Molecular insights into STAT1a protein in rohu (Labeo rohita): unveiling expression profiles, SRC homology domain recognition, and protein-protein interactions triggered by poly I: C.

Introduction: STAT1a is an essential signal transduction protein involved in the interferon pathway, playing a vital role in IFN-alpha/beta and gamma signaling. Limited information is available about the STAT protein in fish, particularly in Indian major carps (IMC). This study aimed to identify and characterize the STAT1a protein in Labeo rohita (LrSTAT1a). Methods: The full-length CDS of LrSTAT1a transcript was identified and sequenced. Phylogenetic analyses were performed based on the nucleotide sequences. The in-vivo immune stimulant poly I: C was used to treat various tissues, and the expression of LrSTAT1a was determined using quantitative real-time polymerase chain reaction (qRT-PCR). A 3D model of the STAT1a protein was generated using close structure homologs available in the database and checked using molecular dynamics (MD) simulations. Results: The full-length CDS of Labeo rohita STAT1a (LrSTAT1a) transcript consisted of 3238 bp that encoded a polypeptide of 721 amino acids sequence was identified. Phylogenetic analyses were performed based on the nucleotide sequences. Based on our findings, other vertebrates share a high degree of conservation with STAT1a. Additionally, we report that the in vivo immune stimulant poly I: C treatment of various tissues resulted in the expression of LrSTAT1a as determined by quantitative real-time polymerase chain reaction (qRT-PCR). In the current investigation, treatment with poly I: C dramatically increased the expression of LrSTAT1a in nearly every organ and tissue, with the brain, muscle, kidney, and intestine showing the highest levels of expression compared to the control. We made a 3D model of the STAT1a protein by using close structure homologs that were already available in the database. The model was then checked using molecular dynamics (MD) simulations. Consistent with previous research, the MD study highlighted the significance of the STAT1a protein, which is responsible for Src homology 2 (SH2) recognition. An important H-bonding that successfully retains SH2 inside the STAT1a binding cavity was determined to be formed by the conserved residues SER107, GLN530, SER583, LYS584, MET103, and ALA106. Discussion: This study provides molecular insights into the STAT1a protein in Rohu (Labeo rohita) and highlights the potential role of STAT1a in the innate immune response in fish. The high degree of conservation of STAT1a among other vertebrates suggests its crucial role in the immune response. The in-vivo immune stimulation results indicate that STAT1a is involved in the immune response in various tissues, with the brain, muscle, kidney, and intestine being the most responsive. The 3D model and MD study provide further evidence of the significance of STAT1a in the immune response, specifically in SH2 recognition. Further research is necessary to understand the specific mechanisms involved in the IFN pathway and the role of STAT1a in the immune response of IMC.

Mammalian cell expressed recombinant trimeric spike protein is a potent vaccine antigen and confers near-complete protection against SARS-CoV-2 infection in Hamster.

Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist. The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses. Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited. In our study, we engineered a recombinant prefusion-stabilized trimeric spike protein antigen, IMT-CVAX, encoded by the IMT-C20 gene. This antigen was expressed utilizing a suspension mammalian cell line (CHO-S). The establishment of a stable cell line expressing IMT-CVAX involved the integration of the gene into the CHO genome, followed by the expression, purification, and characterization of the protein. To gauge the vaccine potential of adjuvanted IMT-CVAX, we conducted assessments in small animals. Analyses of blood collected from immunized animals included measurements of anti-spike IgG, SARS-CoV-2 neutralization, and responses from GC-B and Tfh cells. Furthermore, the protective efficacy of IMT-CVAX was evaluated using a Hamster challenge model. Our findings indicate that adjuvanted IMT-CVAX elicits an excellent immune response in both mice and hamsters. Notably, sera from animals immunized with IMT-CVAX effectively neutralize a diverse range of SARS-CoV-2 variants. Moreover, IMT-CVAX immunization conferred complete protection to hamsters against SARS-CoV-2 infection. In hACE2 transgenic mice, IMT-CVAX vaccination induced a robust response from GC-B and Tfh cells. Based on our preclinical model assessments, adjuvanted IMT-CVAX emerges as a highly efficacious vaccine candidate. This protein-subunit-based vaccine exhibits promise for clinical development, offering an affordable solution for both primary and heterologous immunization against SARS-CoV-2 variants.

Tf2O-mediated [4+2]-annulation of anthranils with 2-chloropyridines: enabling access to pyridoquinazolinones and euxylophoricine B.

We present an efficient approach for synthesizing pyridoquinazolinones in the presence of triflic anhydride utilizing anthranils and 2-chloropyridines as starting materials. In this process, Tf2O initially activates anthranils forming an electrophilic 1-((trifluoromethyl)sulfonyl)benzo[c]isoxazol-1-ium species. This species undergoes an in situ annulation reaction with 2-chloropyridines, resulting in therapeutically useful pyridoquinazolinones. The reaction is tolerant to various functional groups, allowing access to a wide range of substituted pyridoquinazolinones in good yields. Furthermore, the synthesis of euxylophoricine B, known to be an antitumor agent, was also achieved.

Incidence and risk factors associated with surgical site infection in acetabular fracture patients: An experience from north India.

Introduction: Nearly 5-7% of patients undergoing surgical management of acetabular fractures develop surgical site infection (SSI) which is one of the most important factors affecting the hospital stay, success of procedure and overall patient satisfaction. Systematic studies to identify the risk factors and their control could help to reduce the surgical site infection rate considerably. The present study assessed the incidence and risk factors related with SSI in patients undergoing surgical management of acetabular fractures at our center. Methods and materials: This retrospective record review included a total of 228 adult acetabular fracture patients (≥18 years) who were managed surgically. Demographic and clinical profile of the patients was noted and cases developing SSI. Univariate and multivariate association of different demographic and clinical factors was done to identify factors significantly associated with SSI. Univariate analysis was done using chi-square test. Multivariate assessment was done using binary logistic regression. Results: Mean age of patients was 36.40 ± 14.18 years. Majority of patients were males (83.8 %). Incidence of SSI was 6.1 %. On univariate analysis, age ≥40 years, occupation service/business, fall from height, BMI >25 kg/m2, presence of associated injury, ≥48 h gap between injury and surgery, smoking and use of Kocher-Langenbeck approach for surgery were found to be significantly associated with an increased risk of SSI. However, on multivariate analysis only age >40 years (OR = 3.72; 95 % CI = 1.00-3.75; p = 0.049) and BMI>25.0 kg/m2 (OR = 0.20; 95 % CI = 0.05-0.85; p = 0.029) were the significant predictors of SSI. Conclusions: This study identified that surgical site infection rates show a secular stagnating trend. There were almost no modifiable risk factors that could reduce this incidence, however, a strict post-operative care in patients with age >40 years and BMI>25 kg/m2 could help to change the direction of these trends.

Innovations in detecting skull fractures: A review of computer-aided techniques in CT imaging.

BACKGROUND/INTRODUCTION: Traumatic brain injury (TBI) remains a leading cause of disability and mortality, with skull fractures being a frequent and serious consequence. Accurate and rapid diagnosis of these fractures is crucial, yet current manual methods via cranial CT scans are time-consuming and prone to error. METHODS: This review paper focuses on the evolution of computer-aided diagnosis (CAD) systems for detecting skull fractures in TBI patients. It critically assesses advancements from feature-based algorithms to modern machine learning and deep learning techniques. We examine current approaches to data acquisition, the use of public datasets, algorithmic strategies, and performance metrics RESULTS: The review highlights the potential of CAD systems to provide quick and reliable diagnostics, particularly outside regular clinical hours and in under-resourced settings. Our discussion encapsulates the challenges inherent in automated skull fracture assessment and suggests directions for future research to enhance diagnostic accuracy and patient care. CONCLUSION: With CAD systems, we stand on the cusp of significantly improving TBI management, underscoring the need for continued innovation in this field.

Structure-based screening of FDA-approved drugs identifies potential histone deacetylase 3 repurposed inhibitor: molecular docking and molecular dynamic simulation approaches.

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.

Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

Orientia tsutsugamushi: An Unusual Intracellular Bacteria-Adaptation Strategies, Available Antibiotics, and Alternatives for Treatment.

During evolution Orientia tsutsugamushi became a smarter obligate bacterium to establish as intracellular pathogens. O. tsutsugamushi is a human pathogenic bacterium responsible for 1 billion infections of scrub typhus. Several novel mechanisms make this bacterium unique (cell wall, genetic constitutions, secretion system, etc.). In 2007, O. tsutsugamushi Boryong was pioneer strain for whole-genome sequencing. But the fundamental biology of this bacterial cell is a mystery till date. The unusual biology makes this organism as model for host cell interaction. Only a few antibiotics are effective against this intracellular pathogen but emergence of less susceptibility toward antibiotics make the situation alarming. The review was captivated to highlight the unusual aspects of adaptation, antibiotics, and drugs beyond antibiotics.

KLF5 inhibition initiates epithelial-mesenchymal transition in non-transformed human squamous epithelial cells.

The transcriptional regulator Krüppel-like factor 5 (KLF5) is highly expressed in squamous epithelial cells of the esophagus. Increased KLF5 activity induces tumorigenesis and promotes metastasis in several cancers, although this function appears to be context-dependent. Here, we demonstrate that acute KLF5 inhibition, both genetically and with the potent KLF5 inhibitor ML264, causes non-transformed human primary esophageal squamous epithelial cells to enter the epithelial to mesenchymal transition (EMT). Moreover, chronic KLF5 inhibition with ML264 leads to the development of cells with a mesenchymal phenotype characterized by the expression of mesenchymal markers and functionally by reduced cell growth and increased migration and cellular invasion. This EMT resulting from chronic KLF5 inhibition is not driven by ß-Catenin or TGF-ß signaling. Pharmacologically, ML264 inhibits KLF5 by promoting proteasomal-mediated degradation. Taken together, we demonstrate that reduced KLF5 activity reprograms epithelial cells towards a mesenchymal phenotype and enhances their migratory and invasive potential. These findings have potential implications not only for esophageal cancers but also for normal processes such as esophageal tissue repair following injury.

An unprecedented roll-off ratio in high-performing red TADF OLED emitters featuring 2,3-indole-annulated naphthalene imide and auxiliary donors.

The capability of organic emitters to harvest triplet excitons via a thermally activated delayed fluorescence (TADF) process has opened a new era in organic optoelectronics. Nevertheless, low brightness, and consequently an insufficient roll-off ratio, constitutes a bottleneck for their practical applications in the domain of organic light-emitting diodes (OLEDs). To address this formidable challenge, we developed a new design of desymmetrized naphthalimide (NMI) featuring an annulated indole with a set of auxiliary donors on its periphery. Their perpendicular arrangement led to minimized HOMO-LUMO overlap, resulting in a low energy gap (ΔE ST = 0.05-0.015 eV) and efficient TADF emission with a photoluminescence quantum yield (PLQY) ranging from 82.8% to 95.3%. Notably, the entire set of dyes (NMI-Ind-TBCBz, NMI-Ind-DMAc, NMI-Ind-PXZ, and NMI-Ind-PTZ) was utilized to fabricate TADF OLED devices, exhibiting yellow to red electroluminescence. Among them, red-emissive NMI-Ind-PTZ, containing phenothiazine as an electron-rich component, revealed predominant performance with a maximum external quantum efficiency (EQE) of 23.6%, accompanied by a persistent luminance of 38 000 cd m-2. This results in a unique roll-off ratio (EQE10 000 = 21.6%), delineating a straightforward path for their commercial use in lighting and display technologies.

Study of Oral Hypoglycemic Agent-induced Hypoglycemia in Type 2 Diabetes Mellitus in a Tertiary Care Center.

INTRODUCTION: Diabetes prevalence is increasing rapidly; estimates from the International Diabetes Federation put the number at 381 million people have diabetes. Hypoglycemia is a commonly encountered complication in diabetic patients, which, in the short-term, can lead to mortality and, in the long-term, precludes maintenance of euglycemic control. Over 65.2 % of patients have reported at least one incidence of severe and nonsevere hypoglycemia when on oral hypoglycemic agents (OHA) at an annual crude incidence density of 35.1 events per year per person. Insulin more commonly causes hypoglycemia than OHA. However, this study was done with the aim of studying the hypoglycemia specifically caused by OHAs-clinical profile of patients, medications causing hypoglycemia, and the outcome. MATERIALS AND METHODS: This prospective observational study was conducted in the Department of Medicine at a tertiary care hospital in Western Maharashtra. Data was collected over a period of 18 months from Indoor patients on admission having hypoglycemic symptoms with strip blood sugar levels of <70 and on OHAs. Patients on insulin were excluded from the study. RESULTS: There were 60 patients with hypoglycemia with a mean age of 53.65 years and a higher incidence of hypoglycemia in females, 35 (58.3%) compared to males. There was a statistically significant difference between outcome (i.e., discharged or death) and urine protein-creatinine ratio (UPCR), a deranged liver function, that is, serum albumin, serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase, and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (p < 0.05). However, there was no statistically significant difference between outcome (discharged or death) and mean age, gender, mean duration of diabetes mellitus (DM), GCS scoring, and drug type of study subjects (p > 0.05). CONCLUSION: The risk factors for hypoglycemia were middle-aged patients. Females are at higher risk of hypoglycemia than men. Hypoglycemia due to OHAs is known to have a recurrence of hypoglycemia due to the long half-life of the drug; however, patients who were hospitalized were well monitored and did not have any recurrence of hypoglycemia. Deranged liver function or raised UPCR have high mortality after OHA-induced hypoglycemia.

Long-term Outcome of Coronavirus Disease-associated Mucormycosis: 1-year Follow-up Study from India.

IMPORTANCE: Invasive fungal infections have recently become a public health problem, particularly in India following the second wave of coronavirus disease 2019 (COVID-19). India harbors the world's largest population of patients suffering from diabetes. What prompted the sudden spike of mucormycosis infections in the COVID pandemic needs investigation. OBJECTIVE: To determine if COVID-19 infection prompted the spike in invasive fungal infections in diabetic population. To determine the long-term outcome of COVID-associated mucormycosis. To determine if COVID-19 infection causes diabetes mellitus transiently. DESIGN: The study was a prospective cohort study comprising patients suffering from mucormycosis. The study was planned from 20 May 2021, until 30 November 2022, to investigate the long-term follow-up (1 year) of mucormycosis patients. SETTING: The study setting was a referral hospital. PARTICIPANTS: All the consecutive patients admitted to this hospital for treatment of mucormycosis were included in the study who consented to it. Intervention(s) (for clinical trials) or exposure(s) (for observational studies): All patients suffering with mucormycosis underwent treatment at this hospital with surgery and injectable systemic antifungal drugs alongside diabetes management. MAIN OUTCOME(S) AND MEASURE(S): Primary outcome measurement was in the form of survival with cure of mucormycosis. Hypothesis being tested was formulated during data collection. RESULTS: The data of 98 participants was collected, but analysis was done after excluding the case of cutaneous mucormycosis (infant patient). Mean age for patients was 55.5 years, varying from 28 to 88 years. In our study, 63.3% of patients with mucormycosis were males and 37.8% were females, of which 55.7% (34) and 58.3% (21) were known diabetics, respectively. Previous history of diabetes mellitus was identified as an underlying comorbid condition in 56.7% of patients, while the rest were diagnosed with new-onset diabetes mellitus. Sugar levels ranged (on admission) from 112 to 494 mg/dL (median 212 mg/dL) for known diabetics and from 132 to 356 mg/dL (median 204 mg/dL) for newly diagnosed diabetics. Other comorbidities included hypertension (19.5%), ischemic heart disease (8.2%), chronic renal illness (3.09%), and one case (1.03%) of postoperative renal cell carcinoma (disease-free). The majority of cases (91.8%) were not vaccinated for COVID-19, while only two patients reported a history of vaccination with two doses, and six others had received only a single dose. At the 1-year follow-up, 57.7% of cases were disease-free, 30.9% had expired, and 11.3% were lost to follow-up. The mean glycated hemoglobin (HbA1c) at the time of admission was found to be statistically significant when compared between known diabetics and newly diagnosed ones [confidence interval (CI)-95%, p ≤ 0.01]. A total of seven patients from the newly diagnosed diabetic group no longer required medicines for diabetes at the end of 1 year (CI-95%, p ≤ 0.01). CONCLUSIONS AND RELEVANCE: Diabetes mellitus, particularly with poor glycemic control, was the single most important factor associated with and predictor of outcome. Contrary to the popular hypothesis, industrial oxygen and oxygen masks were not the reasons for the mucormycosis pandemic. Additionally, immunization against COVID provided protection not only from severe COVID but also from COVID-associated mucormycosis. It is recommended that patients with mucormycosis be followed for longer periods as a few patients could be suffering from transient diabetes, particularly against the backdrop of a pandemic.

Computational Screening of Repurposed Drugs for HMG-CoA Synthase 2 in Alzheimer's Disease.

Background: HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-ß protein precursor (AßPP) in mitochondria implicates a potential involvement in Alzheimer's disease (AD) pathophysiology. Objective: Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against 'HMGCS2', we present new in-silico insight into structure-based drug repurposing. Results: The initial molecules were screened for their binding affinity to HMGCS2. Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone. Conclusions: The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer's drug development.

ERK3 is involved in regulating cardiac fibroblast function.

ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3+/- than TAC-ERK3+/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3+/- hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and "activated" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-ß-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.

Novel Self-assembling Supramolecular Phenanthro[9,10-a]phenazine Discotic Liquid Crystals: Synthesis, Characterization and Charge Transport Studies.

The incorporation of heteroatoms in the chemical structure of organic molecules has been identified as analogous to the doping process adopted in silicon semiconductors to influence the nature of charge carriers. This strategy has been an eye-opener for material chemists in synthesizing new materials for optoelectronic applications. Phenanthro[9,10-a]phenazine-based mesogens have been synthesized via a cyclo-condensation pathway involving triphenylene-based diketones and o-phenyl diamines. The incorporation of phenazine moiety as discussed in this paper, alters the symmetric nature of the triphenylene. The phenanthro[9,10-a]phenazine-based mesogens exhibited hole mobility in the order of 10-4 cm2/Vs as measured by the space-charge limited current (SCLC) technique. The current density in SCLC device increases with increasing temperature which indicates that the charge transport is associated with the thermally activated hopping process. This report attempts to elucidate the self-organization of asymmetric phenanthro[9,10-a] phenazine in the supramolecular liquid crystalline state and their potential for the fabrication of high-temperature optoelectronic devices. However, the low charge carrier mobility can be one of the challenges for device performance.

A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants.

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18-55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021).

Study of the Practice of Surgical Antibiotic Prophylaxis Use for Elective Neurosurgical Cases in a Tertiary Hospital and Understanding the Rationale.

BACKGROUND: This study aims to evaluate the adherence to surgical antibiotic prophylaxis (SAP) guidelines in elective neurosurgery and assess the impact on surgical site infection (SSI) rates in a tertiary teaching hospital in Malaysia. METHOD: A retrospective review was conducted on patients who underwent elective neurosurgical procedures from January 1, 2021, to December 31, 2021, in a 1600-bed tertiary teaching hospital. The study assessed adherence to national and hospital SAP guidelines, focusing on the choice of antibiotic, dosage, timing, and duration. Additionally, a survey was conducted among neurosurgeons to evaluate their knowledge, attitudes and practices (KAP) regarding SAP. RESULT: Out of 202 patients included, there was a 99% compliance rate with antibiotic choice and 69.8% with the antibiotic duration. The SSI rate was identified at 6.4%. The KAP survey highlighted a strong awareness of SAP guidelines among surgeons, albeit with variations in practice, particularly in antibiotic duration and choice of antibiotics. CONCLUSION: While there is high adherence to the correct choice of antibiotic for SAP in elective neurosurgery, there are gaps in compliance with the recommended duration of antibiotic use. The study highlights the need for targeted interventions to improve adherence to SAP guidelines, which could potentially reduce the incidence of SSI in neurosurgery. Ongoing education and auditing are essential to optimize SAP practices and enhance patient outcomes in neurosurgery.

The Unusual Adverse Effects of Antituberculosis Therapy in Kidney Patients.

BACKGROUND: Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions. METHODS: We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022. RESULTS: We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases. CONCLUSION: The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.

Antiproliferative effect of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues on IL-6 mediated STAT3 and role of the apoptotic pathway in albino Wistar rats of ethyl carbamate-induced lung carcinoma: In-silico, In-vitro, and In-vivo study.

Lung cancer (LC) ranks second most prevalent cancer in females after breast cancer and second in males after prostate cancer. Based on the GLOBOCAN 2020 report, India represented 5.9% of LC cases and 8.1% of deaths caused by the disease. Several clinical studies have shown that LC occurs because of biological and morphological abnormalities and the involvement of altered level of antioxidants, cytokines, and apoptotic markers. In the present study, we explored the antiproliferative activity of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues against LC using in-vitro, in-silico, and in-vivo models. In-vitro screening against A549 cells revealed compounds 9B (8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) and 12B (5-(4-chlorophenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) as potential pyrimidine analogues against LC. Compounds 9B and 12B were docked with different molecular targets IL-6, Cyt-C, Caspase9, and Caspase3 using AutoDock Vina 4.1 to evaluate the binding affinity. Subsequently, in-vivo studies were conducted in albino Wistar rats through ethyl-carbamate (EC)- induced LC. 9B and 12B imparted significant effects on physiological (weight variation), and biochemical (anti-oxidant [TBAR's, SOD, ProC, and GSH), lipid (TC, TG, LDL, VLDL, and HDL)], and cytokine (IL-2, IL-6, IL-10, and IL-1ß) markers in EC-induced LC in albino Wistar rats. Morphological examination (SEM and H&E) and western blotting (IL-6, STAT3, Cyt-C, BAX, Bcl-2, Caspase3, and caspase9) showed that compounds 9B and 12B had antiproliferative effects. Accordingly, from the in-vitro, in-silico, and in-vivo experimental findings, we concluded that 9B and 12B have significant antiproliferative potential and are potential candidates for further evaluation to meet the requirements of investigation of new drug application.

Mucoadhesive Microspheres: A Promising Delivery System for Helicobacter Pylori (H. pylori) Treatment.

A major worldwide health problem, Helicobacter Pylori (H. pylori) infection is associated with a number of gastrointestinal disorders, such as gastric cancer and peptic ulcers. The shortcomings of traditional treatment plans often include adverse effects, low patient compliance, and the emergence of antibiotic resistance. Investigating different delivery methods is thus necessary to improve the effectiveness of treatment. Mucoadhesive microspheres show promise as a method for delivering anti H. pylori drugs in a targeted and sustained manner. With their ability to stick to the stomach mucosa, these microspheres increase the local concentration of the medication and guarantee a more thorough removal of the pathogen. The potential of Mucoadhesive microspheres in the management of H. pylori infection is examined in this review. We explore the properties and benefits of Mucoadhesive polymers, the production techniques for microspheres, and the variables affecting their functionality. To provide a thorough grasp of this delivery system, a variety of drug-loading strategies, release mechanisms, and in vitro and in vivo assessment methodologies are covered. The potential of Mucoadhesive microspheres to overcome the drawbacks of traditional therapy is shown by highlighting recent developments in their formulation and their therapeutic consequences. Mucoadhesive microspheres constitute an important advancement in the treatment of Helicobacter pylori because they guarantee a regulated release of antibiotics and improve medication absorption at the site of infection. In order to fully appreciate the advantages of this novel delivery method, further study is necessary. Future research paths and the difficulties in the clinical translation of this technology are also discussed.