Role of APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T polymorphisms, their expression in patients of HIV-associated lipodystrophy.

Apolipoproteins and Scavenger Receptor Class B1 (SCARB1) proteins are involved in the etiology of HIV-associated lipodystrophy (HIVLD). APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T polymorphisms were linked with increased level of APOB, TG, HDL-C and risk of cardiovascular diseases (CVDs). Hence, we evaluated the genetic variations of APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T in 187 patients of HIV (64 with HIVLD, 123 without HIVLD) and 139 healthy controls using PCR-RFLP and expression by qPCR. The genotypes of SCARB1 1050 TT and APOB 12669AA showed a risk to severe HIVLD (P = 0.23, OR = 4.95; P = 0.16, OR = 2.02). The APOC3 3238 GG genotype was associated with a lesser risk of severe HIVLD (P = 0.07, OR = 0.22). The APOB 12669 GA genotype was associated with a greater risk of HIVLD severity in patients with impaired LDL, triglyceride (TG), and cholesterol levels (P = 0.34, OR = 4.13; P = 0.25, OR = 3.64; P = 0.26, OR = 5.47). Similarly, APOB 12669AA genotypes in the presence of impaired triglyceride levels displayed the susceptibility to severity of HIVLD (P = 0.77, OR = 2.91). APOB 12669 GA genotype along with impaired HDL and cholesterol levels indicated an increased risk for HIVLD acquisition among patients without HIVLD (P = 0.42, OR = 2.42; P = 0.26, OR = 2.27). In patients with and without HIVLD, APOC3 3238CG genotypes having impaired cholesterol and glucose levels had higher risk for severity and development of HIVLD (P = 0.13, OR = 2.84, P = 0.34, OR = 1.58; P = 0.71, OR = 1.86; P = 0.14, OR = 2.30). An increased expression of APOB and SCARB1 genes were observed in patients with HIVLD (+0.51 vs. -0.93; +4.78 vs. +3.29), and decreased expression of APOC3 gene was observed in patients with HIVLD (-0.35 vs. -1.65). In conclusion, the polymorphisms mentioned above were not associated with the modulation of HIVLD. However, in the presence of impaired triglyceride, HDL, cholesterol and glucose levels, APOB 12669AA and 12669 GA, APOC3 3238CG genotypes indicated a risk for the development and severity of HIVLD.

ABCG2 polymorphisms and susceptibility to ARV-associated hepatotoxicity.

BACKGROUND: The ABCG2 421C/A polymorphism contributes significantly to the distribution and absorption of antiretroviral (ARV) regimens and is associated with the undesirable side effects of efavirenz. METHODS: To investigate this, we examined ABCG2 34G/A (rs2231137) and 421C/A (rs2231142) genetic variations in 149 HIV-infected patients (116 without hepatotoxicity, 33 with ARV-induced hepatotoxicity) and 151 healthy controls through the PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS AND DISCUSSION: The ABCG2 34GA genotype and 34A allele indicated a risk for antiretroviral therapy-associated hepatotoxicity development (p = 0.09, OR = 1.58, 95% CI: 0.93-2.69; p = 0.06, OR = 1.50, 95% CI: 0.98-2.30). The haplotype GA was associated with hepatotoxicity (p = 0.042, OR = 2.37, 95% CI: 1.04-5.43; p = 0.042, OR = 2.49, 95% CI: 1.04-5.96). Moreover, when comparing HIV patients with hepatotoxicity to healthy controls, the haplotype GA had an association with an elevated risk for the development of hepatotoxicity (p = 0.041, OR = 1.73, 95% CI: 1.02-2.93). Additionally, the association of the ABCG2 34GA genotype with the progression of HIV (p = 0.02, OR = 1.97, 95% CI: 1.07-3.63) indicated a risk for advanced HIV infection. Furthermore, the ABCG2 421AA genotype was linked to tobacco users and featured as a risk factor for the progression of HIV disease (p = 0.03, OR = 11.07, 95% CI: 1.09-270.89). CONCLUSION: The haplotype GA may enhance the risk of hepatotoxicity development and its severity. Individuals with the ABCG2 34A allele may also be at risk for the development of hepatotoxicity. Additionally, individuals with an advanced stage of HIV and the ABCG2 34GA genotype may be at risk for disease progression.

Identification of novel genetic variations in ABCB6 and GRN genes associated with HIV-associated lipodystrophy.

Protease inhibitors (PIs) are associated with an incidence of lipodystrophy among people living with HIV(PLHIV). Lipodystrophiesare characterised by the loss of adipose tissue. Evidence suggests that a patient's lipodystrophy phenotype is influenced by genetic mutation, age, gender, and environmental and genetic factors, such as single-nucleotide variants (SNVs). Pathogenic variants are considered to cause a more significant loss of adipose tissue compared to non-pathogenic. Lipid metabolising enzymes and transporter genes have a role in regulating lipoprotein metabolism and have been associated with lipodystrophy in HIV-infected patients (LDHIV). The long-term effect of the lipodystrophy syndrome is related to cardiovascular diseases (CVDs). Hence, we determined the SNVs of lipid metabolising enzymes and transporter genes in a total of 48 patient samples, of which 24 were with and 24 were without HIV-associated lipodystrophy (HIVLD) using next-generation sequencing. A panel of lipid metabolism, transport and elimination genes were sequenced. Three novel heterozygous non-synonymous variants at exon 8 (c.C1400A:p.S467Y, c.G1385A:p.G462E, and c.T1339C:p.S447P) in the ABCB6 gene were identified in patients with lipodystrophy. One homozygous non-synonymous SNV (exon5:c.T358C:p.S120P) in the GRN gene was identified in patients with lipodystrophy. One novelstop-gain SNV (exon5:c.C373T:p.Q125X) was found in the GRN gene among patients without lipodystrophy. Patients without lipodystrophy had one homozygous non-synonymous SNV (exon9:c.G1462T:p.G488C) in the ABCB6 gene. Our findings suggest that novel heterozygous non-synonymous variants in the ABCB6 gene may contribute to defective protein production, potentially intensifying the severity of lipodystrophy. Additionally, identifying a stop-gain SNV in the GRN gene among patients without lipodystrophy implies a potential role in the development of HIVLD.

Comparative analysis of MTP -493G/T and ABCG2 34G/A polymorphisms and theirs expression in HIV-associated lipodystrophy patients.

HIV-associated lipodystrophy (HIVLD) is a metabolic condition with an irregularity in the production of lipoprotein particles, and its occurrence varies among HIV-infected patients. MTP and ABCG2 genes have a role in the transport of lipoproteins. The polymorphisms of MTP -493G/T and ABCG2 34G/A affect its expression and influence the secretion and transportation of lipoproteins. Hence, we investigated the MTP -493G/T and ABCG2 34G/A polymorphisms in 187 HIV-infected patients (64 with HIVLD and 123 without HIVLD) along with 139 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism and expression analysis using real-time PCR. ABCG2 34A allele showed an insignificantly reduced risk of LDHIV severity [P = 0.07, odds ratio (OR) = 0.55]. MTP -493T allele exhibited a non-significantly reduced risk for the development of dyslipidemia (P = 0.08, OR = 0.71). In patients with HIVLD, the ABCG2 34GA genotype was linked with impaired low-density lipoprotein levels and showed a reduced risk for LDHIV severity (P = 0.04, OR = 0.17). In patients without HIVLD, the ABCG2 34GA genotype was associated with impaired triglyceride levels with marginal significance and showed an increased risk for the development of dyslipidemia (P = 0.07, OR = 2.76). The expression level of MTP gene was 1.22-fold decreased in patients without HIVLD compared with that in patients with HIVLD. ABCG2 gene was upregulated 2.16-fold in patients with HIVLD than in patients without HIVLD. In conclusion, MTP -493C/T polymorphism influences the expression level of MTP in patients without HIVLD. Individuals without HIVLD having ABCG2 34GA genotype with impaired triglyceride levels may facilitate dyslipidemia risk.

Mitochondrial Dysfunction and Apoptosis in Brain Microvascular Endothelial Cells Following Blast Traumatic Brain Injury.

Blood brain barrier (BBB) breakdown is a key driver of traumatic brain injury (TBI), contributing to prolonged neurological deficits and increased risk of death in TBI patients. Strikingly, the role of endothelium in the progression of BBB breakdown has not been sufficiently investigated, even though it constitutes the bulk of BBB structure. In the current study, we investigate TBI-induced changes in the brain endothelium at the subcellular level, particularly focusing on mitochondrial dysfunction, using a combination of confocal imaging, gene expression analysis, and molecular profiling by Raman spectrometry. Herein, we developed and applied an in-vitro blast-TBI (bTBI) model that employs an acoustic shock tube to deliver injury to cultured human brain microvascular endothelial cells (HBMVEC). We found that this injury results in aberrant expression of mitochondrial genes, as well as cytokines/ inflammasomes, and regulators of apoptosis. Furthermore, injured cells exhibit a significant increase in reactive oxygen species (ROS) and in Ca2+ levels. These changes are accompanied by overall reduction of intracellular proteins levels as well as profound transformations in mitochondrial proteome and lipidome. Finally, blast injury leads to a reduction in HBMVEC cell viability, with up to 50% of cells exhibiting signs of apoptosis following 24 h after injury. These findings led us to hypothesize that mitochondrial dysfunction in HBMVEC is a key component of BBB breakdown and TBI progression.

Microbial Biofilm: A Review on Formation, Infection, Antibiotic Resistance, Control Measures, and Innovative Treatment.

Biofilm is complex and consists of bacterial colonies that reside in an exopolysaccharide matrix that attaches to foreign surfaces in a living organism. Biofilm frequently leads to nosocomial, chronic infections in clinical settings. Since the bacteria in the biofilm have developed antibiotic resistance, using antibiotics alone to treat infections brought on by biofilm is ineffective. This review provides a succinct summary of the theories behind the composition of, formation of, and drug-resistant infections attributed to biofilm and cutting-edge curative approaches to counteract and treat biofilm. The high frequency of medical device-induced infections due to biofilm warrants the application of innovative technologies to manage the complexities presented by biofilm.

Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder.

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

Treatment of intractable cholangitis in children with biliary atresia: Impact on outcome.

OBJECTIVES: To evaluate the response and outcome with prolonged intravenous antibiotics including home-based intravenous antibiotics in children with intractable cholangitis (IC) after Kasai portoenterostomy (KPE) for biliary atresia (BA). METHODS: A retrospective review of treatment and outcome of children with IC post KPE (no resolution after four weeks of antibiotics) was done between 2014 and 2020. A protocol-based antibiotic regimen was used based on sensitivity and hospital antibiogram. Children afebrile for more than three days were discharged on home intravenous antibiotics (HIVA). RESULTS: Twenty children with IC were managed with prolonged antibiotic regimen, including HIVA. All patients were initially listed for liver transplantation (LT) with indication being IC (n = 20) with portal hypertension (n = 12). Seven patients had bile lakes of which four underwent percutaneous transhepatic biliary drainage. Bile culture grew Klebsiella in four and Escherichia coli and Pseudomonas one each. There were eight children with IC who had positive blood culture with most of these organisms being gram-negative (Escherichia coli: 5, Klebsiella pneumoniae: 2, Enterococcus: 1). Median duration of antibiotics was 58 days (interquartile range [IQR] 56-84). Median follow-up period post cholangitis was three years (IQR 2-4). Following treatment, 14 patients were successfully delisted from LT waitlist and are presently jaundice-free. Two of the five patients undergoing LT died of sepsis. One patient died awaiting LT. CONCLUSION: Timely and aggressive step-up antibiotic regimen may successfully treat IC and prevent/delay LT. HIVA provides a cost-effective and comfortable environment for a child which might improve compliance with intravenous antibiotics.

Nanotherapeutic Approach to Delivery of Chemo- and Gene Therapy for Organ-Confined and Advanced Castration-Resistant Prostate Cancer.

Treatments for late-stage prostate cancer (CaP) have not been very successful. Frequently, advanced CaP progresses to castration-resistant prostate cancer (CRPC), with 50#37;-70% of patients developing bone metastases. CaP with bone metastasis-associated clinical complications and treatment resistance presents major clinical challenges. Recent advances in the formulation of clinically applicable nanoparticles (NPs) have attracted attention in the fields of medicine and pharmacology with applications to cancer and infectious and neurological diseases. NPs have been rendered biocompatible, pose little to no toxicity to healthy cells and tissues, and are engineered to carry large therapeutic payloads, including chemo- and genetic therapies. Additionally, if required, targeting specificity can be achieved by chemically coupling aptamers, unique peptide ligands, or monoclonal antibodies to the surface of NPs. Encapsulating toxic drugs within NPs and delivering them specifically to their cellular targets overcomes the problem of systemic toxicity. Encapsulating highly labile genetic therapeutics such as RNA within NPs provides a protective environment for the payload during parenteral administration. The loading efficiencies of NPs have been maximized while the controlled their therapeutic cargos has been released. Theranostic ("treat and see") NPs have developed combining therapy with imaging capabilities to provide real-time, image-guided monitoring of the delivery of their therapeutic payloads. All of these NP accomplishments have been applied to the nanotherapy of late-stage CaP, offering a new opportunity for a previously dismal prognosis. This article gives an update on current developments in the use of nanotechnology for treating late-stage, castration-resistant CaP.

Poly ADP-Ribose Polymerase-1 inhibition by 3-aminobenzamide recuperates HEI-OC1 auditory hair cells from blast overpressure-induced cell death.

Introduction: Poly ADP-Ribose Polymerase-1 (PARP1), a DNA repair enzyme is implicated as a key molecule in the pathogenesis of several neurodegenerative disorders. Traumatic insults inducing oxidative stress results in its over-activation causing inflammation and cell death (Parthanatos). As PARP1 inhibition is known to reduce oxidative stress, we hypothesized that PARP1 inhibition by a known inhibitor 3-aminobenzamide (3AB) might recuperate the damage in an in vitro model of blast injury using HEI-OC1 cells (mouse auditory hair cells). Methods: Here, we evaluated the protective effect of 3AB on HEI-OC1 cells following single and repetitive blast overpressures (BOPs). Results: We found that inhibition of PARP1 b 3AB inhibits the PARP1 enzyme and its action of a post-translational modification i.e. formation of Poly ADP-Ribose Polymers which leads to massive ATP depletion. PARP inhibition (3AB treatment) reduced the oxidative stress (4HNE, a marker of lipid peroxidation, and 8OHdG, a marker of oxidative DNA damage) in cells exposed to single/repetitive BOPS through up-regulation of Nrf2, a transcriptional regulator of antioxidant defense and the GCLC, a rate limiting enzyme in the synthesis of glutathione. Discussion: Overall, we found that PARP inhibition by 3AB helps to maintain the viability of BOP-exposed auditory hair cells by recuperating the ATP pool from both mitochondrial and glycolytic sources.

Combination Modality Using Quercetin to Enhance the Efficacy of Docetaxel in Prostate Cancer Cells.

The standard of care chemotherapy drug presently used to treat castration-resistant prostate cancer (CRPC), docetaxel (Doc), also develops chemoresistance, thereby reducing its clinical utility. Since resistance to chemotherapy drugs can be overcome by co-treatment with plant-based bio-active compounds we undertook the present study to evaluate if quercetin (Que), a flavonoid present in plants such as onions, apples, olives, and grapes can enhance the efficacy of Doc. We studied the separate and combined effects of Que and Doc at different doses and different combination approaches in two different prostate cancer cell lines, DU-145 (moderately aggressive) and PC-3 (very aggressive), and assessed the effects of these combinations on viability, proliferation, and apoptosis. Monotherapy with these drugs showed dose-dependent cytotoxicity; however, only Doc monotherapy showed a statistically significant difference in IC50 levels (IC50 = 4.05 ± 0.52 nM for PC-3 and IC50 = 2.26 ± 0.22 nM for DU-145). In combination treatment, we used three different treatment approaches (TAP). The concentrations and range analyzed were chosen based on the approximate cytotoxicity of 30-50% when the drugs were used individually. Our observations indicate that the most beneficial effect of the Que and Doc combination was obtained with the TAP-2 approach, which is pre-treatment with all doses of Que for 24 h followed by low doses of Doc for another 24 h. Using this approach, we observed synergism at low concentrations of Doc (0.5 and 1.0 nM) and all concentrations of Que. An additive effect was observed at moderate and high concentrations of Doc (1.5, 2.0, and 2.5 nM) and all concentrations of Que in both cell lines. The TAP-2 strategy was also helpful in overcoming Doc resistance in resistant CaP cells. In summary, Que improved the therapeutic effect of Doc in CRPC, and it is proposed that this improvement is mediated through multiple mechanisms. This study provides a novel therapeutic modality for an effective combination using Doc and Que to enhance the efficacy of Doc in an innocuous manner for Doc resistance and CRPC treatment.

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer.

Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions using large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors.Validation studies with cellular toxicity assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Gene expression studies revealed that MAPK expression is strongly correlated with decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. These results indicate that our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales.

Raman spectroscopy based molecular signatures of methamphetamine and HIV induced mitochondrial dysfunction.

METH and HIV Tat treatment results in increased oxidative stress which affects cellular metabolism and causes DNA damage in the treated microglia. Both, METH ± HIV Tat impair mitochondrial respiration, leading to dysfunction in bioenergetics and increased ROS in microglial cells. Our data indicate that mitochondrial dysfunction may be key to the METH and/or HIV Tat-induced neuropathology. METH and/or HIV Tat induced changes in the protein, lipid and nucleotide concentration in microglial cells were measured by Raman Spectroscopy, and we speculate that these fundamental molecular-cellular changes in microglial cells contribute to the neuropathology that is associated with METH abuse in HIV patients.

Use of Glycoproteins-Prostate-Specific Membrane Antigen and Galectin-3 as Primary Tumor Markers and Therapeutic Targets in the Management of Metastatic Prostate Cancer.

Galectins and prostate specific membrane antigen (PSMA) are glycoproteins that are functionally implicated in prostate cancer (CaP). We undertook this study to analyze the "PSMA-galectin pattern" of the human CaP microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. We examined CaP cells and biopsy samples representing different stages of the disease and found that PSMA, Gal-1, Gal-3, and Gal-8 are the most abundantly expressed glycoproteins. In contrast, other galectins such as Gal-2, 4-7, 9-13, were uniformly expressed at lower levels across all cell lines. However, biopsy samples showed markedly higher expression of PSMA, Gal-1 and Gal-3. Independently PSA and Gleason score at diagnosis correlated with the expression of PSMA, Gal-3. Additionally, the combined index of PSMA and Gal-3 expression positively correlated with Gleason score and was a better predictor of tumor aggressiveness. Together, our results recognize a tightly regulated "PSMA-galectin- pattern" that accompanies disease in CaP and highlight a major role for the combined PSMA and Gal-3 inhibitors along with standard chemotherapy for prostate cancer treatment. Inhibitor combination studies show enzalutamide (ENZ), 2-phosphonomethyl pentanedioic acid (2-PMPA), and GB1107 as highly cytotoxic for LNCaP and LNCaP-KD cells, while Docetaxel (DOC) + GB1107 show greater efficacy in PC-3 cells. Overall, 2-PMPA and GB1107 demonstrate synergistic cytotoxic effects with ENZ and DOC in various CaP cell lines.

Mitochondrial Dysfunction: A Prelude to Neuropathogenesis of SARS-CoV-2.

The SARS-CoV-2 virus is notorious for its neuroinvasive capability, causing multiple neurological conditions. The neuropathology of SARS-CoV-2 is increasingly attributed to mitochondrial dysfunction of brain microglia cells. However, the changes in biochemical content of mitochondria that drive the progression of neuro-COVID remain poorly understood. Here we introduce a Raman microspectrometry approach that enables the molecular profiling of single cellular organelles to characterize the mitochondrial molecular makeup in the infected microglia cells. We found that microglia treated with either spike protein or heat-inactivated SARS-CoV-2 trigger a dramatic reduction in mtDNA content and an increase in phospholipid saturation levels. At the same time, no significant changes were detected in Golgi apparatus and in lipid droplets, the organelles that accommodate biogenesis and storage of lipids. We hypothesize that transformations in mitochondria are caused by increased synthesis of reactive oxygen species in these organelles. Our findings call for the development of mitochondria-targeted therapeutic approaches to limit neuropathology associated with SARS-CoV-2.

Thirty-day unplanned readmission in hospitalised asthma patients in the USA.

INTRODUCTION: Hospital quality improvement and hospital performance are commonly evaluated using parameters such as average length of stay (LOS), patient safety measures and rates of hospital readmission. Thirty-day readmission (30-DR) rates are widely used as a quality indicator and a quantifiable metric for hospitals since patients are often readmitted for the exacerbation of conditions from index admission. The quality of patient education and postdischarge care can influence readmission rates. We report the 30-DR rates of patients with asthma using a national dataset for the year 2013. OBJECTIVES: The aim of our study was to assess the 30- day readmission (30-DR) rate as well as, the causes and predictors of readmissions. STUDY DESIGNS/METHODS: Using the Nationwide Readmission Database (NRD) (2013), we identified primary discharge diagnoses of asthma by using International Classification of Diseases, Ninth Revision, Clinical Modification code '493'. Categorical and continuous variables were assessed by a χ2 test and a Student's t-test, respectively. The independent predictors of unplanned 30-DR were detected by multivariate analysis. We used sampling weights, which are provided in the NRD, to generate the national estimates. RESULTS: There were 130 490 (weighted N=311 173) inpatient asthma admissions during 2013. The overall 30-DR for asthma was 11.9%. The associated factors for 30-DR were age 45-84 years (40.32% vs 29.05%; p<0.001), enrolment in Medicare (49.33% vs 30.61% p<0.001), extended LOS (mean, 4.40±0.06 vs 3.25±0.04 days; p<0.001), higher mean cost (US$8593.91 vs US$6741.31; p<0.001) and higher disposition against medical advice (DAMA) (4.14% vs 1.51%; p<0.001). The factors that increased the chance of 30-DR were advanced age (≥45-64 vs ≤17 years; OR 4.61, 95% CI 4.04 to 5.27, p<0.0001), male sex (OR 1.19, 95% CI 1.13 to 1.26, p<0.0001), a higher Charlson Comorbidity Index (CCI) (OR 1.16, 95% CI 1.14 to 1.18, p<0.0001), DAMA (OR 2.32, 95% CI 2.08 to 2.59, p<0.0001), non-compliance with medication (OR 1.34, 95% CI 1.24 to 1.46, p<0.0001), post-traumatic stress disorder (OR 1.48, 95% CI 1.22 to 1.79, p<0.0001), alcohol use (OR 1.45, 95% CI 1.27 to 1.65, p<0.0001), gastro-oesophageal reflux disease (OR 1.20, 95% CI 1.14 to 1.27, p<0.0001), obstructive sleep apnoea (OR 1.11, 95% CI 1.03 to 1.18, p<0.0042) and hypertension (OR 1.11, 95% CI 1.06 to 1.17, p<0.0001). CONCLUSIONS: We found that the overall 30-DR rate for asthma was 11.9% all-cause readmission. Major causes of 30-DR were asthma exacerbation (36.74%), chronic obstructive pulmonary disease (11.47%), respiratory failure (6.46%), non-specific pneumonia (6.19%), septicaemia (3.61%) and congestive heart failure (3.32%). One-fourth of the revisits occurred in the first week, while half of the revisits took place in the first 2 weeks. Education regarding illness and the importance of medicine compliance could play a significant role in preventing asthma-related readmission.

Small molecule based EGFR targeting of biodegradable nanoparticles containing temozolomide and Cy5 dye for greatly enhanced image-guided glioblastoma therapy.

Current glioblastoma multiforme (GBM) treatment is insufficient, facing obstacles like poor tumor accumulation and dose limiting side effects of chemotherapeutic agents. Targeted nanomaterials offer breakthrough potential in GBM treatment; however, traditional antibody-based targeting poses challenges for live brain application. To overcome current obstacles, we introduce here the development of a small molecule targeting agent, CFMQ, coupled to biocompatible chitosan coated poly(lactic-co-glycolic) acid nanoparticles. These targeted nanoparticles enhance cellular uptake and show rapid blood-brain barrier (BBB) permeability in-vitro, demonstrating the ability to effectively deliver their load to tumor cells. Encapsulation of the chemotherapeutic agent, temozolomide (TMZ), decreases the IC50 ~34-fold compared to free-drug. Also, CFMQ synergistically suppresses tumor cell progression, reducing colony formation (98%), cell migration (84%), and cell invasion (77%). Co-encapsulation of Cy5 enables optical image guided therapy. This biocompatible theranostic nanoformulation shows early promise in significantly enhancing the efficacy of TMZ, while providing potential for image-guided therapy for GBM.

Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID.

Emerging clinical data from the current COVID-19 pandemic suggests that ~ 40% of COVID-19 patients develop neurological symptoms attributed to viral encephalitis while in COVID long haulers chronic neuro-inflammation and neuronal damage result in a syndrome described as Neuro-COVID. We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID.

Blast-induced injury responsive relative gene expression of traumatic brain injury biomarkers in human brain microvascular endothelial cells.

Disruption of the blood-brain barrier (BBB) is a critical component of traumatic brain injury (TBI) progression. However, further research into the mechanism of BBB disruption and its specific role in TBI pathophysiology is necessary. To help make progress in elucidating TBI affected BBB pathophysiology, we report herein relative gene expression of eleven TBI biomarkers and other factors of neuronal function in human brain microvascular cells (HBMVEC), one of the main cell types in the BBB. Our in-vitro blast TBI model employs a custom acoustic shock tube to deliver injuries of varying intensities to HBMVECs in culture. Each of the investigated genes exhibit a significant change in expression as a response to TBI, which is dependent on both the injury intensity and time following the injury. This data suggests that cell signaling of HBMVECs could be essential to understanding the interaction of the BBB and TBI pathophysiology, warranting future investigation.