Role of multiresolution vulnerability indices in COVID-19 spread in India: a Bayesian model-based analysis.

OBJECTIVES: COVID-19 has differentially affected countries, with health infrastructure and other related vulnerability indicators playing a role in determining the extent of its spread. Vulnerability of a geographical region to COVID-19 has been a topic of interest, particularly in low-income and middle-income countries like India to assess its multifactorial impact on incidence, prevalence or mortality. This study aims to construct a statistical analysis pipeline to compute such vulnerability indices and investigate their association with metrics of the pandemic growth. DESIGN: Using publicly reported observational socioeconomic, demographic, health-based and epidemiological data from Indian national surveys, we compute contextual COVID-19 Vulnerability Indices (cVIs) across multiple thematic resolutions for different geographical and spatial administrative regions. These cVIs are then used in Bayesian regression models to assess their impact on indicators of the spread of COVID-19. SETTING: This study uses district-level indicators and case counts data for the state of Odisha, India. PRIMARY OUTCOME MEASURE: We use instantaneous R (temporal average of estimated time-varying reproduction number for COVID-19) as the primary outcome variable in our models. RESULTS: Our observational study, focussing on 30 districts of Odisha, identified housing and hygiene conditions, COVID-19 preparedness and epidemiological factors as important indicators associated with COVID-19 vulnerability. CONCLUSION: Having succeeded in containing COVID-19 to a reasonable level during the first wave, the second wave of COVID-19 made greater inroads into the hinterlands and peripheral districts of Odisha, burdening the already deficient public health system in these areas, as identified by the cVIs. Improved understanding of the factors driving COVID-19 vulnerability will help policy makers prioritise resources and regions, leading to more effective mitigation strategies for the present and future.

Region-specific genomic signatures of multidrug-resistant Helicobacter pylori isolated from East and South India.

Helicobacter pylori is a ubiquitous bacterium and contributes significantly to the burden of chronic gastritis, peptic ulcers, and gastric cancer across the world. Adaptive phenotypes and virulence factors in H. pylori are heterogeneous and dynamic. However, limited information is available about the molecular nature of antimicrobial resistance phenotypes and virulence factors of H. pylori strains circulating in India. In the present study, we analyzed the whole genome sequences of 143 H. pylori strains, of which 32 are isolated from two different regions (eastern and southern) of India. Genomic repertoires of individual strains show distinct region-specific signatures. We observed lower resistance phenotypes and genotypes in the East Indian (Kolkata) H. pylori isolates against amoxicillin and furazolidone antibiotics, whereas higher resistance phenotypes to metronidazole and clarithromycin. Also, at molecular level, a greater number of AMR genes were observed in the east Indian H. pylori isolates as compared to the southern Indian isolates. From our findings, we suggest that metronidazole and clarithromycin antibiotics should be used judicially in the eastern India. However, no horizontally acquired antimicrobial resistance gene was observed in the current H. pylori strains. The comparative genome analysis shows that the number of genes involved in virulence, disease and resistance of H. pylori isolated from two different regions of India is significantly different. Single-nucleotide polymorphisms (SNPs) based phylogenetic analysis distinguished H. pylori strains into different clades according to their geographical locations. Conditionally beneficial functions including antibiotic resistance phenotypes that are linked with faster evolution rates in the Indian isolates.

Analysis of colistin resistance in carbapenem-resistant Enterobacterales and XDR Klebsiella pneumoniae.

INTRODUCTION: Increasing occurrence of infections caused by multidrug-resistant Gram-negative bacteria resulted in colistin being the last agent for treatment. Apart from plasmid-mediated mcr genes, mutations involving several genes like mgrB, phoP/phoQ, pmrA, pmrB, pmrC, and crrABC genes, are leading causes of colistin resistance. Four colistin susceptibility testing methods were compared against broth microdilution (BMD) and determined the presence of the mcr1-5 gene. METHODOLOGY: A total of 100 carbapenem-resistant Enterobacterales isolates were tested for colistin susceptibility by commercial broth microdilution (cBMD), E-test, VITEK-2, and rapid polymyxin NP assay (RPNP) and compared with BMD. The presence of the mcr1-5 gene was determined by modified RPNP and PCR. Two non-mcr colistin-resistant XDR isolates were subjected to whole-genome sequencing using Illumina MiSeq sequencing platform. RESULTS: Among 100 carbapenem-resistant Enterobacterales isolates, 15% were resistant to colistin. Essential agreement, categorical agreement, major error, and very major error for cBMD/E-test/VITEK-2/RPNP were 96%/73%/82%/NA; 99%/86%/88%/91%, 1.2%/9.4%/11.8%/8.2% and 0%/40%/13.3%/13.3%, respectively. Only one Klebsiella pneumoniae isolate harbored the mcr-1 gene, observed by both methods. Whole-genome sequencing of two non-mcr XDR Klebsiella pneumoniae showed multiple mutations in 10 genes responsible for lipopolysaccharide biosynthesis. CONCLUSIONS: The performance of cBMD was excellent, whereas the E-test was unacceptable. VITEK-2 and RPNP performed better but remained unreliable due to high error rates. Multiple mutations in the target proteins involving lipopolysaccharide formation, modification, and regulation were seen, resulting in colistin resistance.

Sulbactam and Colistin Susceptibility Pattern Among Multidrug-Resistant Acinetobacter Isolates From Respiratory Samples.

Background Acinetobacter species are known to be important hospital-acquired pathogens. Unfortunately, multidrug-resistant Acinetobacter spp. has very limited options for an effective treatment. Aim To identify the common pathogens causing lower respiratory tract infections (LRTI), their antimicrobial susceptibility pattern, and determine the minimum inhibitory concentration (MIC) of sulbactam and colistin for Acinetobacter spp. Materials and methods A prospective study was done for a period of six months in a tertiary care hospital in Eastern India. The organisms causing LRTI were identified by conventional biochemical techniques and VITEK 2 Compact System (bioMérieux Inc., France). Antimicrobial susceptibility testing was performed using the Kirby­Bauer disc diffusion method. MIC was also measured for Acinetobacter spp. to confirm certain antimicrobial agents using E-strips and micro broth dilution techniques. Results A total of 542 sputum and endotracheal tube aspirate (ETA) samples were examined during the study period. Among these, 109 samples showed growth of significant colony count of one or two organisms, yielding a sum of 115 isolates. Among these, there were 51 (44.35%) isolates of Klebsiella pneumoniae, 32 (27.83%) isolates of Pseudomonas spp., 30 (26.09%) isolates of Acinetobacter spp., and two (1.74%) isolates of Stenotrophomonas maltophilia. Although they were susceptible to colistin, Acinetobacter spp. was highly resistant to sulbactam. Conclusion Although colistin susceptibility was noted, the common pathogens causing LRTI were highly resistant to most drugs. Therefore, the causative organisms of LRTI and their susceptibility pattern should be determined to manage these cases effectively.

IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.

Burden of Serious Fungal Infections in India.

Background: Fungal disease is frequent in India, but its incidence and prevalence are unclear. This review aims at defining the frequency or burden of various fungal infections in India. Methods: A systematic review of the literature on the PubMed, Embase, and Web of Science (WOS) databases was conducted using appropriate search strings. Deterministic modeling determined annual incidence and prevalence estimates for multiple life- and sight-threatening infections with significant morbidity. Results: Literature searches yielded >2900 papers; 434 papers with incidence/prevalence/proportion data were analyzed. An estimated 57 251 328 of the 1 393 400 000 people in India (4.1%) suffer from a serious fungal disease. The prevalence (in millions) of recurrent vulvovaginal candidiasis is 24.3, allergic bronchopulmonary aspergillosis is 2.0, tinea capitis in school-age children is 25, severe asthma with fungal sensitization is 1.36, chronic pulmonary aspergillosis is 1.74, and chronic fungal rhinosinusitis is 1.52. The annual incidence rates of Pneumocystis pneumonia (58 400), invasive aspergillosis (250 900), mucormycosis (195 000), esophageal candidiasis in HIV (266 600), candidemia (188 000), fungal keratitis (1 017 100), and cryptococcal meningitis (11 500) were also determined. Histoplasmosis, talaromycosis, mycetoma, and chromoblastomycosis were less frequent. Conclusions: India's fungal burden is high and underappreciated in clinical practice.

Plasma Gradient of Soluble Urokinase-Type Plasminogen Activator Receptor Is Linked to Pathogenic Plasma Proteome and Immune Transcriptome and Stratifies Outcomes in Severe COVID-19.

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.

One Health aspects & priority roadmap for fungal diseases : A mini-review.

Fungal diseases have not been taken seriously in public health agendas as well as research priorities, despite of globally causing an estimated two million deaths every year, and the emergence of many troublesome fungal pathogens like Candida auris, azole resistant Aspergillus fumigatus, terbinafine and azole resistant dermatophytes, and zoonotic sporotrichosis in humans. Fungi are also responsible for huge losses of agricultural products and stored crops as well as recent massive and unexpected mortality in animals caused by white-nose syndrome in the bats and Chytridiomycosis in amphibians. This review aims to underscore the need for collaborative, multisectoral, and trans-disciplinary approach to include the One Health approach as an essential component of surveillance, prevention, and control of globally emerging fungal diseases. Rigorous evidence based surveillance of the environment as well as strengthening rapid and quality diagnosis of fungal diseases can save millions of lives and reduce significant morbidity.

Nontuberculous mycobacteria: A report of eighteen cases from a tertiary care center in India.

CONTEXT: Nontuberculous mycobacteria (NTM) are ubiquitous mycobacteria present in environment and generally affect patients with either structural lung disease or immunosuppression and commonly involve lungs, lymph node, or skin. MATERIALS AND METHODS: Between July 2016 and February 2019, 18 cases of NTM were diagnosed and their relevant clinical, diagnostic, and treatment details were recorded after taking informed consent. RESULTS: We report 18 cases of NTM involving lungs (n = 11), skin and soft tissue (n = 3), joint (n = 2), genitourinary (n = 1), and central nervous system (n = 1). History of immunosuppression was present in two patients, whereas history of some form of intervention was seen in six patients. Mycobacterium fortuitum group (n = 5) was the most commonly isolated organism, followed by Mycobacterium avium complex (n = 4), Mycobacterium abscessus (n = 3), Mycobacterium kansasii (n = 2), and Mycobacterium chelonae (n = 1). In two patients, M. chelonae and M. abscessus were isolated in succession. Of these 18 patients, clinical response was present in 15 of the patients. Diagnosis and treatment of NTM in resource limited settings is extremely challenging. CONCLUSION: Most of the patients with NTM are misdiagnosed and are treated as tuberculosis in India, sometimes with a multidrug resistance regimen, which results in significant morbidity and mortality. We present these cases to shed some light on the epidemiology of NTM in this part of India.

Impact of trainee-driven Antimicrobial Stewardship Program in a high burden resource-limited setting.

Antimicrobial Stewardship Program (ASP) is one of the most critical interventions required to halt the growing global antimicrobial resistance. The study aimed to evaluate the effect of trainee driven ASP implementation with limited available resources on outcome variables. An ASP team comprising of infectious diseases trainees and consultants was constituted to conduct stewardship activities in the Department of Medicine, All India Institute of Medical Sciences, a tertiary care apex institute in north India. Prospective audit and feedback were conducted by the team, and the following outcome variables were recorded and analyzed: the practice of sending cultures, appropriateness of prescribed empiric antibiotics, gross antimicrobial consumption and mortality. ASP intervention led to an increase in blood culture positivity rates by two folds (p<0.001). The trend of empiric prescription choices gradually shifted over time towards the use of more effective antibiotics according to the local antibiogram. Redundant usage of antibiotics substantially reduced over time. There was no impact of the antimicrobial stewardship program on the all-cause mortality rate. ASP had a significant effect on the practice of sending cultures and appropriateness of antibiotic usage. In resource-limited settings, trainee-driven antimicrobial stewardship program can succeed in inculcating rational practices among fellow residents and practicing physicians.

A study to assess the effectiveness of a nutrition education session using flipchart among school-going adolescent girls.

INTRODUCTION: Adolescence is characterized by a rapid phase of growth and development during which the requirement of nutrition and micronutrients is relatively high. Although there is a decreasing trend in the prevalence of undernutrition among adolescents, the current prevalence of undernutrition is still very high (41.9%). Adolescents with good nutrition knowledge are more likely to follow healthy eating habits. In the light of this, the current study was planned to assess the baseline nutrition-related knowledge of adolescent girls and the effectiveness of nutrition education material (flipchart) in increasing their nutrition-related knowledge. MATERIALS AND METHODS: A school-based interventional study was conducted among adolescent girls of class 9th of a school in an urban slum of Delhi. A structured pretested Knowledge Assessment Questionnaire consisting of 10 multiple-choice questions in Hindi with a maximum score of 10 was used. The intervention was a nutrition education session conducted by doctors of Community Health department using specially designed flipcharts covering important aspects of nutrition relevant for adolescent girls. A demonstration of food items and charts and flex material was also given. The total sample size was 265 adolescent girls. RESULTS: Baseline knowledge as assessed by mean pretest score was poor (3.698 ± 1.81). The students' baseline knowledge was significantly associated with mother's educational status (P = 0.024). There was a significant increase (mean difference was 1.7890 ± 0.1434) in the nutrition-related knowledge of the participants after the intervention (P < 0.001). The proportion of students who improved, i.e., 147 (55.47%) was more than proportion who deteriorated (25 [9.43%]) after the educational session. This difference was found to be statistically significant (P ≤ 0.001). CONCLUSION: Nutrition knowledge was found poor among school-going adolescent girls, which significantly improved after the nutrition education session.

Molecular insights into the genome dynamics and interactions between core and acquired genomes of Vibrio cholerae.

Bacterial species are hosts to horizontally acquired mobile genetic elements (MGEs), which encode virulence, toxin, antimicrobial resistance, and other metabolic functions. The bipartite genome of Vibrio cholerae harbors sporadic and conserved MGEs that contribute in the disease development and survival of the pathogens. For a comprehensive understanding of dynamics of MGEs in the bacterial genome, we engineered the genome of V. cholerae and examined in vitro and in vivo stability of genomic islands (GIs), integrative conjugative elements (ICEs), and prophages. Recombinant vectors carrying the integration module of these GIs, ICE and CTXΦ, helped us to understand the efficiency of integrations of MGEs in the V. cholerae chromosome. We have deleted more than 250 acquired genes from 6 different loci in the V. cholerae chromosome and showed contribution of CTX prophage in the essentiality of SOS response master regulator LexA, which is otherwise not essential for viability in other bacteria, including Escherichia coli In addition, we observed that the core genome-encoded RecA helps CTXΦ to bypass V. cholerae immunity and allow it to replicate in the host bacterium in the presence of similar prophage in the chromosome. Finally, our proteomics analysis reveals the importance of MGEs in modulating the levels of cellular proteome. This study engineered the genome of V. cholerae to remove all of the GIs, ICEs, and prophages and revealed important interactions between core and acquired genomes.

The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence.

A novel coronavirus (nCoV) spillover event, with its epicenter in Wuhan, People's Republic of China, has emerged as a public health emergency of international concern. This began as an outbreak in December 2019, and till February 28, 2020, there have been 83,704 confirmed cases of novel coronavirus disease 2019 (COVID-19) globally, with 2,859 deaths, resulting in an overall case fatality rate of 3.41 per cent (95% confidence interval 3.29-3.54%). By this time (February 28, 2020) 58 countries or territories and one international conveyance (Diamond Princess Cruise Ship) were affected. As a part of the global response to manage and contain the pandemic, major emphasis was placed on generating research intelligence to guide evidence-based responses to contain the virus, which was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), owing to its genetic similarities with the SARS virus. This review summarizes the emerging evidence which can help guide the public health response, particularly in India. Key areas have been identified in which research needs to be conducted to generate critical intelligence for advising prevention and control efforts. The emergence of SARS-CoV-2 has once again exposed the weaknesses of global health systems preparedness, ability to respond to an infectious threat, the rapidity of transmission of infections across international borders and the ineffectiveness of knee-jerk policy responses to emerging/re-emerging infectious disease threats. The review concludes with the key learning points from the ongoing efforts to prevent and contain COVID-19 and identifies the need to invest in health systems, community-led response mechanisms and the need for preparedness and global health security.

Brain abscess in patients with chronic kidney disease: A case-based approach to management in resource-limited settings.

The management of patients with brain abscess poses a significant challenge to clinicians in patients with chronic kidney disease. Obtaining a biopsy sample from the affected area is the mainstay in the diagnosis, but it is often unavailable. In most cases, therapy is guided by clinical findings and imaging alone. We discuss three cases of brain abscess- each with a different scenario and discuss the issues faced in management. The first case was a 32-year-old post-renal transplant male patient with a brain abscess due to dematiaceous fungi and was treated with amphotericin. The second case was a 42-year-old female patient with stage 5 chronic kidney disease on maintenance hemodialysis who presented with a brain abscess due to suspected fungal infection based on imaging findings and was managed with antibiotics and voriconazole. The third case was a 42-year-old post-renal transplant male patient who presented with a brain abscess due to nocardiosis and was managed with cotrimoxazole, meropenem and linezolid. We also summarize the approach to the management of brain abscess in resource-limited settings.

The effect of extracellular matrix protein binding and culture confluence status on the effect of ROCK on TNF-α- and IL-1-stimulated CXCL8 secretion by colonic epithelial cell.

Colonic and intestinal epithelial cells (EC) attach to a basement membrane of laminins, fibronectin, and collagen IV. Wounding of the epithelial layer can change the types of extracellular matrix (ECM) proteins to which the EC attach. In this study, we determined the effect of culturing Caco-2 cells on different ECM proteins on the capacity of EC to produce TNF-α- or IL-1-stimulated CXCL8. The effect of the ECM proteins was such that CXCL8 secretion by cells cultured on collagen I > collagen IV > fibronectin or laminin-111. However, suppression of ROCK activity resulted in a similar 75 to 85% suppression of CXCL8 secretion regardless of the ECM protein type. This suggests that EC can produce different levels of CXCL8 depending on the type of ECM proteins they attach to, but all cases result in a similar requirement for ROCK activity for optimal CXCL8 secretion. Furthermore, when confluent cells were compared to subconfluent cells, the level of TNF- or IL-1-stimulated CXCL8 secretion was greatly elevated with the subconfluent cells and inhibiting ROCK had no effect on CXCL8 secretion levels by the confluent cells. These experiments suggest that CXCL8 responses by confluent cells, which would model for intact, unwounded epithelial, do not involve ROCK activation. However, CXCL8 responses by subconfluent cells, which would model for cells attaching to and moving on ECM proteins in wounded epithelia, require ROCK activation for greatly elevated CXCL8 responses. These results provide a model to examine the important conditions which regulate chemokine production by EC in wounded epithelia.

Scar arcoidosis on 18F-FDG PET/CT.

18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is an important imaging modality in the clinical workup of patients with chronic inflammatory disorders which present quite often with a fever of unknown origin. Sarcoidosis is a multisystem chronic inflammatory disorder with a wide clinical spectrum that can involve different organs. The diagnosis of sarcoidosis is usually based on the observation of noncaseating granulomas in biopsy specimens and exclusion of other granulomatous diseases. Skin involvement can occur in 20-25% of sarcoidosis cases. However, scar involvement in sarcoidosis is a rare condition. Herein, we present a case of multisystem sarcoidosis in a 45-year-old woman, who was previously treated with steroids and was in remission for 8 months. The patient presented with multiple skin nodules on the chest and back, a history of intermittent fever, headache, and mild itching at the abdominal scar site for 3 months. Blood investigations revealed elevated serum angiotensin-converting enzyme levels. The 18F-FDG PET/CT revealed a metabolically active involvement of the cutaneous tissue (posthysterectomy scar), apart from other sites of involvement. Biopsy of the scar site revealed multiple epithelioid cell granulomas with giant cells surrounding the collagenous fibers of the scar tissue.

Nipah virus disease: A rare and intractable disease.

Nipah virus, an enveloped ribonucleic acid virus, has been a major cause of encephalitis out-breaks with high mortality, primarily in the Indo-Bangladesh regions. Except for the first outbreak in Malaysia-Singapore, which was related to contact with pigs and the outbreak in Philippines associated with horse slaughter, most other outbreaks have affected the Indo- Bangladesh regions. The Indo-Bangladesh outbreaks were associated with consumption of raw date palm sap contaminated by fruit bats and had a very high secondary attack rate. The patient usually presents with fever, encephalitis and/or respiratory involvement with or without thrombocytopenia, leukopenia and transaminitis. Diagnosis can be confirmed by isolation and nucleic acid amplification in the acute phase or antibody detection during the convalescent phase. Treatment is mostly limited to supportive care and syndromic management of acute encephalitis syndrome. Ribavirin, m102.4 monoclonal antibody and favipiravir are the only anti-virals with some activity against Nipah virus. Standard precautions, hand hygiene and personal protective equipments are the cornerstone of comprehensive infection prevention and control strategy. With the recent outbreaks affecting newer geographical areas, there is a need for physicians to be aware of this disease and keep abreast of its current detection and management strategies.