Hyperglycemia suppresses Lactate Clearance during Exercise in Type 1 Diabetes.

CONTEXT: Circulating lactate concentration is an important determinant of exercise tolerance. OBJECTIVE: To determine the role of hyperglycemia on lactate metabolism during exercise in type 1 diabetes (T1D). DESIGN: Protocol involved compared T1D participants and participants without diabetes (ND) at euglycemia [5.5mM] or hyperglycemia [9.2mM] in random order in T1D and at euglycemia in ND. SETTING: Clinical Research Unit, University of Virginia, Charlottesville, VA. PARTICIPANTS: 7 T1D and 7 ND. INTERVENTION: [1-13C] lactate infusion, exercise at 65% VO2max, euglycemia and hyperglycemia visits. MAIN OUTCOME MEASURE: Lactate turnover before, during and after 60 min of exercise at 65% VO2max. RESULTS: A two-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND (p=0.76) and concordant to plasma volume (∼40ml/kg). Circulating lactate concentrations were higher (p<0.001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise induced lactate appearance did not differ (p=0.13) between hyperglycemia and euglycemia. However, lactate clearance was lower (p=0.03) during hyperglycemia than euglycemia in T1D. There were no differences in any of the above parameters between T1D and ND during euglycemia. CONCLUSIONS: Hyperglycemia modulates lactate metabolism during exercise by lowering lactate clearance leading to higher circulating lactate concentrations in T1D. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance for both providers and recreationally active people with Type 1 diabetes.

Reinvestigation of SnCl4 catalyzed efficient synthesis of 2,3-unsaturated glycopyranosides.

The Ferrier rearrangement is a powerful tool to prepare 2,3-unsaturated glycopyranosides. We have reinvestigated SnCl4 catalyzed Ferrier rearrangements through direct allylic substitution of the hydroxyl group at the C-3 position of glycals, resulting in the formation of stereoselective 2,3-unsaturated glycosides at 0 °C. The catalytic amount of SnCl4 (0.1 equiv.) was successfully used to promote this transformation on 3,4,6-tri-O-acetyl-D-glucal, 3,4,6-tri-O-acetyl-D-galactal and 3,4-di-O-acetyl-D-arabinal using various nucleophiles viz alcohols, azide and thiols to form a variety of 2,3-unsaturated glycopyranosides (pseudoglycals). This straightforward process is notable for its strong anomeric selectivity, excellent yields and shorter reaction time.

In Situ Measurement of Effective Gate Bias Voltage in Ionic Liquid-Gated Organic Field-Effect Transistors: Exploring Intrinsic Performance and Trap Density of States.

Electric double layer (EDL)-mediated transistors with ionic liquid (IL) gating have garnered substantial interest due to their exceptional properties, such as high transconductance and low-voltage operation, positioning them as promising candidates for organic electronics. In this study, we present an in situ measurement of effective gate bias voltage (VGS,eff) in IL-gated organic field-effect transistors (IL-OFETs) using a modified current-voltage measurement configuration. The results reveal a significant deviation between VGS,eff and the applied gate bias (VGS,app), indicating that the EDL at the gate/IL interface screens the applied voltage. It is observed that the screening effect varies depending on the specific cation and anion present in the IL. The evaluation of VGS,eff plays a pivotal role in understanding the intrinsic behavior of IL-OFETs and addresses the challenges associated with accurate performance assessment. Inherently, IL-OFETs demonstrate high transconductance, achieving values of approximately 9 mS while operating at a low threshold voltage of around 0.55 V. Through the acquisition of VGS,eff, we have successfully addressed the limitations impeding the numerical estimation of the trap density of states (trap DOS) in IL-OFETs. Remarkably, our calculations reveal an exceptionally low density of deep traps, which serves as a crucial factor contributing to the near-ideal subthreshold swing (61-68 mV dec-1) observed in IL-OFETs. Further investigations unveil the neutral electrical nature of the IL bulk during OFET operation, confirming the hypothesis that the applied gate bias voltage in electrolyte-gated OFETs drops across the EDLs formed at the interfaces. The impedance spectroscopic (IS) analysis confirms the low contact resistance (≈1 Ω·m) of IL-OFETs calculated using the transition voltage method. The IS analysis also reveals the low-transmissive nature of the IL/organic semiconductor interface. The knowledge gained from this study holds significant implications for realizing high-performance electrolyte-gated OFETs in various applications including digital electronics, energy storage, and sensing. By unraveling the factors influencing the device performance, such as VGS,eff and trap DOS, this research contributes to the advancement of organic electronics and paves the way for future developments in the field.

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents.

Viral infections are the most important health concern nowadays to mankind, which is unexpectedly increasing the health complications and fatality rate worldwide. The recent viral infection outbreak developed a pressing need for small molecules that can be quickly deployed for the control/treatment of re-emerging or new emerging viral infections. Numerous viruses, including the human immunodeficiency virus (HIV), hepatitis, influenza, SARS-CoV-1, SARS-CoV-2, and others, are still challenging due to emerging resistance to known drugs. Therefore, there is always a need to search for new antiviral small molecules that can combat viral infection with new modes of action. This review highlighted recent progress in developing new antiviral molecules based on natural product-inspired scaffolds. Herein, the structure-activity relationship of the FDA-approved drugs along with the molecular docking studies of selected compounds have been discussed against several target proteins. The findings of new small molecules as neuraminidase inhibitors, other than known drug scaffolds, Anti-HIV and SARS-CoV are incorporated in this review paper.

Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds.

This review highlights the recent synthetic developments of benzothiazole based anti-tubercular compounds and their in vitro and in vivo activity. The inhibitory concentrations of the newly synthesized molecules were compared with the standard reference drugs. The better inhibition potency was found in new benzothiazole derivatives against M. tuberculosis. Synthesis of benzothiazole derivatives was achieved through various synthetic pathways including diazo-coupling, Knoevenagel condensation, Biginelli reaction, molecular hybridization techniques, microwave irradiation, one-pot multicomponent reactions etc. Other than recent synthetic developments, mechanism of resistance of anti-TB drugs is also incorporated in this review. Structure activity relationships of the new benzothiazole derivatives along with the molecular docking studies of selected compounds have been discussed against the target DprE1 in search of a potent inhibitor with enhanced anti-tubercular activity.

Anterior scleral thickness in patients of central serous chorioretinopathy: A Case-control study.

BACKGROUND: The aim of this study was to determine whether anterior scleral thickness (AST) varies significantly between patients with central serous chorioretinopathy (CSCR) versus normal individuals. To validate scleral thickness measurements by ultrasound biomicroscopy (UBM) vis a vis anterior segment optical coherence tomography (ASOCT). METHODS: This case-control study analyzed 50 eyes of 50 patients with CSCR (cases) and compared it with that of 50 eyes of 50 age- and gender-matched controls. In cases, AST was measured at 1 mm and 2 mm temporal to the temporal scleral spur by ASOCT and UBM. In controls, AST was measured only by ASOCT. In all participants, posterior choroidal thickness (CT) was measured subfoveally, 1 mm nasal and 1 mm temporal to fovea by enhanced depth imaging optical coherence tomography. RESULTS: The mean AST, as measured by ASOCT among cases and controls was 703.86 µm and 667.54 µm, respectively (P = 0.006). The mean AST by ASOCT and UBM in cases were 703.86 µm and 657.42 µm, respectively (P = 0.001). AST measurement by ASOCT and UBM showed a positive and statistically significant correlation (r = 0.431, P = 0.000). The mean CT among cases and controls was 443.56 µm and 373.88 µm, respectively (P = 0.000). We found a weak positive correlation (r = 0.11) in cases and weaker positive correlation in controls, between CT and AST measured by ASOCT. CONCLUSIONS: Our findings suggest that AST varies significantly between patients with CSCR versus normal individuals. We found poor agreement of AST when measured by ASOCT and UBM.

Hesperetin-loaded polymeric nanofibers: assessment of bioavailability and neuroprotective effect.

OBJECTIVE: The purpose of the study is to assess the bioavailability and neuroprotective effect of hesperetin (Hesp)-loaded nanofibers. METHODS: Electrospinning was used to create and characterize polyvinyl pyrrolidone-based Hesp-loaded nanofibers. To evaluate the produced nanofibers, preclinical studies were conducted. The study involved five groups of Wistar rats, and the treatments were administered as follows. Group 1 (control) was given regular saline for 14 d. On the 14th day, Group 2 was given scopolamine. Group 3 was given donepezil for 14 d and then scopolamine on the 14th. Group 4 was given Hesp for 14 d and then scopolamine on the 14th. Group 5 was given Hesp-loaded nanofibers for 14 d, followed by scopolamine on the 14th. On the 14th day, rats' memory was tested using Cook's pole climbing apparatus and the Morris water maze (MWM). On the 15th day, rats from each group were slaughtered, brain tissues were separated, and biochemical and histological analyses were performed. In addition, in vitro dissolution experiments and pharmacokinetic studies were carried out. RESULTS: When compared to the control group, scopolamine-treated rats had considerably longer escape latency times, as well as increased acetylcholinesterase (AChE) activity, lipid peroxidation, degeneration, and inflammation in the hippocampus. These parameters were greatly recovered by donepezil and Hesp-loaded nanofibers that had been pretreated. Because of the greatly improved bioavailability of Hesp, the Hesp-loaded nanofibers significantly protected rats from scopolamine-induced amnesia. CONCLUSIONS: Hesp-loaded nanofibers have an excellent neuroprotective effect against scopolamine-induced amnesia due to enhanced bioavailability.

Conformationally locked sugar derivatives and analogues as potential neuraminidase inhibitors.

The influenza virus remains a major health concern for mankind because it tends to mutate frequently and cause high morbidity. Influenza prevention and treatment are greatly aided by the use of antivirals. One such class of antivirals is neuraminidase inhibitors (NAIs), effective against influenza viruses. A neuraminidase on the virus's surface serves a vital function in viral propogation by assisting in the release of viruses from infected host cells. Neuraminidase inhibitors are the backbone in stoping such virus propagation thus helps in the treatment of influenza viruses infections. Two NAI medicines are licensed globally: Oseltamivir (Tamiflu™) and Zanamivir (Relanza™). There are two molecules that have acquired Japanese approval recently: Peramivir and Laninamivir, whereas Laninamivir octanoate is in Phase III clinical trials. The need for novel NAIs is due to frequent mutations in viruses and the rise in resistance against existing medication. The NA inhibitors (NAIs) are designed to have (oxa)cyclohexene scaffolds (a sugar scaffold) to mimic the oxonium transition state in the enzymatic cleavage of sialic acid. This review discusses in details and comprises all such conformationally locked (oxa)cyclohexene scaffolds and their analogues which have been recently designed and synthesized as potential neuraminidase inhibitors, thus as antiviral molecules. The structure-activity relationship of such diverese molecules has also been discussed in this review.

Pregnancy Outcomes in Women With SARS-CoV-2 Infection During the First and Second Waves of the COVID-19 Pandemic in a Tertiary Care Hospital in Ayodhya, Uttar Pradesh, India: A Comparative Study.

Introduction Pregnancy is an altered immunological state and not necessarily an immune-compromised state. These immune changes subject pregnant women to increased susceptibility to infection. During the coronavirus disease 2019 (COVID-19) pandemic, pregnant women were more susceptible to serious illness for reasons other than their immune response. The purpose of this study was to compare the feto-maternal outcome (morbidity and mortality) in relation to pre-existing maternal co-morbidities, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-related disease severity, and its impact on the mode of delivery and long-term sequelae in pregnant women in the first and second waves of the COVID-19 pandemic. Materials and methods This was a hospital-based comparative study carried out on 101 pregnant patients during the first wave (April 2020 to December 2020) and 22 patients in the second wave (March 2021 to July 2021) of the COVID-19 pandemic, in Rajashri Dashrath Autonomous State Medical College, Ayodhya, India. All pregnant women with COVID-19 in the first and second waves were included. Non-pregnant patients with COVID-19 infection, pregnant patients lost to follow-up, pregnant patients without COVID-19 infection, and patients in the puerperal period were excluded. Results Seventy-three (72.27%) patients in the first wave and 12 (54.54%) in the second wave were asymptomatic. Those with mild disease numbered 20 (25.74%) in the first wave and six (27.27%) in the second wave. Disease severity was more in the second wave, that is four (18.18%) as compared to one (0.99%) in the first wave. Severe anemia was the most common co-morbidity associated with both first (n=4, 3.96%) and second (n=5, 22.72%) waves. Four (6.45%) spontaneous abortions occurred in the first wave as compared to three (20%) in the second wave. Intensive care unit (ICU) admission was more in the second wave (n=4, 26.66%) as compared to the first wave (n=1, 1.61%). Two (13.33%) maternal deaths occurred in the second wave and none in the first wave. Cesarean sections in both the first and second waves were performed for obstetric indications only. No newborns tested positive in the COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) in the first and second waves at the time of birth; however, three (4.83%) tested positive on day five of birth in the first wave. Fever was the most common presentation in newborns; seven (11.26%) in the first wave and three (20%) in the second wave. No neonatal death occurred in the first or second waves. No congenital anomalies were noted in the first or second waves of COVID-19. Conclusion In this study, we found that the maximum number of COVID-19-positive pregnant patients in both the first and second waves of COVID-19 were either asymptomatic or had mild infections. Second-wave infection was more lethal as compared to the first wave in terms of adverse maternal as well as fetal outcomes. No gestational age was an exception to the severity of disease and its adverse feto-maternal outcome. In our study, maternal co-morbidities did not impact the overall outcome. All cesarean sections were performed for indications other than COVID-19 infection. Long-term sequelae associated with COVID-19 were seen in both groups but more so in the second wave. No long-term sequelae like congenital anomalies in the babies were associated with COVID-19 either in the first or second wave.

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 subjects with type 2 diabetes (8 women; 60 ± 11 years; BMI 32 ± 5 kg/m2) and 19 anthropometrically matched subjects with no diabetes (ND; 11 women; 53 ± 12 years; BMI 29 ± 5 kg/m2) were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 g carbohydrates) on 3 consecutive days in a randomized Latin square design. Three stable isotopes of glucose were ustilized to estimate meal fluxes, and mathematical models were used in estimating indices of insulin action and ß-cell function. Postmeal glucose excursions were higher at D versus B and at D versus L in type 2 diabetes (P < 0.05), while in ND they were higher at D versus B (P = 0.025) and at L versus B (P = 0.04). The insulin area under the curve was highest at B compared with L and D in type 2 diabetes, while no differences were observed in ND. Disposition index (DI) was higher at B than at L (P < 0.01) and at D (P < 0.001) in ND subjects, whereas DI was low with unchanging pattern across B-L-D in individuals with type 2 diabetes. Furthermore, between-meal differences in ß-cell responsivity to glucose (F) and insulin sensitivity (SI) were concurrent with changes in the DI within groups. Fasting and postmeal glucose, insulin, and C-peptide concentrations, along with estimates of endogenous glucose production (EGP), Rd, SI, F, hepatic extraction of insulin, insulin secretion rate, extracted insulin, and DI, were altered in type 2 diabetes compared with ND (P < 0.011 for all). The data show a diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose-tolerant ND individuals that differs from overweight individuals with type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes, but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.

BACKGROUND: The antiretroviral protease inhibitor drug, lopinavir (LPV), is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues. METHODS: The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS. RESULTS: The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension). CONCLUSION: The LPV-SNEDDS could be a potential carrier for LPV oral delivery.

Investigation of the Asyogh's rectangular device for learning and memory testing in Wistar rats.

This study aimed to design Asyogh's rectangular device that is used for memory testing in rodents. It was found that scopolamine (3 mg/kg i.p.) and diazepam (1 mg/kg i.p.) caused significant memory deficits in rats, as evidenced by increased transfer latency times. However, these memory deficits were significantly reversed when the rats were pretreated with Donepezil. It further demonstrates that pretreated donepezil is able to effectively restore the memory deficits induced by scopolamine and diazepam, as indicated by the significant recovery in TLT. The present study showed that the device used to measure transfer latency time that was a valuable tool for assessing memory and cognitive function in rodents.

Morphological and Skeletal Abnormalities Induced by Rolapitant: An Antiemetic Agent.

Introduction Rolapitant hydrochloride is a highly selective, long-acting antagonist of the neurokinin-1 (NK1RA) receptor with a high level of central nervous system (CNS) penetrance. Clinically, it is given to cancer patients with high and moderate emetogenic chemotherapy to prevent chemotherapy-induced nausea and vomiting (CINV). The facts produced in this research support the interpretation of teratogenic effects like anatomical malformations and abnormal skeletal changes affected by high doses of rolapitant in developed chick embryos, which can be extrapolated to humans due to gaps in the literature regarding the teratogenic potential of rolapitant. As rolapitant is metabolized by the liver and excreted through the kidney by leaving a deep impact on the various systems of the body and due to its high plasma concentration with a half-life of more than 180 hours, the study was conducted to acquire some additional information about its adverse effects over the various body systems. Chick is one of the best animals for embryological laboratory research. For various reasons, it is preferred to research embryology in chicks or domestic hens (Gallus domesticus). Chick eggs are large, readily available all year, easy to incubate, and regulate artificially. Aim This study aimed to determine the morphological and skeletal abnormalities due to the effect of rolapitant, an antiemetic agent, in developing White Leghorn (G. domesticus) chicken eggs. Materials and methods The experiment used 300 fertilized White Leghorn chicken eggs. The eggs were categorized into five experimental groups (A, B, C, D, and E, each with 30 eggs) and five control groups (a, b, c, d, and e, each with 30 eggs). Rolapitant was administered into the five experimental groups of eggs on incubation day five at various concentrations of 0.00039, 0.0005, 0.00075, 0.001, and 0.00125 mg, respectively, while the control groups received the same volume (0.039, 0.05, 0.075, 0.1, and 0.125 ml, respectively) of normal saline. Results At all doses, the mean weight and crown-rump (CR) length of chick embryos were significantly greater in the control group than in the experimental group. The experimental group died at a higher rate than the control group. Additionally, it was found that the mortality due to the rolapitant dosages increases with dose. All groups except group A showed skeletal anomalies such as poor ossification, bent, and displacement, and morphological abnormalities such as yolk sac retraction, hematoma, and scanty feathers were found in experimental groups C, D, and E. This was shown to be more prevalent in the experimental groups and was exacerbated by subsequent rolapitant dosages. Conclusion Rolapitant is toxic when taken in large doses and for an extended period. As a result, rolapitant should be taken only when a valid diagnosis has been established and only at the recommended dose, not at a larger dose or for an extended period of time.

Risk factors and outcomes associated with diabetes mellitus in COVID-19 patients: a meta-analytic synthesis of observational studies.

Purpose: We carried out a meta-analytic synthesis to evaluate the association between diabetes mellitus (DM) and related clinical outcomes, co-morbidities, their risk factors and resource utilization in patients with COVID-19. Methods: The MEDLINE and Web of Science databases were reviewed for identification of eligible studies. Meta-analysis was carried out using Review Manager 5.3. The random- effects model was used to compute the pooled estimates of odds ratio (OR)/mean difference and 95% confidence interval (CI). Results: A total of 14 studies including 3,644 individuals without DM and 1,428 with DM were included in the meta-analysis. Cardiovascular diseases (CVDs) [OR 2.91, 95% CI 2.34, 3.63], hypertension [OR 2.19, 95% CI 1.39, 3.46], acute kidney injury (AKI) [OR 3.59, 95% CI 1.46, 8.84], cerebrovascular disease [OR 2.09, 95% CI 1.22, 3.61], and acute respiratory distress syndrome (ARDS) [OR 3.40, 95% CI 2.09, 5.55] were significantly associated with DM in COVID-19 patients compared with non-DM patients (p < 0.05 for all instances). Mortality was significantly higher among COVID-19 patients with DM [OR 2.46, 95% CI 1.68, 3.58]. Intensive Care Unit (ICU) admission and use of mechanical ventilation were significantly associated with COVID-19 patients with DM [OR 2.79, 95% CI 1.79, 4.34], and [OR 3.33, 95% CI 2.05, 5.42], respectively. No significant difference was observed in the length of stay (LOS) and hospitalization. Conclusions: This meta-analysis shows that CVDs, hypertension, AKI, cerebrovascular disease, and ARDS are significantly higher among DM patients with COVID-19 compared with non-DM patients. Mortality, ICU admission and the use of mechanical ventilation were significantly associated with COVID-19 patients with DM. Further long-term, multinational and large sample size clinical studies are warranted to justify the current findings.

Morphometric Analysis of the Cervical Canal Using Computed Tomography Scan Among Patients With Neck Pain in North India.

Introduction Cervical spinal stenosis is a common disease that results in considerable morbidity and disability. To avoid long-term disability caused by irreversible spinal cord damage, quick diagnosis and treatment are required. To our knowledge, until recently, there has been no report or study evaluating the cervical canal stenosis and associated facet joint arthrosis as the major cause of neck pain, so the current study used computed tomography (CT) scans to determine the prevalence of cervical canal stenosis and facet joint osteoarthrosis in patients who presented with neck pain, including its relationship with age, sex, and cervical spinal levels (C3-C7). Methods The current clinical descriptive cross-sectional study was conducted in the Department of Anatomy and Radiodiagnosis at Santosh Medical College, Ghaziabad, for a period of 24 months among newly diagnosed outpatient department (OPD) cases of neck pain (18 years or older) with suspected cervical canal stenosis and facet joint arthrosis. Clinical history, patient-specific clinical examination, and relevant information were obtained in a structured data collection schedule through interviews during OPD hours. All of the participants underwent a CT scan of the cervical region. The independent factors (age, gender, height, and weight) were used in a multiple linear regression analysis of neck pain grading, Torg ratio (TR), and right and left facet joint degeneration, which were expressed as R-squared (R2) and adjusted R-squared (aR2). Statistical tests were executed at a 5% level of significance; an association was considered significant if the p-value was <0.05. Results A total of 83 subjects were enrolled in this study with equal representation from both sexes, i.e., males (49.4%) and females (50.6%). The transverse vertebral canal (T-VC) diameter was narrowest at the level of C3 (25.00 ± 1.13) and gradually increased at the level of C6 (25.18 ± 1.14) in this study. The mean TR of cervical vertebrae C3-C4 dropped gradually from C3 (0.78 ± 0.05) to C7 (0.76 ± 0.05) in this study. Severe left and right facet joint degeneration were observed in 13.3% and 10.5% of study subjects, respectively. In almost every subject, neck pain was a neurological symptom, so multiple linear regression analysis of neck pain grading was carried out with the independent variables (age, gender, height, and weight) and it was found to be not significant (R2 = 0.0617, aR2 = 0.0136, p = 0.2842). Conclusion The articulations of the posterior arch of the vertebrae are known as facet joints. They are a vital component of the vertebral column's structural stability. The superior and inner articular facets of the vertebrae are joined by these joints, which are encased in a fibrous capsule.

13C15N: glucagon-based novel isotope dilution mass spectrometry method for measurement of glucagon metabolism in humans.

BACKGROUND: Glucagon serves as an important regulatory hormone for regulating blood glucose concentration with tight feedback control exerted by insulin and glucose. There are critical gaps in our understanding of glucagon kinetics, pancreatic α cell function and intra-islet feedback network that are disrupted in type 1 diabetes. This is important for translational research applications of evolving dual-hormone (insulin + glucagon) closed-loop artificial pancreas algorithms and their usage in type 1 diabetes. Thus, it is important to accurately measure glucagon kinetics in vivo and to develop robust models of glucose-insulin-glucagon interplay that could inform next generation of artificial pancreas algorithms. METHODS: Here, we describe the administration of novel 13C15N heavy isotope-containing glucagon tracers-FF glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N)] and FFLA glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N; Leu 14 13C6,15N; Ala 19 13C3)] followed by anti-glucagon antibody-based enrichment and LC-MS/MS based-targeted assays using high-resolution mass spectrometry to determine levels of infused glucagon in plasma samples. The optimized assay results were applied for measurement of glucagon turnover in subjects with and without type 1 diabetes infused with isotopically labeled glucagon tracers. RESULTS: The limit of quantitation was found to be 1.56 pg/ml using stable isotope-labeled glucagon as an internal standard. Intra and inter-assay variability was < 6% and < 16%, respectively, for FF glucagon while it was < 5% and < 23%, respectively, for FFLA glucagon. Further, we carried out a novel isotope dilution technique using glucagon tracers for studying glucagon kinetics in type 1 diabetes. CONCLUSIONS: The methods described in this study for simultaneous detection and quantitation of glucagon tracers have clinical utility for investigating glucagon kinetics in vivo in humans.

Management of Glucocorticoid-Induced Hyperglycemia.

Glucocorticoids are potent immunosuppressive and anti-inflammatory drugs used for various systemic and localized conditions. The use of glucocorticoids needs to be weighed against their adverse effect of aggravating hyperglycemia in persons with diabetes mellitus, unmask undiagnosed diabetes mellitus, or precipitate glucocorticoid-induced diabetes mellitus appearance. Hyperglycemia is associated with poor clinical outcomes, including infection, disability after hospital discharge, prolonged hospital stay, and death. Furthermore, clear guidelines for managing glucocorticoid-induced hyperglycemia are lacking. Therefore, this consensus document aims to develop guidance on the management of glucocorticoid-induced hyperglycemia. Twenty expert endocrinologists, in a virtual meeting, discussed the evidence and practical experience of real-life management of glucocorticoid-induced hyperglycemia. The expert group concluded that we should be proactive in terms of diagnosis, management, and post-steroid care. Since every patient has different severity of underlying disease, clinical stratification would help understand patient profiles and determine the treatment course. Patients at home with pre-existing diabetes who are already on oral or injectable therapy can continue the same as long as they are clinically stable and eating adequately. However, depending on the degree of hyperglycemia, modification of doses may be required. Initiating basal bolus with correction regimen is recommended for patients in non-intensive care unit settings. For patients in intensive care unit, variable rate intravenous insulin infusion could be temporarily used, but under supervision of diabetes inpatient team, and patients can be transitioned to subcutaneous insulin once stable baseline assessment and continual evaluation are crucial for day-to-day decisions concerning insulin doses. Glycemic variability should be carefully monitored, and interventions to treat patients should also aim at achieving and maintaining euglycemia. Rational use of glucose-lowering drugs is recommended and treatment regimen should ensure maximum safety for both patient and provider. Glucovigilance is required as the steroids taper during transition, and insulin dosage should be reduced subsequently. Increased clinical and economic burden resulting from corticosteroid-related adverse events highlights the need for effective management. Therefore, these recommendations would help successfully manage GC-induced hyperglycemia and judiciously allocate resources.

Optimization of a Cefuroxime Axetil-Loaded Liquid Self-Nanoemulsifying Drug Delivery System: Enhanced Solubility, Dissolution and Caco-2 Cell Uptake.

Cefuroxime axetil (CA) is an oral cephalosporin which hydrolyzes rapidly to the active parent compound cefuroxime. CA is known to have incomplete oral bioavailability (30−50%) due to its poor solubility and enzymatic conversion to cefuroxime in the gut lumen. In order to overcome these drawbacks, a lipid-based self-nanoemulsifying drug delivery system (SNEDDS) has been developed and optimized. The SNEDDS formulations were prepared using the aqueous phase titration method. The greatest self-emulsifying area was found in the 2:1 Smix ratio. As a result, different SNEDDS formulations were carefully selected from this phase diagram based on their smaller droplet size < 100 nm, polydispersity index ≤ 0.5, dispersibility (Grade A), and transmittance (%) > 85%. Thermodynamic stability tests were carried out in order to rule out any metastable/unstable SNEDDS formulations. The droplet size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of optimized CA-loaded SNEDDS (C-3) were 18.50 ± 1.83 nm, 0.064 ± 0.008, −22.12 ± 1.20 mV, and 97.62 ± 1.06%, respectively. In vitro release studies revealed that the SNEDDS formulation had increased CA solubility. CA-SNEDDS-C3 increased CA cellular uptake, possibly due to increased CA solubility and the inhibition of enzymatic conversion to cefuroxime. Finally, in terms of the improvement of oral bioavailability, CA-loaded-SNEDDS could be a viable alternative to commercially available CA formulations.

Maternal and Perinatal Outcomes of Hospitalized COVID-19 Positive Pregnant Women.

Introduction The consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) /Coronavirus disease 2019 (COVID-19) on mothers and neonates are uncertain due to the lack of robust evidence from various available studies. Furthermore, conflicting data exist regarding the vertical transmission of coronavirus. Therefore, a hospital-based study was conducted to evaluate the effect of COVID-19 on maternal and perinatal outcomes of COVID-19 infected pregnant women. Methodology A hospital-based retrospective observational study was conducted between July-December 2020 in Rajarshi Dashrath Autonomous State Medical College, Ayodhya, Uttar Pradesh, a designated level-2 COVID-19 Hospital. A total of 37 confirmed COVID-19 positive pregnant women (mean age 27.5 ± 05 years) of more than 28 weeks of gestation were included in this study to evaluate the effect of COVID-19 on maternal and perinatal outcomes. Maternal symptoms related to COVID-19, comorbidities, intensive care unit (ICU) admissions, intrauterine growth retardation (IUGR), leaking per vagina, mode of delivery, preterm deliveries, and maternal deaths were recorded. Birth weight of newborns, neonatal intensive care unit (NICU) admissions, neonatal illness, neonatal deaths, and COVID-19 testing reports were recorded.  Result Out of 37 COVID-19 positive pregnant women, 27 (72.9%) women were asymptomatic, nine (24.4%) women were having mild disease, and one (2.7%) developed severe disease requiring ICU admission. No maternal deaths were observed. Twenty-six (70.3%) women were delivered by caesarean section, 11 (29.7%) women by normal vaginal delivery, four (10.8%) were of leaking per vagina. Among newborns, five (13.5%) were preterm, one (2.7%) newborn require NICU admission, two (5.4%) were tested COVID-19 positive on the 5th day of life but were asymptomatic, and four (10.8%) newborns developed a fever but were COVID-19 negative. One case (2.7%) was of stillbirth. No neonatal deaths were observed. Conclusion The present study did not reveal any direct evidence for vertical transmission of SARS-CoV-2 virus through the placenta and during vaginal delivery, but the possibility of mother-to-child infection cannot be completely ignored. SARS-CoV-2 infection during late pregnancy may have a maternal and neonatal impact. COVID-19 infections in late pregnancy might lead to an increased incidence of caesarean deliveries as observed in the present study. This study reveals that most of the COVID-19 positive pregnant women remained asymptomatic or had mild infections. Hence, efforts to limit exposure to COVID-19 of pregnant women should be strengthened for saving mother and child.

Inhibition of 11ß-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study.

AIM: To evaluate whether short-term treatment with a selective 11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D). MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C cortisone to 13 C cortisol in the liver. RESULTS: A total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between-group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity. CONCLUSION: Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.