LC-Orbitrap HRMS-Based Proteomics Reveals Novel Mitochondrial Dynamics Regulatory Proteins Associated with RasV12-Induced Glioblastoma (GBM) of Drosophila.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor found in adult humans with a poor prognosis and average survival of 14-15 months. In order to have a comprehensive understanding of proteome and identify novel therapeutic targets, this study focused mainly on the differentially abundant proteins (DAPs) of RasV12-induced GBM. RasV12 is a constitutively active Ras mutant form essential for tumor progression by continuously activating signaling pathways leading to uncontrolled tumor growth. This study used a transgenic Drosophila model with RasV12 overexpression using the repo-GAL4 driver line, specifically in glial cells, to study GBM. The high-resolution mass spectrometry (HRMS)-based proteomic analysis of the GBM larval central nervous system identified three novel DAPs specific to mitochondria. These DAPs, probable maleylacetoacetate isomerase 2 (Q9VHD2), bifunctional methylene tetrahydrofolate dehydrogenase (Q04448), and glutamine synthetase1 (P20477), identified through HRMS were further validated by qRT-PCR. The protein-protein interaction analysis revealed interactions between RasV12 and DAPs, with functional links to mitochondrial dynamics regulators such as Drp1, Marf, Parkin, and HtrA2. Notably, altered expressions of Q9VHD2, P20477, and Q04448 were observed during GBM progression, which offers new insights into the involvement of mitochondrial dynamic regulators in RasV12-induced GBM pathophysiology.

Fractal dimension and lacunarity measures of glioma subcomponents are discriminative of the grade of gliomas and IDH status.

Since the overall glioma mass and its subcomponents-enhancing region (malignant part of the tumor), non-enhancing (less aggressive tumor cells), necrotic core (dead cells), and edema (water deposition)-are complex and irregular structures, non-Euclidean geometric measures such as fractal dimension (FD or "fractality") and lacunarity are needed to quantify their structural complexity. Fractality measures the extent of structural irregularity, while lacunarity measures the spatial distribution or gaps. The complex geometric patterns of the glioma subcomponents may be closely associated with the grade and molecular landscape. Therefore, we measured FD and lacunarity in the glioma subcomponents and developed machine learning models to discriminate between tumor grades and isocitrate dehydrogenase (IDH) gene status. 3D fractal dimension (FD3D) and lacunarity (Lac3D) were measured for the enhancing, non-enhancing plus necrotic core, and edema-subcomponents using preoperative structural-MRI obtained from the The Cancer Genome Atlas (TCGA) and University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) glioma cohorts. The FD3D and Lac3D measures of the tumor-subcomponents were then compared across glioma grades (HGGs: high-grade gliomas vs. LGGs: low-grade gliomas) and IDH status (mutant vs. wild type). Using these measures, machine learning platforms discriminative of glioma grade and IDH status were developed. Kaplan-Meier survival analysis was used to assess the prognostic significance of FD3D and Lac3D measurements. HGG exhibited significantly higher fractality and lower lacunarity in the enhancing subcomponent, along with lower fractality in the non-enhancing subcomponent compared to LGG. This suggests that a highly irregular and complex geometry in the enhancing-subcomponent is a characteristic feature of HGGs. A comparison of FD3D and Lac3D between IDH-wild type and IDH-mutant gliomas revealed that mutant gliomas had ~2.5-fold lower FD3D in the enhancing-subcomponent and higher FD3D with lower Lac3D in the non-enhancing subcomponent, indicating a less complex and smooth enhancing subcomponent, and a more continuous non-enhancing subcomponent as features of IDH-mutant gliomas. Supervised ML models using FD3D from both the enhancing and non-enhancing subcomponents together demonstrated high-sensitivity in discriminating glioma grades (~97.9%) and IDH status (~94.4%). A combined fractal estimation of the enhancing and non-enhancing subcomponents using MR images could serve as a non-invasive, precise, and quantitative measure for discriminating glioma grade and IDH status. The combination of 2-hydroxyglutarate-magnetic resonance spectroscopy (2HG-MRS) with FD3D and Lac3D quantification may be established as a robust imaging signature for glioma subtyping.

Genetic diversity, spatial connectivity, and population structure of Asian silurid catfish Wallago attu (Bloch and Schneider, 1801) in the Ganga River System: insights from mitochondrial DNA analysis.

BACKGROUND: The Ganga River System (GRS) is a biodiversity hotspot, its ecological richness is shaped by a complex geological history. In this study, we examined the genetic diversity, spatial connectivity, and population structure of the Asian Silurid catfish, Wallago attu, across seven tributaries of the GRS. METHODS AND RESULTS: We employed three mitochondrial DNA (mtDNA) regions: cytochrome c oxidase subunit I (COXI), cytochrome b (Cyt b), and control region (CR). Our comprehensive dataset encompassed 2420 bp of mtDNA, derived from 176 W. attu individuals across 19 sampling sites within the seven rivers of GRS. Our findings revealed high gene diversity (Hd:0.99) within W. attu populations. Analysis of Molecular Variance (AMOVA) highlighted that maximum genetic variations were attributed within the populations, and the observed genetic differentiation among the seven populations of W. attu ranged from low to moderate. Network analysis uncovered the presence of three distinct genetic clades, showing no specific association with seven studied rivers. Bayesian skyline plots provided insights into the demographic history of W. attu, suggesting a recent population expansion estimated to have occurred approximately 0.04 million years ago (mya) during the Pleistocene epoch. CONCLUSIONS: These results significantly enhance our understanding of the genetic diversity and spatial connectivity of W. attu, serving as a vital foundation for developing informed conservation strategies and the sustainable management of this economically valuable resource within the Ganga River System.

Comparison of intravascular ultrasound, optical coherence tomography, and conventional angiography-guided percutaneous coronary interventions: A systematic review, network meta-analysis, and meta-regression.

BACKGROUND: Intracoronary imaging modalities, including intravascular ultrasound (IVUS) and optical coherence tomography (OCT), provide valuable supplemental data unavailable on coronary angiography (CA) and have shown to improve clinical outcomes. We sought to compare the clinical efficacy of IVUS, OCT, and conventional CA-guided percutaneous coronary interventions (PCI). METHODS: Frequentist and Bayesian network meta-analyses of randomized clinical trials were performed to compare clinical outcomes of PCI performed with IVUS, OCT, or CA alone. RESULTS: A total of 28 trials comprising 12,895 patients were included. IVUS when compared with CA alone was associated with a significantly reduced risk of major adverse cardiovascular events (MACE) (risk ratio: [RR] 0.74, 95% confidence interval: [CI] 0.63-0.88), cardiac death (RR: 0.64, 95% CI: 0.43-0.94), target lesion revascularization (RR: 0.68, 95% CI: 0.57-0.80), and target vessel revascularization (RR: 0.64, 95% CI: 0.50-0.81). No differences in comparative clinical efficacy were found between IVUS and OCT. Rank probability analysis bestowed the highest probability to IVUS in ranking as the best imaging modality for all studied outcomes except for all-cause mortality. CONCLUSION: Compared with CA, the use of IVUS in PCI guidance provides significant benefit in reducing MACE, cardiac death, and revascularization. OCT had similar outcomes to IVUS, but more dedicated studies are needed to confirm the superiority of OCT over CA.

Busulfan and cyclophosphamide-based conditioning regimen still holds the promise of being a safe and efficacious regimen for allogeneic transplantation in patients with transfusion-dependent thalassemia, even in high risk.

Busulfan and cyclophosphamide (BuCy)-based regimen has been used as a standard myeloablative chemotherapy for haematopoietic stem cell transplantation in thalassemia. However, treosulfan-based conditioning regimen has emerged due to concerns of toxicities. We retrospectively analysed the safety and efficacy of fludrabine/Bu/Cy/antithymocyte globulin (ATG) versus treosulfan/thiotepa/fludrabine regimens for Hematopoietic Stem Cell Transplant (HSCT) in transfusion-dependent thalassemia (TDT) conducted at our institute (2013-2021). In 75 patients, 36 (48%) received Flu/Bu/Cy/ATG whereas 39 (52%) received Treo/Thio/Flu. Median age was 6 (1-12) and 9 (1-15) years, respectively. Number of patients with Classes I, II, and III were 14, 10, and 12 in Flu/Bu/Cy/ATG versus 2, 19, and 18 in Treo/Thio/Flu group, respectively. Graft was growth factor mobilized bone marrow in Flu/Bu/Cy/ATG versus peripheral blood stem cell in Treo/Thio/Flu group. Mean stem cell dose was 3.82 (2.2-9.1) versus 5 (1.65-8.01) 106 /kg in Flu/Bu/Cy/ATG versus Treo/Thio/Flu group, respectively. Neutrophils and platelets engrafted at a median of 16 (14-21) and 16 (9-47) days in Flu/Bu/Cy/ATG and 15 (10-20) and 13 (9-41) days in Treo/Thio/Flu group. Median duration of follow-up was 28 (23-32.9) months. Five (6.6%) patients had rejection (all secondary). Venoocclusive disease was observed in 2 (5.7%) versus 4 (10.3%) patients (p = .047), respectively. Flu/Bu/Cy/ATG had 4 (11.4%) patients with acute GVHD versus 15 (38.5%) patients which had significant impact on survival (p = .038). We observed chronic GVHD in 4 (11.4%) and 11 (28.2%) patients, respectively, with significant impact on survival (p = .031). Four (5.1%) patients had TRM in Treo/Thio/Flu group, in contrast to none in Flu/Bu/Cy/ATG group. Mixed chimerism was common in Flu/Bu/Cy/ATG {20 (57.1%)} versus Treo/Thio/Flu group {12 (30.1%)}. Five-year Event Free Survival (EFS) and OS of entire cohort were 87% + 4% and 94% + 3%, respectively. Estimated TFS, EFS, OS of Flu/Bu/Cy/ATG versus Treo/Thio/Flu was 97.1% + 2.9% versus 89.2% + 5.1% (p = .251), 97 + 3% versus 80.7 + 6% (p = .041) and 100% versus 90.4 + 5% (p = .067), respectively. In our experience, Flu/Bu/Cy/ATG regimen is safe and effective even in high-risk TDT. However, one needs to be vigilant for mixed chimerism.

The analgesic efficacy of intravenous dexamethasone for post-caesarean pain: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Analgesic efficacy of intravenous dexamethasone has not been well defined after caesarean delivery. We performed a systematic review and meta-analysis to evaluate the impact of peri-operative dexamethasone administration on postoperative pain after caesarean delivery. OBJECTIVES: We investigated the impact of perioperative intravenous dexamethasone on postoperative pain after caesarean delivery. The two primary outcomes of interest were early (4 to 6 h) resting pain scores and time to first rescue analgesia. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: PubMed, EMBASE, Scopus and the Cochrane central registers of controlled trials were searched to identify RCTs from inception to April 2021. ELIGIBILITY CRITERIA: Prospective RCTs comparing the role of intravenous dexamethasone with non-active control were eligible for inclusion. Exclusion criteria included trials comparing various doses of dexamethasone without any control treatment arm, dexamethasone with other active drugs and trials comparing different routes of dexamethasone, for example, wound infiltration. RESULTS: Thirteen RCTs constituting of 988 parturients undergoing caesarean delivery were included. Patients receiving dexamethasone had lower pain scores at rest at 4 to 6 h after surgery, mean difference -1.29 [95% confidence interval (CI), -1.85 to -0.73], P < 0.0001, with low quality of evidence (I2 = 94%). Moderate quality of evidence (I2 = 17%) suggested that the time to first rescue analgesia in the dexamethasone group was significantly longer, mean difference 2.64 h (95% CI, 1.85 to 3.42), P  < 0.0001. Trial sequential analysis for pain scores suggested the benefit of dexamethasone; however, the requisite information size (RIS) could not be reached, whereas RIS was adequate for time to rescue analgesia. Significant reduction in pain scores at all times and opioid consumption at 24 h with dexamethasone were observed with sparse reporting on adverse effects. CONCLUSION: Peri-operative intravenous dexamethasone was associated with a significant decrease in postoperative pain scores at rest and a longer time to first rescue analgesia, along with a small but statistically significantly reduced opioid consumption after caesarean delivery compared with nonactive control.

Experience with combination of hydroxyurea and low-dose thalidomide in transfusion-dependent beta thalassemia patients.

Hydroxyurea (HU) and thalidomide have been reported to improve clinical and hematological parameters in transfusion-dependent beta thalassemia (TDT). Therefore, we retrospectively analyzed the combination of HU and thalidomide in 140 transplant ineligible TDT, ≥ 10 years old, visiting our thalassemia clinic between October 2014 and November 2019. Responses were defined as maintenance of hemoglobin ≥9gm/dl without transfusion as complete response (CR) and with at least 50% reduction in transfusion burden as partial response (PR). Patients with less than 50% transfusion burden reduction for consecutive 6 months of therapy were defined as non-responders (NR), and treatment was discontinued thereafter. Primary end point was overall response rate (ORR) at last follow-up. At median follow-up of 22.6 (95% CI 16.4-28.7) months, 76 (57.2%) patients achieved CR and 19 (14.3%) achieved PR, accounting to an ORR of 71.5%. Among responders at last follow-up, a significant increase in the post-treatment hemoglobin (0.88±0.37gm/dl, p<0.0001) and drop in serum ferritin (-1490.5ng/ml, p<0.0001) were observed. Median time to CR was 124 (95% CI 75.3-172.6) days. Median longest continuous CR was 791 (95% CI 662.2-919.7) days. Common toxicities observed were sedation (25%), hyperbilirubinemia {(23.57%, grade 3/4 =17 (12.14%)}, and constipation (22.8%). Nearly three-fourth of the patients has responded with majority having CR. Adverse events are a concern; hence, regular close monitoring is a prerequisite.

Follow-up colonoscopy after an abnormal stool-based colorectal cancer screening result: analysis of steps in the colonoscopy completion process.

BACKGROUND: Delays in receiving follow-up colonoscopy after an abnormal fecal immunochemical test (FIT) result are associated with increased colorectal cancer incidence and mortality. Little is known about patterns of follow-up colonoscopy completion in federally qualified health centers. METHODS: We abstracted the medical records of health center patients, aged 50-75 years, who had an abnormal FIT result between August 5, 2017 and August 4, 2018 (N = 711). We assessed one-year rates of colonoscopy referral, pre-procedure visit completion, colonoscopy completion, and time to colonoscopy; associations between these outcomes and patient characteristics; and reasons for non-completion found in the medical record. RESULTS: Of the 711 patients with an abnormal FIT result, 90% were referred to colonoscopy, but only 52% completed a pre-procedure visit, and 43% completed a colonoscopy within 1 year. Median time to colonoscopy was 83 days (interquartile range: 52-131 days). Pre-procedure visit and colonoscopy completion rates were relatively low in patients aged 65-75 (vs. 50-64), who were uninsured (vs. insured) or had no clinic visit in the prior year (vs. ≥ 1 clinic visit). Common reasons listed for non-completion were that the patient declined, or the provider could not reach the patient. DISCUSSION: Efforts to improve follow-up colonoscopy rates in health centers might focus on supporting the care transition from primary to specialty gastroenterology care and emphasize care for older uninsured patients and those having no recent clinic visits. Our findings can inform efforts to improve follow-up colonoscopy uptake, reduce time to colonoscopy receipt, and save lives from colorectal cancer. TRIAL REGISTRATION: National Clinical Trial (NCT) Identifier: NCT03925883.

First-principles study of a 2-dimensional C-silicyne monolayer as a promising anode in Na/K ion secondary batteries.

With the depleting resources of energy and increasing demand, the need for sustainable and renewable energy resources has become the need of the hour. The low storage capacity of current materials for Na/K ion batteries has led to the quest to identify suitable materials for an electrode with excellent electrochemical properties. In the present work, a systematic theoretical investigation of C-silicyne, a planar 2-dimensional hexagonal lattice, is performed to establish the geometric and thermal properties and stability. The electronic properties illustrate the metallic nature of C-silicyne, which is conserved even after the effective adsorption of Na/K ions on the surface of the monolayer. For the practical functionality, the storage capacity of C-silicyne is evaluated as 591 mA h g-1 for Na ions and 443 mA h g-1 for K ions. Moreover, the low diffusion barriers for the Na (0.57 eV) and K (0.34 eV) ions display their feasible movement across the monolayer as the electrochemical cycle progresses. The average working voltage is found to lie in the range of 0.1-1 V, which is required for the effective functioning of the anode in a Na/K ion battery. These results demonstrate the potential of C-silicyne as a material for the anode in Na/K ion batteries.

Emerging trends from COVID-19 research registered in the Clinical Trials Registry - India.

Since the beginning of the year, the deadly coronavirus pandemic, better known as coronavirus disease 2019 (COVID-19), brought the entire world to an unprecedented halt. In tandem with the global scenario, researchers in India are actively engaged in the conduct of clinical research to counter the pandemic. This review attempts to provide a comprehensive overview of the COVID-19 research in India including design aspects, through the clinical trials registered in the Clinical Trials Registry - India (CTRI) till June 5, 2020. One hundred and twenty two registered trials on COVID-19 were extracted from the CTRI database. These trials were categorized into modern medicine (n=42), traditional medicine (n=67) and miscellaneous (n=13). Of the 42 modern medicine trials, 28 were on repurposed drugs, used singly (n=24) or in combination (n=4). Of these 28 trials, 23 were to evaluate their therapeutic efficacy in different severities of the disease. There were nine registered trials on cell- and plasma-based therapies, two phytopharmaceutical trials and three vaccine trials. The traditional medicine trials category majorly comprised Ayurveda (n=45), followed by homeopathy (n=14) and others (n=8) from Yoga, Siddha and Unani. Among the traditional medicine category, 31 trials were prophylactic and 36 were therapeutic, mostly conducted on asymptomatic or mild-to-moderate COVID-19 patients. This review would showcase the research being conducted on COVID-19 in the country and highlight the research gaps to steer further studies.

Impact of COVID-19 on life expectancy at birth in India: a decomposition analysis.

BACKGROUND: Quantifying excess deaths and their impact on life expectancy at birth (e0) provide a more comprehensive understanding of the burden of coronavirus disease of 2019 (COVID-19) on mortality. The study aims to comprehend the repercussions of the burden of COVID-19 disease on the life expectancy at birth and inequality in age at death in India. METHODS: The mortality schedule of COVID-19 disease in the pandemic year 2020 was considered one of the causes of death in the category of other infectious diseases in addition to other 21 causes of death in the non-pandemic year 2019 in the Global Burden of Disease (GBD) data. The measures e0 and Gini coefficient at age zero (G0) and then sex differences in e0 and G0 over time were analysed by assessing the age-specific contributions based on the application of decomposition analyses in the entire period of 2010-2020. RESULTS: The e0 for men and women decline from 69.5 and 72.0 years in 2019 to 67.5 and 69.8 years, respectively, in 2020. The e0 shows a drop of approximately 2.0 years in 2020 when compared to 2019. The sex differences in e0 and G0 are negatively skewed towards men. The trends in e0 and G0 value reveal that its value in 2020 is comparable to that in the early 2010s. The age group of 35-79 years showed a remarkable negative contribution to Δe0 and ΔG0. By causes of death, the COVID-19 disease has contributed - 1.5 and - 9.5%, respectively, whereas cardiovascular diseases contributed the largest value of was 44.6 and 45.9%, respectively, to sex differences in e0 and G0 in 2020. The outcomes reveal a significant impact of excess deaths caused by the COVID-19 disease on mortality patterns. CONCLUSIONS: The COVID-19 pandemic has negative repercussions on e0 and G0 in the pandemic year 2020. It has severely affected the distribution of age at death in India, resulting in widening the sex differences in e0 and G0. The COVID-19 disease demonstrates its potential to cancel the gains of six to eight years in e0 and five years in G0 and has slowed the mortality transition in India.

A Meta-analysis and Systematic Review of Valvular Heart Disease in Systemic Lupus Erythematosus and Its Association With Antiphospholipid Antibodies.

BACKGROUND: Valvular heart disease (VHD) is a known cardiac manifestation of systematic lupus erythematosus (SLE). This systematic review aims to pool data from studies to estimate the frequency of valvular lesions in SLE patients. It also aims to demonstrate the association between VHD in SLE and antiphospholipid antibodies positivity. METHODS: We included 27 studies after identifying relevant abstracts from PubMed, Scopus, and Google Scholar from the time of inception of database to 2019. Inclusion criteria consisted of English-language case-control and cohort studies. Three reviewers independently performed study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale for assessing risk for bias. RESULTS: For VHD in SLE patients, the most commonly involved valve was the mitral valve, with 19.7% lesions being mitral regurgitation. In terms of morphological lesions, valve thickening (11.06%) and vegetations (11.76%) were among the most prevalent. Other commonly encountered lesions were mitral valve prolapse and tricuspid regurgitation in 9.25% and 10.86% of patients, respectively. A meta-analysis of 21 studies with 2163 SLE patients, of which 23.3% had valvular lesions, showed a significant association of anticardiolipin antibodies positivity with VHD (relative risk, 1.55; confidence interval, 1.10-2.18). CONCLUSIONS: Systemic lupus erythematosus is associated with VHD, and it should be considered a clinical manifestation of SLE in the absence of other valvular pathologies. There is a clear association between VHD in SLE and immunoglobulin G anticardiolipin antibodies positivity. This association suggests that this subgroup of SLE patients might benefit from a screening echocardiogram.

Advances in the Pharmacogenomics of Antiplatelet Therapy.

BACKGROUND: Acute coronary syndrome (ACS) is a highly thrombotic state, and a sustained antiplatelet effect is vital to the prevention of thrombotic complications. Clopidogrel, the most widely used oral P2Y12 receptor antagonist in ACS, has attracted considerable attention because of significant variability in antiplatelet effect depending on the presence of CYP2C19 allele. Other P2Y12 receptor antagonists offer sustained and more predictable antiplatelet effects than clopidogrel albeit at an increased cost. Several studies have demonstrated the promising application of pharmacogenetics in choosing personalized antiplatelet therapy using the point-of-care genotype assays. AREAS OF UNCERTAINTY: Guidelines regarding the genotype-guided approach to the selection of antiplatelet therapy have been conflicting, and studies evaluating the effect of pharmacogenetic-guided selection of antiplatelet therapy on the outcomes have demonstrated mixed results. DATA SOURCES: A literature search was conducted using MEDLINE and EMBASE for studies reporting the association of pharmacogenetic-guided selection of antiplatelet therapy and the outcomes in patients with ACS until December 2018. RESULTS: Presence of specific CYP2C19 allele significantly influences clopidogrel metabolism and associated outcomes in patients with ACS. Thrombotic and bleeding complications are more common in patients with loss-of-function (LOF) and gain-of-function (GOF) alleles, respectively. Although the pharmacogenetic-guided approach to the selection of antiplatelet therapy appears promising in ACS, studies have shown conflicting results, and direct randomized evidence linking this approach with the better outcomes is lacking. CONCLUSIONS: Genotype-guided selection of antiplatelet therapy is expected to be useful in patients undergoing percutaneous coronary intervention (PCI) with a high risk of adverse outcomes. The patient-physician discussion should be an essential part of this decision-making process. Large-scale multicenter randomized controlled trials using the point-of-care genotype assay are needed to investigate this approach further before its use can be recommended in all comers.

Rate and impact of venous thromboembolism in patients with ST-segment elevation myocardial infarction: Analysis of the Nationwide Inpatient Sample database 2003-2013.

Venous thromboembolism (VTE) and coronary artery disease are major health issues that cause substantial morbidity and mortality. New data have emerged suggesting that these two conditions could have a close relationship. Thus, we sought to determine the trends in annual rate of VTE occurrence in patients with ST-segment elevation myocardial infarction (STEMI) and measure its impact on in-hospital mortality, bleeding complications, and cost and length of hospitalization. We queried the 2003-2013 Nationwide Inpatient Sample databases to identify adults with primary diagnosis of STEMI. VTE events were then allocated. Inpatient outcomes of patients with VTE were compared to those without VTE. Out of 2,495,757 hospitalizations for STEMI, VTE was diagnosed in 25,149 (1%) hospitalizations. Patients who experienced VTE were older (mean age: 67.5 vs 64.8, p < 0.01) and had a higher proportion of black patients (10.1% vs 7.7%, p < 0.001) and females (40.1% vs 35%, p < 0.001) compared to patients without VTE. There was an increasing trend in the rate of VTE during the study period (2003: 0.8% vs 2013: 1.0%, p < 0.001). Patients with VTE had a prolonged hospitalization (median: 9 vs 3 days, p < 0.001), increased cost, higher risk of gastrointestinal bleeding (OR: 2.13, p < 0.001), intracranial hemorrhage (OR: 2.14, p < 0.001), blood transfusions (OR: 1.94, p < 0.001), and mortality (OR: 1.39, p < 0.001). The rate of VTE occurrence in patients with STEMI in our study was 10 per 1000 admissions. VTE was associated with more bleeding complications, longer hospital stays, higher costs, and mortality. These findings suggest that a more aggressive approach for VTE prophylaxis may be warranted in this population.

Autologous stem cell transplantation in first remission is associated with better progression-free survival in multiple myeloma.

Autologous stem cell transplant (ASCT) is standard consolidation therapy in management of multiple myeloma (MM) patients. We reviewed records of all consecutive MM patients who underwent ASCT with high-dose melphalan at our center from year 2002 to 2016. A total of 141 ASCT were conducted (90 males and 51 females) with median age of 55 years (23-68 years). Median time from diagnosis to transplant was 7 months (3-79), with majority of patients underwent transplant in first remission, while 17 (12%) patients received transplant beyond first remission. Eighty-three percent patients obtained CR/VGPR post-ASCT. Transplant-related mortality was 2.1%. At a median follow up of 54 months, mean overall survival (OS) and progression-free survival (PFS) group were 128.3 months (95% C.I. 111.9-144.7 months) and 73.8 months (95% C.I. 57.7-89.9 months), respectively. On univariate analysis, OS was adversely affected by renal insufficiency (p = 0.024), while OS was better with CR/VGPR post-ASCT (p < 0.001) and lenalidomide maintenance therapy (p = 0.009). PFS was affected by CR/VGPR pre-ASCT (p = 0.021), CR/VGPR post-ASCT (p < 0.001), and transplant in first remission (p = 0.034). On multivariate analysis, lenalidomide maintenance (versus thalidomide) (p = 0.007) and CR/VGPR response post-ASCT (p = 0.0003) were found to be predictors for better OS and CR/VGPR response at transplant for better PFS (p = 0.038). Transplant in first remission versus beyond first remission showed a trend for better PFS (p = 0.073). CONCLUSION: Majority of patients obtained CR/VGPR post-ASCT. Longer PFS was seen with patients who were transplanted in first remission.

Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes.

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

Magnitude and kinetics of a set of neuroanatomic volume and thickness together with white matter hyperintensity is definitive of cognitive status and brain age.

Even among the subjects classified as cognitively normal, there exists a subset of individuals at a given chronological age (CA) who harbor white matter hyperintensity (WMH) while another subset presents with low or undetectable WMH. Here, we conducted a comprehensive MRI segmentation of neuroanatomic structures along with WMH quantification in groups of cognitively normal (CN), cognitively impaired (CI) individuals, and individuals with an etiological diagnosis of cognitive impairment owing to Alzheimer's Disease (CI-AD) across the early (50-64 years), intermediate (65-79 years), and late (≥80 years) age groups from the NACC cohort. Neuroanatomic volumetry quantification revealed that thinning of the parahippocampal gyrus in the early (p = 0.016) and intermediate age groups (p = 0.0001) along with an increase in CSF (p = 0.0009) delineates between CI and CI-AD subjects. Although, a significant loss of ~5-10% in volume of gray matter (p(CN vs CI) < 0.0001, p(CN vs CI-AD) < 0.0001), white matter (p(CN vs CI) = 0.002, p(CN vs CI-AD) = 0.0003) and hippocampus (p(CN vs CI) = 0.007, p(CN vs CI-AD) < 0.0001) was evident at the early age groups in the CI and CI-AD compared to CN but it was not distinct between CI and CI-AD. Using the neuroanatomic and WMH volume, and the supervised decision tree-based ML modeling, we have established that a minimum set of Three brain quantities; Total brain (GM + WM), CSF, and WMH volume, provide the Optimal quantitative features discriminative of cognitive status as CN, CI, and CI-AD. Furthermore, using the volume/thickness of 178 neuroanatomic structures, periventricular and deep WMH volume quantification for the 819 CN subjects, we have developed a quantitative index as 'Brain Age' (BA) depictive of neuroanatomic health at a given CA. Subjects with elevated WMH load (5-10 ml) had increased BA ( + 0.6 to +4 years) than the CA. Increased BA in the subjects with elevated WMH is suggestive of WMH-induced vascular insult leading to accelerated and early structural loss than expected for a given CA. Henceforth, this study establishes that quantification of WMH together with an optimal number of neuroanatomic features is mandatory to delve into the biological underpinning of aging and aging-associated cognitive disorders.

Analysis of the gamma index using an indigenously developed anthropomorphic heterogeneous female pelvis (AHFP) phantom.

BACKGROUND: It is essential in modern radiotherapy treatment practices to evaluate the quality assurance (QA) of the treatment plan prior to the exclusion of patient from treatment. The typical suitable tools used for patient pretreatment QA are phantoms representing the human anatomy. An anthropomorphic heterogeneous female pelvic (AHFP) phantom has been developed to represent the real female pelvic structure. PURPOSE: The objective of the current study is to assess the findings of relative dosimetry carried out utilizing an electronic portal imaging device (EPID) on the AHFP phantom fabricated. METHODS: The planning target volume (PTV) was created on CT slices of an AHFP phantom to confirm the tool's ability to represent female pelvic anatomy and serve as a QA tool. In order to assess the dose received by healthy organs during radiotherapy, organs at risk such as the bladder and rectum were additionally drawn alongside the PTV. Rapid Arc and Intensity modulated radiation therapy (IMRT) were both used to create the treatment plan on treatment planning system, and the Anisotropic Analytical Algorithm Version 11.0.31 was used to calculate the dose. RESULTS: The results obtained for the average gamma value in RapidArc plans are 0.26, 0.27, and 0.28 (g ≤1) and IMRT plans are 0.39, 0.40, and 0.46 (g ≤1) for target 1, target 2, and target 3, respectively. CONCLUSION: According to the findings of the current study, the AHFP phantom was used to explore the potential of relative dosimetry using EPID as a QA tool, which was found to be suitable.

Role of Cytochrome P450 3A4 in Cancer Drug Resistance: Challenges and Opportunities.

One of the biggest obstacles to the treatment of diseases, particularly serious conditions like cancer, is therapeutic resistance. The process of drug resistance is influenced by a number of important variables, including MDR genes, drug efflux, low-quality medications, inadequate dosage, etc. Drug resistance must be addressed, and new combinations based on the pharmacokinetics/pharmacodynamics (PK-PD) characteristics of the partner pharmaceuticals must be developed in order to extend the half-lives of already available medications. The primary mechanism of drug elimination is hepatic biotransformation of medicines by cytochrome P450 (CYP) enzymes; of these CYPs, CYP3A4 makes up 30-40% of all known cytochromes that metabolize medications. Induction or inhibition of CYP3A4-mediated metabolism affects the pharmacokinetics of most anticancer drugs, but these details are not fully understood and highlighted because of the complexity of tumor microenvironments and various influencing patient related factors. The involvement of CYPs, particularly CYP3A4 and other drug-metabolizing enzymes, in cancer medication resistance will be covered in the current review.

Multidetector Computed Tomography Used in Evaluation of Olfactory Fossa Depth in a Tertiary Hospital in Eastern Region of Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Olfactory fossa (OF) is a depression in most infero-medial portion of anterior cranial fossa formed by cribriform plate, crista galli and lateral lamella of cribriform plate (LLCP). LLCP being thinnest and extremely variable parts, more prone for iatrogenic injury during sinus surgery in case of asymmetric and deep OF. Multidetector computed tomography (MDCT) is frequently used imaging modality in the evaluation of paranasal sinus. The objective of the study is to classify the OF depth according to the Keros classification. METHODS: In this ethically approved prospective, cross-sectional descriptive study, CT scan was done in 530 consecutive patients from February 2022 to July 2023. Coronal CT images of paranasal sinuses and nose were used to measure the OF depth. The data collected was analyzed using SPSS. RESULTS: Out of 530 patients included in this study, 310 (58.49%) were male and 220 (41.51%) were female with mean age of 40.46±11.56 years. Total of 1060 olfactory fossa were analyzed with mean depth of 4.96±1.88 mm. In our study, 310 (29.24%) had type I, 730 (68.88%) had type II and 20 (1.88%) had type III according to Keros classification. CONCLUSIONS: Keros type II OF is more common. The dangerous type III OF having low prevalence, more commonly seen on right side and in males.