Isoniazid-induced pancreatitis: A systematic review.

BACKGROUND: Isoniazid-induced pancreatitis is a potentially serious adverse drug reaction, however, the frequency of its occurrence is unknown. We conducted a systematic review to explore this adverse drug reaction comprehensively. METHODS: We performed an advanced search in PubMed, Web of Science, Scopus, Ovid, and Embase for studies that reported isoniazid-induced pancreatitis. From the extracted data of eligible cases, we performed a descriptive analysis and a methodological risk of bias assessment using a standardized tool. RESULTS: We included 16 case reports from eight countries comprising 16 patients in our systematic review. Most of the isoniazid-induced pancreatitis cases were extrapulmonary tuberculosis cases. We found the mean age across all case reports was 36.7 years. In all the cases, discontinuation of isoniazid resulted in the resolution of pancreatitis. CONCLUSIONS: We found the latency period for isoniazid-induced pancreatitis to be ranged from 12 to 45 days after initiation of isoniazid therapy. A low threshold for screening of pancreatitis by measuring pancreatic enzymes in patients on isoniazid presenting with acute abdominal pain is recommended. This would facilitate an early diagnosis and discontinuation of isoniazid, thus reducing the severity of pancreatitis and preventing the complications of pancreatitis.

Antiapoptotic PON2 expression and its clinical implications in locally advanced oral squamous cell carcinoma.

Locally advanced oral squamous cell carcinoma poses a significant challenge in oncology due to its rising incidence and mortality rates. Despite therapeutic progress, understanding molecular intricacies is essential. This study explored the role of PON2, a multifunctional enzyme implicated in antiapoptotic mechanisms. Aberrant PON2 expression in oral cancers raises questions regarding its involvement in evading programmed cell death and treatment resistance. Patients with locally advanced disease were enrolled, and molecular analyses were undertaken on the collected tumor and normal tissues. Utilizing computational datasets, this study used in silico gene expression analysis, differential gene expression analysis in our patient cohort, survival analysis, and gene set enrichment analysis to unravel role of PON2 in disease prognosis. The results showed elevated PON2 levels in advanced tumor stages, correlating with factors such as tobacco exposure, higher tumor grade, and nodal metastasis. Survival analysis revealed prognostic relevance of PON2, with lower expression linked to extended survival rates. Gene set enrichment analysis identified pathways aiding in cancer metastasis influenced by PON2. This study underscores the significance of PON2 expression as a prognostic marker for oral malignancies, with increased expression associated with advanced disease stages. Understanding the molecular profile of the PON2 gene suggests its potential as a valuable biomarker for the management of cancer.

Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients.

BACKGROUND AND AIM: Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram. METHODS: A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions. RESULTS: Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models. CONCLUSION: Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine.

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.

Factors associated with dietary and exercise compliance among elderly with chronic conditions of hypertension and type 2 diabetes mellitus residing in rural areas of coastal Karnataka: A community-based cross-sectional study.

BACKGROUND: Compliance with diet, exercise regimen, and medication is vital to maintain an acceptable range of blood pressure and glycemic level among elderly with hypertension and diabetes mellitus. However, these are considered to be more challenging tasks among elderly. The aim of this study is to identify dietary and exercise compliance among elderly with hypertension and type 2 diabetes mellitus and to find its influencing factors. MATERIALS AND METHODS: The community-based survey was done in rural areas of five randomly selected clusters of primary health centers (PHC) using PPS sampling technique. After ethical clearance, a total of 360 consented participants residing in selected clusters were interviewed using pre-designed rating scale and questionnaire on dietary and exercise compliance, respectively. In this study, compliance refers to practicing prescribed diet and exercise regimen regularly by the elderly with HTN and T2DM. The data were analyzed using SPSS version 16.0. RESULTS: Eighty percent (n = 287) of study participants had moderate adherence to diet and only, 37.8% (n = 136) of them practice physical exercise. A Chi-square test report confirmed that there is a significant association (P < 0.05) between dietary compliance and level of education, occupation, family income, procurement of insurance, poor memory, multiple functional impairments, duration of hypertensive, and diabetes illness. Exercise compliance is influenced by factors such as gender, level of education, family income, and procurement of insurance (P < 0.05). CONCLUSION: Adherence to diet and exercise among elderly with chronic conditions are influenced by various socio-demographic or environmental, poor health or physiological and cognition or psychological factors.

Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high-risk factors in locally advanced oral squamous cell carcinoma.

BACKGROUND: PTGS2 encodes cyclooxygenase-2 (COX-2), which catalyses the committed step in prostaglandin synthesis. Various in vivo and in vitro data suggest that COX-2 mediates the VEGF signalling pathway. In silico analysis performed in TCGA, PanCancer Atlas for head and neck cancers, demonstrated significant expression and co-expression of PTGS2 and genes that regulate VEGF signalling. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma (OSCC). METHODOLOGY: Tumour and normal tissue samples were collected from patients with locally advanced OSCC. RNA was isolated from tissue samples, followed by cDNA synthesis. The cDNA was used for gene expression analysis (RT-PCR) using target-specific primers. The results obtained were compared with the in silico gene expression of the target genes in the TCGA datasets. Co-expression analysis was performed to establish an association between PTGS2 and VEGF signalling genes. RESULTS: Tumour and normal tissue samples were collected from 24 OSCC patients. Significant upregulation of PTGS2 expression was observed. Furthermore, VEGFA, KDR, CXCR1 and CXCR2 were significantly upregulated in tumour samples compared with paired normal samples, except for VEGFB, whose expression was not statistically significant. A similar expression pattern was observed in silico, except for CXCR2 which was highly expressed in the normal samples. Co-expression analysis showed a significant positive correlation between PTGS2 and VEGF signalling genes, except for VEGFB which showed a negative correlation. CONCLUSION: PTGS2 and VEGF signalling genes are upregulated in OSCC, which has a profound impact on clinical outcomes.

Developing mathematical models to compare and analyse the pharmacokinetics of morphine and fentanyl.

Background and Aims: The two-compartment model is generally used in pharmacokinetics to illustrate the distribution and excretion of drugs. In this study, we evaluated the distribution patterns of morphine and fentanyl by using a two-compartment model. Methods: Using numeric analysis techniques, non-linear ordinary differential equations were used to mathematically analyse drug distribution, transition, and concentration in the body compartments. Math Works, Inc., MATLAB, version 2023a, a programming tool, was used to characterise the impact of initial concentration and rate constants on the kinetics of the drug. For a definite therapeutic concentration of morphine and fentanyl in blood, pharmacokinetic characteristics were plotted. Results: The study results showed the time taken by morphine and fentanyl to reach a target concentration in the blood that is sufficient to generate the preferred therapeutic effects. The mathematical models comparing morphine and fentanyl pharmacokinetics showed that fentanyl reached the target therapeutic concentration 125 minutes earlier than morphine and was metabolised and removed from the body more rapidly (44 minutes earlier than morphine). Conclusion: These comparative mathematical models on morphine and fentanyl enable the determination of drug dosages and understanding of drug efficacy that facilitates optimising dosing regimens. The right choice between them can be made based on the time to reach the target therapeutic concentration in the blood, elimination time, severity of pain, and patient characteristics.

Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS: A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS: NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION: The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.

Circulating cell-free DNA as a diagnostic and prognostic marker for cervical cancer.

Circulating cell-free DNA (cfDNA) is a promising tool for liquid biopsy-based tests. cfDNA has been reported to help in the diagnosis, quantification of minimal residual disease, prognosis, and identification of mutations conferring resistance in various types of cancers. Cervical cancer is the fourth most common cancer among women worldwide. High-risk human papillomavirus (hr-HPV) infections have been associated with almost all cervical cancers. Lack of HPV vaccines in national vaccination programs and irregular screening strategies in nations with low or moderate levels of human development index have led to cervical cancer becoming the second leading cause of cancer mortality in women. As HPV integration and overexpression of E6/E7 oncoprotein are crucial steps in the development of cancer, HPV cfDNA could potentially be used as a specific biomarker for the detection of cervical cancer. Many studies have used HPV cfDNA and other gene mutations or mRNA expression profiles for diagnosis and disease surveillance in patients with cervical cancer at various stages of disease progression. In this review we present an overview of different studies discussing the utility of cfDNA in cervical cancer and summarize the evidence supporting its potential use in diagnosis and treatment monitoring.

Increased Gene Expression of C1orf74 Is Associated with Poor Prognosis in Cervical Cancer.

C1orf74, also known as URCL4, has been reported to have higher expression and be associated with poor prognosis in lung adenocarcinoma patients, and its role in regulation of the EGFR/AKT/mTORC1 pathway has been recently elucidated. In the current study, we used publicly available data and experimental validation of C1orf74 gene expression and its association with prognosis in cervical cancer patients. qRT-PCR was performed using RNA from cervical cancer cell lines and twenty-five cervical cancer patients. Data from TNMplot revealed that mRNA expression of the C1orf74 gene in primary tumor tissues, as well as metastatic tissues from cervical cancer patients, was significantly higher compared to normal cervical tissues. HPV-positive tumors had higher expression of this gene compared to HPV-negative tumors. qPCR analysis also demonstrated higher expression of C1orf74 in HPV-positive cervical cancer cell lines and most cervical cancer patients. The promoter methylation levels of the C1orf74 gene in cervical cancer tissues were lower compared to normal cervical tissues (p < 0.05). Collectively, our study indicates that higher expression of the C1orf74 gene caused by hypomethylation of its promoter is associated with poor overall survival in cervical cancer patients. Thus, C1orf74 is a novel prognostic marker in cervical cancer.

Lineage classification and antitubercular drug resistance surveillance of Mycobacterium tuberculosis by whole-genome sequencing in Southern India.

Whole-genome sequencing has created a revolution in tuberculosis management by providing a comprehensive picture of the various genetic polymorphisms with unprecedented accuracy. Studies mapping genomic heterogeneity in clinical isolates of Mycobacterium tuberculosis using a whole-genome sequencing approach from high tuberculosis burden countries are underrepresented. We report whole-genome sequencing results of 242 clinical isolates of culture-confirmed M. tuberculosis isolates from tuberculosis patients referred to a tertiary care hospital in Southern India. Phylogenetic analysis revealed that the isolates in our study belonged to five different lineages, with Indo-Oceanic (lineage 1, n = 122) and East-African Indian (lineage 3, n = 80) being the most prevalent. We report several mutations in genes conferring resistance to first and second line antitubercular drugs including the genes rpoB, katG, ahpC, inhA, fabG1, embB, pncA, rpsL, rrs, and gyrA. The majority of these mutations were identified in relatively high proportions in lineage 1. Our study highlights the utility of whole-genome sequencing as a potential supplemental tool to the existing genotypic and phenotypic methods, in providing expedited comprehensive surveillance of mutations that may be associated with antitubercular drug resistance as well as lineage characterization of M. tuberculosis isolates. Further larger-scale whole-genome datasets with linked minimum inhibition concentration testing are imperative for resolving the discrepancies between whole-genome sequencing and phenotypic drug sensitivity testing results and quantifying the level of the resistance associated with the mutations for optimization of antitubercular drug and precise dose selection in clinics. IMPORTANCE Studies mapping genetic heterogeneity of clinical isolates of M. tuberculosis for determining their strain lineage and drug resistance by whole-genome sequencing are limited in high tuberculosis burden settings. We carried out whole-genome sequencing of 242 M. tuberculosis isolates from drug-sensitive and drug-resistant tuberculosis patients, identified and collected as part of the TB Portals Program, to have a comprehensive insight into the genetic diversity of M. tuberculosis in Southern India. We report several genetic variations in M. tuberculosis that may confer resistance to antitubercular drugs. Further wide-scale efforts are required to fully characterize M. tuberculosis genetic diversity at a population level in high tuberculosis burden settings for providing precise tuberculosis treatment.

Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.

BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein. OBJECTIVE: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib. METHOD: A combined approach of molecular docking and ex vivo everted gut sac model was implemented to predict the potential of proton pump inhibitors i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place. RESULTS: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In ex vivo studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and ex vivo studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib. CONCLUSION: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.

Determinants of Medication Non-Adherence Among the Elderly with Co-Existing Hypertension and Type 2 Diabetes Mellitus in Rural Areas of Udupi District in Karnataka, India.

Purpose: Medication adherence is a crucial component in the management of elderly with co-morbid chronic conditions. Hence, this study aimed to investigate the determinants of medication non-adherence among rural elderly with co-morbid chronic conditions of hypertension (HTN) and type 2 diabetes mellitus (T2DM) in India. Patients and Methods: This cross-sectional study adopted the probability proportional to size (PPS) sampling technique to find the determinants of medication non-adherence among elderly residing in rural coverage areas of five randomly selected primary health centres (PHC) in Udupi district, Karnataka, India. A total of 360 elderly (72 samples from each cluster) who met the inclusion criteria and consented were interviewed using predesigned prevalidated and standardized or reliable tools. The data were coded and entered in SPSS version 16.0 and analyzed using both descriptive and inferential statistics. Results: The study found that 55.6% (n=200) of rural elderly with co-morbid conditions HTN and T2DM were non-adherent to their medications and established Spearman correlation coefficient rank (r) value between undesirable person-related factors (r=-0.444); good family support (including financial support) (r=0.185); poor accessibility to healthcare facility (r=-0.209); detrimental medication-related factors including high cost of medication (r=-0.237) were found to be significant at 0.05 level of confidence (p < 0.05). Further, the study depicted that the chi-square test (χ2) was identified to be significantly associated (p<0.05) with a variable such as education, knowledge, number of illnesses and impairments, vision, memory, and physical impairments. Conclusion: Medication adherence could be improved among rural elderly with co-morbid conditions by identifying and addressing the determinants at the earliest. Further, it is vital to identify the suitable intervention program to address these avoidable problems.

Genetic and Epigenetic Basis of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of postmarketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors, can contribute to development and progression of DILI. Studies on microRNA, histone modification, DNA methylation, and single nucleotide polymorphisms related to DILI were retrieved from databases and were analyzed for the current research and updated to develop this narrative review. We have compiled some of the major genetic, epigenetic, and pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolizing enzymes, HLA alleles, and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and on implementation of personalized medicine.

The association between micronutrient levels and diabetic foot ulcer: A systematic review with meta-analysis.

Background: Diabetic foot ulcers (DFU) are a major complication of diabetes mellitus (DM). Nutrient deficiencies are among the major risk factors in DFU development and healing. In this context, we aimed to investigate the possible association between micronutrient status and risk of DFU. Methods: A systematic review (Prospero registration: CRD42021259817) of articles, published in PubMed, Web of Science, Scopus, CINAHL Complete, and Embase, that measured the status of micronutrients in DFU patients was performed. Results: Thirty-seven studies were considered, of which thirty were included for meta-analysis. These studies reported levels of 11 micronutrients: vitamins B9, B12, C, D, E, calcium, magnesium, iron, selenium, copper, and zinc. DFU, compared to healthy controls (HC) had significantly lower vitamin D (MD: -10.82 14 ng/ml, 95% CI: -20.47, -1.16), magnesium (MD: -0.45 mg/dL, 95% CI: -0.78, -0.12) and selenium (MD: -0.33 µmol/L, 95% CI: -0.34, -0.32) levels. DFU, compared to DM patients without DFU, had significantly lower vitamin D (MD: -5.41 ng/ml, 95% CI: -8.06, -2.76), and magnesium (MD: -0.20 mg/dL, 95% CI: -0.25, -0.15) levels. The overall analysis showed lower levels of vitamin D [15.55ng/ml (95% CI:13.44, 17.65)], vitamin C [4.99µmol/L (95% CI:3.16, 6.83)], magnesium [1.53mg/dL (95% CI:1.28, 1.78)] and selenium [0.54µmol/L (95% CI:0.45, 0.64)]. Conclusion: This review provides evidence that micronutrient levels significantly differ in DFU patients, suggesting an association between micronutrient status and risk of DFU. Therefore, routine monitoring and supplementations are warranted in DFU patients. We suggest that personalized nutrition therapy may be considered in the DFU management guidelines. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=259817, identifier CRD42021259817.

Crizotinib induces Par-4 secretion from normal cells and GRP78 expression on the cancer cell surface for selective tumor growth inhibition.

Lung cancer is the leading cause of cancer-related deaths. Lung cancer cells develop resistance to apoptosis by suppressing the secretion of the tumor suppressor Par-4 protein (also known as PAWR) and/or down-modulating the Par-4 receptor GRP78 on the cell surface (csGRP78). We sought to identify FDA-approved drugs that elevate csGRP78 on the surface of lung cancer cells and induce Par-4 secretion from the cancer cells and/or normal cells in order to inhibit cancer growth in an autocrine or paracrine manner. In an unbiased screen, we identified crizotinib (CZT), an inhibitor of activated ALK/MET/ROS1 receptor tyrosine kinase, as an inducer of csGRP78 expression in ALK-negative, KRAS or EGFR mutant lung cancer cells. Elevation of csGRP78 in the lung cancer cells was dependent on activation of the non-receptor tyrosine kinase SRC by CZT. Inhibition of SRC activation in the cancer cells prevented csGRP78 translocation but promoted Par-4 secretion by CZT, implying that activated SRC prevented Par-4 secretion. In normal cells, CZT did not activate SRC and csGRP78 elevation but induced Par-4 secretion. Consequently, CZT induced Par-4 secretion from normal cells and elevated csGRP78 in the ALK-negative tumor cells to cause paracrine apoptosis in cancer cell cultures and growth inhibition of tumor xenografts in mice. Thus, CZT induces differential activation of SRC in normal and cancer cells to trigger the pro-apoptotic Par-4-GRP78 axis. As csGRP78 is a targetable receptor, CZT can be repurposed to elevate csGRP78 for inhibition of ALK-negative lung tumors.

Role and Clinical Significance of Monocarboxylate Transporter 8 (MCT8) During Pregnancy.

The review aims to summarize the available research focusing on the importance of monocarboxylate transporter (MCT8) in thyroid hormone trafficking across the placenta and fetal development. A systematic search was carried out in PubMed; studies available in English related to "monocarboxylate transporter", "adverse pregnancy", "fetal development," and "thyroid hormone" were identified and assessed. The references within the resulting articles were manually searched. MCT8 is a highly active and selective thyroid hormone transporter that facilitates the cellular uptake of triiodothyronine (T3), thyroxine (T4), reverse triiodothyronine (rT3), and diiodothyronine (T2) in different tissues. MCT8 is expressed in the placenta from the first trimester onwards, allowing the transport of thyroid hormone from mother to fetus. Mutations in MCT8 cause an X-linked disorder known as Allan-Herndon-Dudley syndrome (AHDS), characterized by severe psychomotor impairment and peripheral thyrotoxicosis. Hence, any maternal thyroid dysfunction may cause severe consequences for the fetus and newborn. Further research regarding MCT8 gene expression, polymorphic variation, and adverse pregnancy outcomes must be done to establish that MCT8 is a novel prognostic marker for the early detection of pregnancy-related complications.

Vitamin D attenuates biofilm-associated infections via immunomodulation and cathelicidin expression: a narrative review.

INTRODUCTION: Infections are becoming more difficult to treat, at least partly on account of microbes that produce biofilms. Reports suggest that decreased levels of antimicrobial peptides like cathelicidin, elevated levels of inflammatory cytokines, and biofilm formation are all associated with vitamin D deficiency, making vitamin D - deficient individuals more susceptible to infection. Infections attributable to biofilm-producing microbes can be managed by adjuvant therapy with vitamin D because of its immunomodulatory role, particularly because of the ability of vitamin D-pathway to induce the antimicrobial peptides like cathelicidin and decrease proinflammatory cytokines. AREAS COVERED: This narrative review covers biofilm formation, infections associated with biofilm due to vitamin D deficiency, putative role of vitamin D in host protection and the effect of vitamin D supplementation in biofilm-associated infections. A comprehensive literature search in PubMed and Google Scholar utilizing suitable keywords at multiple time points extracted relevant articles. EXPERT OPINION: Although vitamin D deficiency has been associated with infections by biofilm producing microbes, comprehensive clinical trials in various ethnicities are required to understand the likely relationships between vitamin D receptor gene expression, cathelicidin levels, and infection outcome. Current evidence hypothesizes that maintaining normal vitamin D level can help prevent and treat these infections.

Impact of tuberculosis disease on human gut microbiota: a systematic review.

INTRODUCTION: This systematic review evaluates the gut microbiota (GM) status in tuberculosis (TB) patients compared to healthy volunteers due to the disease or its treatment. AREAS COVERED: We conducted a systematic review of all articles published in PubMed, Web of Science, and Embase that assessed the impact of TB disease and anti-tubercular therapy (ATT) on GM from inception till January 2022 (Protocol registration number in PROSPERO: CRD42021261884). Regarding the microbial diversity indices and taxonomy, we found a significant difference in GM status between the TB and healthy control (HC) groups. We found an overabundance of Phylum Proteobacteria and depletion of some short-chain fatty acid-producing bacteria genera like Bifidobacteria, Roseburia, and Ruminococcus in the TB group. We found that ATT exacerbates the degree of dysbiosis caused by Mycobacteria tuberculosis disease. EXPERT OPINION: The modulation of GM in TB patients in clinical practice may serve as a promising target to reverse the dysbiosis caused. Moreover, this can optimistically change the TB treatment outcome. We expect that appropriate probiotic supplementation with antimycobacterial treatment during tuberculosis disease will help stabilize the GM throughout the treatment phase and protect the GM from dysbiosis.

Cefepime-induced Neurotoxicity: A Retrospective Cohort Study in a South-Indian Tertiary Healthcare Facility.

BACKGROUND: Cefepime is a fourth-generation cephalosporin with a broad spectrum coverage and anti-pseudomonal activity. The safety profile of cefepime was relatively favourable until neurotoxicity was first reported in 1999. Despite cefepime-induced neurotoxicity (CIN), it continues to be a principal part of parenteral treatment for various infections. OBJECTIVE: The study aimed to determine the incidence and risk factors for CIN compared to other antibiotics. METHODS: A retrospective cohort study was conducted involving 738 patients over eight months in Kasturba Medical College and Hospital, Manipal, India. Patients with cefepime were selected as study cohort (SC; n= 496), and other antibiotics were included in the reference cohort (RC; n=242). RESULTS: The results showed that 53 (10.7%) patients developed neurotoxicity in the SC, whereas 12 (5%) patients in the RC. A significant association was found between neurotoxicity and cefepime use (X2 =6.641; p=0.01). SC has a 2.29 times increased risk of neurotoxicity than RC (OR: 2.29; 95% CI: 1.2-4.38). Risk estimation showed that renal failure patients had a 5.5 times higher risk for CIN than non-renal failure patients (OR: 5.5; 95% CI: 2.98 - 10.17). CIN symptoms were disorientation (38.5%), loss of consciousness (23.1%), drowsiness (18.5%), etc. The calculated number needed to harm (NNH) for cefepime was 17.2. CONCLUSION: The study found a higher incidence of CIN compared to other antibiotics-induced neurotoxicity and a harmful association between cefepime use and CIN development. Besides, renal failure is a risk factor for CIN. Therefore, the study warrants the use of cefepime, where no other alternatives are available.