showed potent activity with MIC50 and MIC90 of 0.015-0.03 and 0.06 mg/L, respectively, regardless of the macrolide resistance mechanisms. CONCLUSIONS: Indian pneumococcal isolates show poor susceptibilities to macrolides, in concordance with the global trend. Nafithromycin overcomes erm as well as mef-mediated macrolide resistance mechanisms expressed individually or concurrently in S. pneumoniae. This study supports continued clinical development of nafithromycin for pneumococcal infections including CABP.

Whole genome shotgun sequences of Streptococcus pyogenes causing acute pharyngitis from India.

Streptococcus pyogenes, belonging to group A streptococcus (GAS), causes over 600 million infections annually being a predominant human pathogen. Lack of genomic data on GAS from India is one limitation to understand its virulence and antimicrobial resistance determinants. The genome of GAS isolates from clinical samples collected at Navi Mumbai, India was sequenced and annotated. Sequencing was performed on Ion Torrent PGM platform. The size of annotated S. pyogenes genomes ranged from ~1.69 to ~1.85 Mb with coverage of 38× to 189×. Most of the isolates had msr(D) and mef(A), and four isolates had erm(B) gene for macrolide resistance. The genome harboured multiple virulence factors including exotoxins in addition to phage elements in all GAS genomes. Four isolates belonged to sequence type ST28, 7 were identified as ST36 and 1 as ST55.

Invasive pneumococcal disease in children aged younger than 5 years in India: a surveillance study.

BACKGROUND: Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children younger than 5 years of age in India. We aimed to provide nationally representative data for the pattern of disease due to Streptococcus pneumoniae, trends in the serotype of invasive pneumococci, and invasive pneumococci antimicrobial resistance patterns, in India. METHODS: In this prospective hospital-based and retrospective laboratory-based surveillance study, we prospectively enrolled children aged younger than 5 years with suspected or proven invasive pneumococcal disease from 18 hospitals or institutional centres and retrospectively included laboratory-confirmed pneumococcal isolates from ten sentinel laboratories, together representing 11 states in India. Eligibility criteria were fever higher than 38°C without localising symptoms, clinical presentation of suspected meningitis or pneumonia, and evidence of radiographic pneumonia. We cultured blood and other normally sterile body fluids, reconfirmed and serotyped pneumococcal isolates, and established antimicrobial susceptibility using standard study protocols. FINDINGS: Between Jan 1, 2011, and June 30, 2015, we enrolled 4377 patients. Among 361 (8%) patients with culture-proven pneumococcal disease, all clinical data were known for 226 (63%); among these patients, 132 (58%) presented with pneumonia, 78 (35%) presented with meningitis, and 16 (7%) had other clinical conditions. 131 (3%) died overall and 29 (8%) patients with invasive pneumococcal disease died. Serotypes 14 (52 [14%] of 361), 1 (49 [14%]), 5 (37 [10%]), and 19F (33 [9%]) were the most common. Penicillin non-susceptibility occurred in isolates from 29 (8%) patients, co-trimoxazole resistance occurred in 239 (66%), erythromycin resistance occurred in 132 (37%), and chloramphenicol resistance occurred in 33 (9%). We found multidrug resistance in 33 (9%) of 361 patients. INTERPRETATION: The proportion of positive blood cultures, number of isolates, geographical representation, and data generated over the 4·5 years of the study are representative of data for most of India. Continued surveillance is warranted as the decision to introduce protein conjugated vaccine in India is made. FUNDING: GlaxoSmithKline India.