A Comparison of Emergency Room Visits and Hospital Admissions Between People with Prediabetes and Diabetes.

The purpose of this study was to characterize risk factors and groups at risk among people with diabetes and prediabetes for increased hospital utilization. Electronic health records for all people who visited the emergency department (ED) and had type II diabetes mellitus (PWD) or prediabetes (PWPD) were collected. ED use, hospital admissions, demographics, and clinical characteristics were compared between the groups. Multivariable logistic regression was used to compare the odds of ED high utilization (HU) (3+ visits per year) and hospital admissions between PWD and PWPD with interactions for socioeconomic status, race, marital status, and total comorbidities. PWD had higher mean ED visits per year compared with PWPD (1.5 vs. 1.2) and were more likely to be admitted (57.3% vs. 34.9%). PWD had higher odds of ED HU (2.1 [1.6, 2.7]) and hospital admissions (1.9 [1.6, 2.1]). Among PWD, Black, not married, and those with more than one comorbidity had the highest odds of ED HU. Among PWPD, those of low SES, Black, and divorced had the higher odds of ED HU. Hospital admissions were a risk for PWD and PWPD with increasing comorbidities. Early recognition and identification of prediabetes and clear criteria for diagnosis could reduce ED visits and hospital admissions.

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.

An Imbalance of Pathophysiologic Factors in Late Postprandial Hypoglycemia Post Bariatric Surgery: A Narrative Review.

With a rise in obesity and more patients opting for bariatric surgery, it becomes crucial to understand associated complications like postprandial hypoglycemia (PPH). After bariatric surgery, significant changes are seen in insulin sensitivity, beta cell function, glucagon-like peptide 1 (GLP-1) levels, the gut microbiome, and bile acid metabolism. And in a small subset of patients, exaggerated imbalances in these functional and metabolic processes lead to insulin-glucose mismatch and hypoglycemia. The main treatment for PPH involves dietary modifications. For those that do not respond, medications or surgical interventions are considered to reverse some of the imbalances. We present a few case reports of patients that safely tolerated GLP-1 agonists. However, larger randomized control trials are needed to further characterize PPH and understand its treatment.

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.

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.

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.

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.

Maternal Metabolic Health, Lifestyle, and Environment - Understanding How Epigenetics Drives Future Offspring Health.

The incidence of metabolic disorders, such as obesity and type two diabetes (T2DM), continues to increase worldwide, and their onset is often attributed to adherence to a western diet and a sedentary lifestyle. However, large variability exists in one's likelihood of developing metabolic dysregulation, illustrating that our understanding of heritability patterns remains poorly understood. Diabetes and obesity are multifactorial diseases, and their onset is influenced by both genetic and environmental factors. Genome-wide association studies report a number of alterations in the coding sequence associated with the onset of T2DM and obesity. However, these genes explain only a fraction of the cases, leaving the majority unaccounted for. The missing heritability question implies that other factors are responsible for the onset and development of the disease. Given that the developing fetus is susceptible to the maternal environment, a growing body of evidence demonstrates that maternal metabolic characteristics as well as disruptions to the prenatal environment may induce long-term genetic, phenotypic, and physiologic adaptations in the developing fetus, which could have a permanent effect on its future health. This phenomenon is known as developmental programming and is mediated through epigenetic modifications, which include modulation of gene expressions that do not alter the original deoxyribonucleic (DNA) sequence. Epigenetic modifications are capable of changing gene expression in metabolism-related genes and are accomplished through DNA methylation, histone acetylation, and ribonucleic acid (RNA) mechanisms. In this review, we discuss maternal metabolic factors, such as obesity, dyslipidemia, and gestational diabetes (GDM) that lead to epigenetic changes in the offspring and predispose future generations to metabolic abnormalities. We will also describe the association between maternal lifestyle factors and exposure to toxins with epigenetic modulations in the offspring. Lastly, we will provide a brief review of the possibility of using epigenetics as potential interventions and therapeutic modalities to help in early diagnosis and prevention of metabolic disorders.

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.

The time is now for new, lower diabetes diagnostic thresholds.

Current thresholds for diagnosing diabetes are outdated and do not represent advancements in disease understanding or ability to impact course. Today, evidence supports intervening earlier along the disease continuum to mitigate transition to frank disease and delay/reduce adverse clinical outcomes. We believe it is time for lower diabetes diagnostic criteria.

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.

IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma.

Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th1/Th2 response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease.

The Diabetes Syndrome - A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms.

The four basic pathophysiologic mechanisms which damage the ß-cell within diabetes (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance [IR]) also contribute to cell and tissue damage and elevate the risk of developing all typical diabetes-related complications. Genetic susceptibility to damage from abnormal external and internal environmental factors has been described including inflammation and IR. All these mechanisms can promote epigenetic changes, and in total, these pathophysiologic mechanisms interact and react with each other to cause damage to cells and tissues ultimately leading to disease. Importantly, these pathophysiologic mechanisms also serve to link other common conditions including cancer, dementia, psoriasis, atherosclerotic cardiovascular disease (ASCVD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). The "Diabetes Syndrome", an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions. Recognizing the association of the conditions within the Diabetes Syndrome due to common pathophysiologies has the potential to provide both benefit to the patient (eg, prevention, early detection, precision medicine) and to the advancement of medicine (eg, driving education, research, and dynamic decision-based medical practice).

Diabetes and Psoriasis: Different Sides of the Same Prism.

Diabetes and psoriasis are prevalent conditions with a spectrum of serious adverse outcomes. Both diseases are common comorbidities for each other, and diabetes is considered as a risk factor for psoriasis and vice versa. However, it is our contention that these diseases are not merely comorbidities of each other but rather share common underlying pathophysiologies (ie, genes and epigenetic changes, inflammation, abnormal environment, and insulin resistance) that drive disease. As such, they can be viewed as facets of the same prism. Genes can cause or permit susceptibility to damage from abnormal external and internal environmental factors, inflammation, and insulin resistance which can also drive epigenetic changes. These co-existing mechanisms act in a vicious cycle over time to potentiate cell and tissue damage to ultimately drive disease. Viewing diabetes and psoriasis through the same prism suggests potential for therapies that could be used to treat both conditions. Although additional controlled trials and research are warranted, we believe that our understanding of the overlapping pathophysiologies continues to grow, so too will our therapeutic options.

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia.

AIMS/HYPOTHESIS: We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations. METHODS: A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants. RESULTS: Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16-25 and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10-7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans. CONCLUSIONS/INTERPRETATION: The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.