Emerging trends in antimicrobial resistance in bloodstream infections: multicentric longitudinal study in India (2017-2022).

Background: Antimicrobial resistance (AMR) has escalated to pandemic levels, posing a significant global health threat. This study examines the patterns and trends of AMR in Bloodstream Infections (BSIs) across India, aiming to inform better surveillance and intervention strategies. Methods: Six-year data from 21 tertiary care centers in the Indian Council of Medical Research's AMR Surveillance Network (IAMRSN) were retrospectively analyzed to estimate cluster-robust trends in resistance. Time-series analysis was used to discern lead/lag relationships between antibiotic pairs and the directional influence of resistance in community and hospital-acquired BSIs(CA/HA BSIs). A data-driven Bayesian network ensemble averaged over 301 bootstrap samples was modelled to uncover systemic associations between AMR and Sustainable Development Goals (SDGs). Findings: Our findings indicate significant (p < 0.001) monthly increases in Imipenem and Meropenem resistance for Klebsiella, E. coli, and Acinetobacter BSIs. Importantly, Carbapenem resistance in HA-BSIs preceded that in CA-BSIs for Klebsiella and Acinetobacter (p < 0.05). At a national level, Cefotaxime resistance emerged as a potential early indicator for emerging Carbapenem resistance, proposing a novel surveillance marker. In Klebsiella BSIs, states with higher achievement of SDG3 goals showed lower Imipenem resistance. A model-based AMR scorecard is introduced for focused interventions and continuous monitoring. Interpretation: The identified spatiotemporal trends and drug resistance associations offer critical insights for AMR surveillance aligning with WHO GLASS standards.The escalation of carbapenem resistance in BSIs demands vigilant monitoring and may be crucial for achieving SDGs by 2030. Implementing the proposed framework for data-driven evidence can help nations achieve proactive AMR surveillance. Funding: No specific funding was received for this analysis.

The BKCa (slo) channel regulates the cardiac function of Drosophila.

The large conductance, calcium, and voltage-active potassium channels (BKCa) were originally discovered in Drosophila melanogaster as slowpoke (slo). They are extensively characterized in fly models as ion channels for their roles in neurological and muscular function, as well as aging. BKCa is known to modulate cardiac rhythm and is localized to the mitochondria. Activation of mitochondrial BKCa causes cardioprotection from ischemia-reperfusion injury, possibly via modulating mitochondrial function in adult animal models. However, the role of BKCa in cardiac function is not well-characterized, partially due to its localization to the plasma membrane as well as intracellular membranes and the wide array of cells present in mammalian hearts. Here we demonstrate for the first time a direct role for BKCa in cardiac function and cardioprotection from IR injury using the Drosophila model system. We have also discovered that the BKCa channel plays a role in the functioning of aging hearts. Our study establishes the presence of BKCa in the fly heart and ascertains its role in aging heart function.

Molecular targeted therapies for cutaneous squamous cell carcinoma: recent developments and clinical implications.

Cutaneous Squamous Cell Carcinoma (cSCC) is a common and potentially fatal type of skin cancer that poses a significant threat to public health and has a high prevalence rate. Exposure to ultraviolet radiation on the skin surface increases the risk of cSCC, especially in those with genetic syndromes like xerodermapigmentosum and epidermolysis bullosa. Therefore, understanding the molecular pathogenesis of cSCC is critical for developing personalized treatment approaches that are effective in cSCC. This article provides a comprehensive overview of current knowledge of cSCC pathogenesis, emphasizing dysregulated signaling pathways and the significance of molecular profiling. Several limitations and challenges associated with conventional therapies, however, are identified, stressing the need for novel therapeutic strategies. The article further discusses molecular targets and therapeutic approaches, i.e., epidermal growth factor receptor inhibitors, hedgehog pathway inhibitors, and PI3K/AKT/mTOR pathway inhibitors, as well as emerging molecular targets and therapeutic agents. The manuscript explores resistance mechanisms to molecularly targeted therapies and proposes methods to overcome them, including combination strategies, rational design, and optimization. The clinical implications and patient outcomes of molecular-targeted treatments are assessed, including response rates and survival outcomes. The management of adverse events and toxicities in molecular-targeted therapies is crucial and requires careful monitoring and control. The paper further discusses future directions for therapeutic advancement and research in this area, as well as the difficulties and constraints associated with conventional therapies.

A case series of post-infectious chikungunya myeloradiculoneuropathy.

Chikungunya fever is an arboviral illness caused by chikungunya virus (CHIKV) and transmitted by the bite of Aedes aegypti and Aedes albopictus. It is an RNA virus belonging to the genus Alphavirus and family Togaviridae. We present a case series of three patients with chikungunya illness developing para/post-infectious myeloradiculoneuropathy.These patients developed neurological symptoms in the form of bilateral lower limb weakness with sensory and bowel involvement after the recovery from the initial acute episode of chikungunya fever. Clinical examination findings suggested myeloradiculoneuropathy with normal Magnetic Resonance Imaging of the Spine, with the nerve conduction study showing sensorimotor axonal polyneuropathy. All the patients were treated with 1 g of methylprednisolone once a day for five days, and case 2 was given intravenous immunoglobulin also. In the follow-up, cases 1 and 2 showed complete recovery without recurrence, and case 3 did not show improvement at one month.

Characterizing the Conformational Dynamics of Human SUMO2: Insights into its Interaction with Metal Ions and SIMs.

SUMO (Small Ubiquitin-like Modifiers) proteins are involved in a crucial post-translational modification commonly termed as SUMOylation. In this work, we have investigated the native-state conformational flexibility of human SUMO2 and its interaction with Cu2+ and Zn2+ ions using 15N-1H based 2D NMR spectroscopy. After SUMO1, SUMO2 is the most studied SUMO isoform in humans which shares 45 % and ~80 % similarity with SUMO1 in terms of sequence and structure, respectively. In this manuscript, we demonstrate that compared to SUMO1, several amino acids around the α1-helix region of SUMO2 access energetically similar near-native conformations. These conformations could play a crucial role in SUMO2's non-covalent interactions with SUMO interaction motifs (SIMs) on other proteins. The C-terminal of SUMO2 was found to bind strongly with Cu2+ ions resulting in a trimeric structure as observed by gel electrophoresis. This interaction seems to interfere in its non-covalent interaction with a V/I-x-V/I-V/I based SIM in Daxx protein.

Chloride ions in health and disease.

Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.

Molecular detection and characterization of prevailing Theileria equi genotype in equine from northern India.

Equine piroplasmosis caused by Theileria equi is a febrile, tick-borne disease of equids. However, there is limited literature about the genotyping of T. equi in India. Blood samples were collected from 202 horses and subjected to microscopy and PCR to detect T. equi. Initially, a universal screening primer pair targeting 18S ribosomal RNA genes common for Babesia caballi and T. equi was employed to amplify the DNA of both parasites. Thereafter additional primers were employed for species-specific detection resulting in amplification of approximately 435 bp specific for T. equi. T.equi was detected in 9.9% and 20.79% of horses screened by microscopy and PCR, respectively. The representative samples confirmed positive by PCR were sequenced, submitted to NCBI (OR651254, OR687254, OR685656, OR650830, OR650834), and used for genotype characterization and phylogenetic analysis. Employing Genetool and MEGA X software, the T. equi Indian isolates and across the globe were compared, and the results demonstrated 99.05-100% and 95.86-100% homologies, respectively. All the T. equi Indian isolates belonged to genotype A. Phylogeny based on the EMA-1 gene of five isolates (OR731831, OR731833, OR731829, OR731830, OR731832) were also characterized by sequencing and support the previous findings. Genotypes C and D, as well as genotypes B and E, exhibited lower levels of evolutionary divergence compared to other genotypes. The EMA-1 gene exhibited limited diversity and might not be the most suitable target for assessing variability within T. equi populations. The findings also reveal a significant association (p < 0.01) between T. equi infection and the presence of ticks.

Pneumothorax Secondary to a Traumatic Brazilian Jiu-Jitsu Injury.

A pneumothorax is a medical condition characterized by the presence of free air in the pleural cavity. Pneumothorax can be classified as spontaneous, traumatic, or iatrogenic. Spontaneous pneumothorax sustained from a jiu-jitsu-induced blunt trauma has not been described in any sports literature. This case report involves a 26-year-old male athlete who presented to the emergency room complaining of right-sided chest pain in the recumbent position and shortness of breath upon exertion. Breath sounds were diminished on the right with hyper resonance to percussion. Inspection of the chest revealed diffuse erythema on the right side. A chest X-ray revealed a right tension pneumothorax that was treated with a 20-French chest tube. This report aims to highlight the importance of recognizing the possibility of pneumothorax in jiu-jitsu athletes, implementing early treatment, and exploring potential causes of pneumothorax in otherwise healthy individuals.

Unusual Sites of Visceral Spread in Prostate Cancer: A Prostate-Specific Membrane Antigen-Based Theranostic Imaging Series.

ABSTRACT: Prostate cancer commonly metastasizes to lymphatic and skeletal systems with lesser frequency to visceral organs; however, uncommon visceral sites have also been found and reported as case reports. We present a series of uncommon metastatic visceral spread in prostate cancer on prostate-specific membrane antigen-based diagnostic and posttherapeutic imaging modalities.

In silico approach for the identification of tRNA-derived small non-coding RNAs in SARS-CoV infection.

tsRNAs (tRNA-derived small non-coding RNAs), including tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been implicated in some viral infections, such as respiratory viral infections. However, their involvement in SARS-CoV infection is completely unknown. A comprehensive analysis was performed to determine tsRNA populations in a mouse model of SARS-CoV-infected samples containing the wild-type and attenuated viruses. Data from the Gene Expression Omnibus (GEO) dataset at NCBI (accession ID GSE90624 ) was used for this study. A count matrix was generated for the tRNAs. Differentially expressed tRNAs, followed by tsRNAs derived from each significant tRNAs at different conditions and time points between the two groups WT(SARS-CoV-MA15-WT) vs Mock and ΔE (SARS-CoV-MA15-ΔE) vs Mock were identified. Notably, significantly differentially expressed tRNAs at 2dpi but not at 4dpi. The tsRNAs originating from differentially expressed tRNAs across all the samples belonging to each condition (WT, ΔE, and Mock) were identified. Intriguingly, tRFs (tRNA-derived RNA fragments) exhibited higher levels compared to tiRNAs (tRNA-derived stress-induced RNAs) across all samples associated with WT SARS-CoV strain compared to ΔE and mock-infected samples. This discrepancy suggests a non-random formation of tsRNAs, hinting at a possible involvement of tsRNAs in SARS-CoV viral infection.

Behind the wheel: Probing into personality, skills, and driving behavior's role in bus rapid transit crashes.

OBJECTIVE: Personality traits and driving skills are significantly associated with driving behaviors and crashes. In the case of professional bus drivers, the relationships amongst these variables have not been sufficiently examined in terms of road crashes. Therefore, this study seeks to examine the relationship between personality traits, driving skills, driving behaviors, and crash involvement among Bus Rapid Transit (BRT) drivers. METHODS: The study employed a comprehensive data collection strategy involving self-reported questionnaires, including the driver behavior questionnaire, driver skill inventory, and Big Five inventory, alongside Global Positioning System (GPS)-extracted speeding data from a sample of 166 drivers. To explore the relationship between variables, the study utilized the Partial Least Squares Structural Equation Model (PLS-SEM) as the analytical method. RESULT: The findings reveal that self-reported violations and actual speeding performed by drivers were positively associated with crash involvement, whereas positive driving behavior negatively influences violation, errors, speeding and crash involvement. The study also found that the safety skills were negatively associated with violations, errors, and speeding, while higher perceptual-motor skills were associated with higher instances of speeding violations, resulting to a higher possibility of getting involved in a crash. Finally, the study reveals that certain personality traits (extraversion and neuroticism) were positively associated with violations, errors, and speeding, leading to a higher risk of getting involved in crashes, whereas certain personality traits (conscientiousness and agreeableness) were associated with safe driving. CONCLUSION: The study findings offer valuable insights into the predictors of crashes among professional BRT drivers, which can be used to enhance driving practices, ensuring the safety of the public. Moreover, these findings provide transportation agencies with better management and decision-making capabilities to implement effective interventions to improve road safety.

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.

Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of antimalarial drug resistant strains of Plasmodium falciparum. Heat shock proteins (HSPs), particularly P. falciparum HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages. Despite structural similarities between human and malarial HSPs posing challenges, there is substantial evidence for subtle differences that could be exploited for selective drug targeting. This review provides an update on the potential of targeting various PfHSP families (particularly PfHSP40, PfHSP70, and PfHSP90) and their interactions within PfHSP complexes as a strategy to develop new antimalarial drugs. In addition, the need for a deeper understanding of the role of HSP complexes at the host-parasite interface is highlighted, especially heterologous partnerships between human and malarial HSPs, as this opens novel opportunities for targeting protein-protein interactions crucial for malaria parasite survival and pathogenesis.

Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis.

BACKGROUND: Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). METHODS: To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). FINDINGS: A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). INTERPRETATION: Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. FUNDING: US Food and Drug Administration.

Unravelling the link between SARS-CoV-2 mutation frequencies, patient comorbidities, and structural dynamics.

Genomic surveillance is crucial for tracking emergence and spread of novel variants of pathogens, such as SARS-CoV-2, to inform public health interventions and to enforce control measures. However, in some settings especially in low- and middle- income counties, where sequencing platforms are limited, only certain patients get to be selected for sequencing surveillance. Here, we show that patients with multiple comorbidities potentially harbour SARS-CoV-2 with higher mutation rates and thus deserve more attention for genomic surveillance. The relationship between the patient comorbidities, and type of amino acid mutations was assessed. Correlation analysis showed that there was a significant tendency for mutations to occur within the ORF1a region for patients with higher number of comorbidities. Frequency analysis of the amino acid substitution within ORF1a showed that nsp3 P822L of the PLpro protease was one of the highest occurring mutations. Using molecular dynamics, we simulated that the P822L mutation in PLpro represents a system with lower Root Mean Square Deviation (RMSD) fluctuations, and consistent Radius of gyration (Rg), Solvent Accessible Surface Area (SASA) values-indicate a much stabler protein than the wildtype. The outcome of this study will help determine the relationship between the clinical status of a patient and the mutations of the infecting SARS-CoV-2 virus.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2 , hospitalized and received supplemental O2 , admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.