Initiation or switch to insulin degludec/insulin aspart in adults with type 2 diabetes in India: Results from a prospective, non-interventional, real-world study.

Aim: To investigate clinical outcomes in adults with type 2 diabetes (T2D) after insulin degludec/insulin aspart (IDegAsp) treatment in a real-world setting. Methods: The 26 weeks study involved 1102 adults with T2D who were either initiated with or switched to IDegAsp according to local practice in six countries. It was an open-label, non-interventional study. The primary endpoint was the change in glycosylated haemoglobin (HbA1c) levels from baseline to the end of study (EOS). Results: From India, 185 adults participated in this study with mean age of 58.1 (10.3) years and 14.4 (8.1) years of mean duration of T2D. Mean HbA1c decreased from 9.8% (1.8) at baseline to 8.2% (0.1) at the EOS; change in HbA1c from baseline [95% CI]: -1.6% (0.1) [-1.8; -1.4], P < 0.0001. There was a significant reduction in mean fasting plasma glucose (FPG) level from 190.0 (65.8) mg/dl at baseline to 141.9 (4.3) mg/dl at EOS; change in FPG from baseline [95% CI]: -52.2 (4.3) mg/dl [-60.7; -43.7], P < 0.0001. There was a numerical reduction in resource utilization related to diabetes and its complications and hypoglycaemic episodes. From baseline to EOS, the participants with outpatient visits (72 to 32) and workdays missed (2 to 0) decreased. Additionally, the number of patient-reported non-severe hypoglycaemic (47 to 8) and severe hypoglycaemic (4 to 1) episodes decreased as well. Conclusion: Initiation or switching to IDegAsp led to improvement in glycaemic control in real-world population of Indian adults with T2D. This was accompanied by a numerical reduction in resource utilization and patient-reported hypoglycaemia. Clinical trial registration: NCT04042441.

Exploring the novel duo of Reticulocalbin, and Sideroflexin as future biomarker candidates for Exacerbated Chronic Obstructive Pulmonary Disease.

BACKGROUND: COPD is a complex respiratory disorder with high morbidity and mortality rates. Even with the current conventional diagnostic methods, including circulating inflammatory biomarkers, underdiagnosis rates in COPD remain as high as 70%. Our study was a comparative cross-sectional study that aimed to address the diagnostic challenges by identifying future biomarker candidates in COPD variants. METHODS: This study used a label-free plasma proteomics approach that combined mass spectrometric data with bioinformatics to shed light on the functional roles of differentially expressed proteins in the COPD lung microenvironment. The predictive capacity of the screened proteins was assessed using Receiver Operating Characteristic (ROC) curves, with Western blot analysis validating protein expression patterns in an independent cohort. RESULTS: Our study identified three DEPs-reticulocalbin-1, sideroflexin-4, and liprinα-3 that consistently exhibited altered expression in COPD exacerbation. ROC analysis indicated strong predictive potential, with AUC values of 0.908, 0.715, and 0.856 for RCN1, SFXN4, and LIPα-3, respectively. Validation through Western blot analysis confirmed their expression patterns in an independent validation cohort. CONCLUSIONS: Our study discovered a novel duo of proteins reticulocalbin-1, and sideroflexin-4 that showed potential as valuable future biomarkers for the diagnosis and clinical management of COPD exacerbations.

Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors.

Human acetylcholinesterase (hAChE) has a potential role in the management of acetylcholine, one of the neurotransmitters that modulate the overall activity of cholinergic system, AChE inhibitors have a greater impact in the therapeutics. Though the atomic structure of hAChE has been extensively studied, the precise active site geometry upon binding to different ligands are yet to be explored. In the present study, an extensive structural analysis of our recently reported hAChE-tacrine complex has carried out and revealed the presence of two prominent sub-pockets located at the vicinity of the hAChE active site. Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs), their molecular docking, free energy estimations revealed that they are stronger than tacrine in terms of binding affinity. Our in vitro studies also supported the in silico findings, all these SPFTDs are having better potencies than tacrine. Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.

Management of Hypertension in Patients with Diabetes: A Comprehensive Review of the Perceptions and Practices of Health Care Providers in India.

OBJECTIVES: This study evaluated the perception and practices of health care providers (physicians, diabetologists, and endocrinologists) regarding the treatment of hypertension in patients with diabetes in India. METHODS: Health care providers throughout India who treated patients with diabetes and hypertension were invited to participate in an online survey and periodic 21 virtual meetings. They were questioned about their perception and practices in managing these patients, and strategies to improve blood pressure (BP). RESULTS: The online survey was completed by 2,513 health care providers, and 344 participated in virtual meetings. More than 50% reported that 31-50% of their patients with diabetes also had hypertension. Home BP monitoring was recommended by 88%, and lifestyle modifications were consistently recommended. Choice of antihypertensive treatment varied based on comorbidities, and a renin-angiotensin system blocker plus a calcium channel blocker (CCB) was the most common combination for dual antihypertensive therapy. Suggested strategies to improve BP control included patient awareness/education, lifestyle modifications, better follow-up/monitoring, and optimization of therapy. CONCLUSION: Indian health care providers were aware of clinical recommendations and practices regarding treatment of patients with diabetes and hypertension, and generally make clinical decisions consistent with current guidelines. Optimization of care for these patients is essential to reduce cardiovascular disease risk and improve patient outcomes.

Identification of Novel Serum Proteins Associated with Myelination and Cholesterol Transport in Neuromyelitis Optica Spectrum Disorders by Mass Spectrometry.

Neuromyelitis optica spectrum disorders (NMOSD) is a demyelinating autoimmune disease affecting the central nervous system causing inflammatory lesions in the optic nerves, spinal cord and other vital areas of CNS. The clinical manifestations include acute transverse myelitis with paraplegia and optic neuritis with impaired vision. In the present study we focussed on comparative expression of serum proteins between NMOSD variants and control. The study has identified a plethora of novel and unexplored acute phase proteins involved in lipid transport and myelination in perspective of NMOSD. The serum proteins obtained after albumin globulin depletion were subjected to LC-MS/MS. The commonly altered proteins in all NMOSD variants with respect to control were smaug homolog protein and serum amyloid A. Truncated breast and ovarian cancer susceptibility protein and cystic fibrosis transmembrane conductance regulator protein were specifically upregulated and can act as potential biomarkers for neuromyelitis optica with autoantibody negativity to Aquaporin - 4 (AQP-4) and myelin oligodendrocyte (MOG) immunoglobulins. In addition, the uniquely downregulated proteins such as antithrombin III and histidine rich glycoprotein in NMO/MOG autoantibody negative samples can be accounted for its dysregulated fibrinolysis associated with NMO. The differentially expressed proteins were involved in cholesterol transport, synaptic vesicle mediated transport, neurotransmission and immune regulation which are closely associated with myelin formation and protection. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-021-01004-w.

Utility of TSH Receptor Antibodies in the Differential Diagnosis of Hyperthyroidism in Clinical Practice.

Graves' disease (GD) is the most common cause of hyperthyroidism in iodine-sufficient areas. It is important to distinguish GD from other causes of hyperthyroidism for optimal management. Thyroid stimulating hormone receptor antibody (TRAb) test is a commonly used test for this purpose. However, the sensitivity for this test in routine clinical practice may be affected by various factors leading to fallacies in diagnosis. Materials and Methods: A retrospective study was performed to assess the utility of an automated electrochemiluminescence TRAb immunoassay (Roche) in differentiating GD from non-Graves' disease (NGD) in routine clinical practice. Results: In 227 subjects, 146 had GD and 81 had NGD. Total T3, Total T4, Free T4, and TRAb were significantly higher in people with GD in comparison to NGD. The area under the receiver operating characteristics (ROC) curve for the assay was 0.96 (95% CI: 0.926 to 0.984, P < 0.0001). The optimal threshold for the test derived from the ROC was 3.37 IU/L, which is more than the cut-off of 1.75 IU/L suggested by the manufacturer. The sensitivity/specificity of TRAb in the diagnosis of GD at presentation was 98.4%/62.9% at 1.75 IU/L and 91.2%/90.12% at 3.37 IU/L, respectively. Conclusion: The TRAb test is a sensitive test to differentiate between subjects with GD and NGD presenting with hyperthyroidism. However, the cutoff (1.75 IU/L) as per the kit manufacturer may lead to a lower specificity for diagnosis. A modified cut-off of 3.37 IU/L should be considered for optimizing the diagnostic efficacy of the test.

Role and importance of high fiber in diabetes management in India.

BACKGROUND & AIMS: India is facing a triple burden of pre-diabetes, diabetes, and obesity. Unhealthy eating habits and physical inactivity have been linked to the onset and progression of type 2 diabetes mellitus (T2DM). Despite dietary recommendations, individuals consume inadequate amounts or unsuitable type of dietary fiber (DF) which needs correction. An Expert group attempted to review and report on the role and importance of high DF in the management of T2DM and offer practical guidance on high fiber use in daily diet. METHODOLOGY: Twelve diabetologists and two expert dietitians from India were chosen to ensure diversity of the members both in professional interest and cultural background. The authors convened virtually for one group meeting and actively participated in a detailed discussion. Multiple reviews of the draft document followed by focused teleconference calls & email helped to reach consensus on final recommendations between Aug 2021 and Dec 2021. RESULTS: Evidence has shown that medical nutrition therapy (MNT) is a valuable approach and an essential component of T2DM prevention and management. Studies have shown that fiber rich diabetes nutrition (FDN) has multi-systemic health benefits, including, improvement in glycemic control, reduction in glucose spikes, decrease in hyperinsulinemia, improvement in plasma lipid concentrations and weight management in T2DM patients. CONCLUSION: A high fiber diet is vital for people with diabetes and associated conditions. Increasing fiber intake, preferably through food or through dietary supplement, may help. Fiber rich diabetes nutrition (FDN) is recommended in order to prevent and manage T2DM.

Cardiovascular risk in newly diagnosed type 2 diabetes patients in India.

BACKGROUND: Type 2 diabetes mellitus (T2DM) worldwide continues to increase, in particular in India. Early T2DM diagnosis followed by appropriate management will result in more cardiovascular event free life years. However, knowledge of the cardiovascular profile of newly diagnosed T2DM patients is still limited. The aim of this study was to understand the extent of cardiovascular disease (CVD) risk of newly diagnosed T2DM patients in India. METHODS: A cross sectional observational study was conducted to evaluate clinical laboratory and socio-demographic parameters of 5,080 newly diagnosed T2DM patients (48.3 ± 12.8 years of age; 36.7% female). In addition, we determined their cardiovascular risk according to the guidelines of the Lipid Association of India (LAI) and the criteria of the QRISK3 score. RESULTS: Of the newly T2DM diagnosed patients in India 2,007(39.5%) were classified as "High risk" and 3,073 (60.5%) were classified as "Very high risk" based on LAI criteria. On average, patients had 1.7 ± 0.9 major atherosclerotic cardiovascular disease (ASCVD) risk factors. Low HDL-C value was the most frequent major risk (2,823; 55.6%) followed by high age (2,502; 49.3%), hypertension (2,141; 42.1%), smoking/tobacco use (1,078; 21.2%) and chronic kidney disease stage 3b or higher (568; 11.2%). In addition, 4,192 (82.5%) patients appeared to have at least one cholesterol abnormality and, if the latest LAI recommendations are applied, 96.5% (4,902) presented with lipid values above recommended targets. Based on the QRISK3 calculation Indian diabetes patients had an average CVD risk of 15.3 ± 12.3%, (12.2 ± 10.1 vs. 17.1 ± 13.5 [p<0.001] for females and males, respectively). CONCLUSIONS: Newly diagnosed Indian T2DM patients are at high ASCVD risk. Our data therefore support the notion that further extension of nationwide ASCVD risk identification programs and prevention strategies to reduce the occurrence of cardiovascular diseases are warranted.

Testosterone replacement therapy in men with type 2 diabetes mellitus and functional hypogonadism -an Integrated Diabetes and Endocrine Academy (IDEA) consensus guideline.

BACKGROUND: Though testosterone replacement therapy in men with organic hypogonadism is established, its role in men with type 2 diabetes mellitus (T2DM) and functional hypogonadism is unclear. METHODS: Thirteen experts addressed ten topic-specific questions after an in-depth review of literature, where all relevant issues were critically evaluated. RESULTS: Ten recommendations concerning diagnosis and management of men with T2DM and functional hypogonadism have been put forward. CONCLUSION: Routine measurement of serum testosterone in all, and inappropriate replacement of testosterone in asymptomatic T2DM men with functional hypogonadism and borderline low serum testosterone values, is not recommended.

Cardiometabolic vigilance in COVID-19 and resource husbandry in resource-challenged times: Clinical practice- based expert opinion.

BACKGROUND AND AIMS: The ongoing pandemic of coronavirus disease 2019 (COVID-19) is rapidly evolving, thereby posing a profound challenge to the global healthcare system. Cardiometabolic disorders are associated with poor clinical outcomes in persons with COVID-19. Healthcare challenges during the COVID-19 pandemic are linked to resource constraints including shortage of Personal Protective Equipment's (PPE), laboratory tests and medication. In this context, a group of clinical experts discussed the endocrine and cardiology vigilance required in times of COVID-19. Further, the group proposed certain resource husbandry recommendations to be followed during the pandemic to overcome the constraints. METHOD: The clinical experts discussed and provided their inputs virtually. The expert panel included clinical experts comprising endocrinologists, Consultant Physicians and cardiologists from India. The panel thoroughly reviewed existing literature on the subject and proposed expert opinion. RESULTS: The expert panel put forward clinical practice-based opinion for the management of cardiometabolic conditions including diabetes mellitus and hypertension. As these conditions are associated with poor clinical outcomes, the expert panel recommends that these persons be extra-cautious and take necessary precautions during the ongoing pandemic. Further, experts also provided appropriate, affordable, available and accessible solution to the resource constraint situations in times of COVID-19 pandemic. CONCLUSION: The clinical expert opinion put forward in this article will serve as a reference for clinicians treating diabetes and cardiovascular disease during the COVID-19 pandemic.

Use of Gla-100 in Special Situations.

Insulin therapy is the cornerstone of diabetes management in people with type 2 diabetes mellitus (T2DM). Therefore, its use is recommended even in special populations and situations such as the elderly, pregnant women, obese individuals, people observing religious fasting, and in the presence of comorbidities such as renal insufficiency, and cancer. Since these special situations predispose to complications such as a high risk of hypoglycemia, patients need constant glucose monitoring and insulin dose adjustments, wherever applicable. This review discusses the various considerations that might guide the decision-making process in the special situations alluded to here. It also throws light on how insulin glargine 100 U/mL has emerged as a preferred choice of insulin therapy in most of these situations, on the strength of its inherently low hypoglycemia and weight gain potential, which has found traction even in the recent diabetes guidelines.

An Unusual Cause of Chylothorax after Esophagectomy.

Chylothorax due to inadvertent thoracic duct injury after esophagectomy is a well-known complication and requires careful postoperative management and timely intervention to prevent potential morbidity and mortality. We present a case of high-output chylothorax after esophagectomy where the source of chyle leak was not in the thorax.

Modern sulphonylureas and cardiovascular adverse effects: Will CAROLINA put an end to the controversy?

Sulphonylureas (SU) form an important role in management of people with type 2 diabetes. This safety history of SU was tainted for various reasons, the predominant one being lack of demonstration of cardiovascular safety. Since its introduction, SU's have never been subjected to a formal study for its cardiovascular safety. The cardiovascular safety of SUs was derived from small, inadequately powered randomised controlled trials (RCT) and observational studies. CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) trial planned as a cardiovascular outcome trial randomised people with type 2 diabetes and high cardiovascular risk to Linagliptin and Glimepiride. This opinion paper outlines the salient features of this landmark trial and its implications in general cardiology practice.

Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines.

Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal-bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.

Long-acting porcine ACTH stimulated salivary cortisol in the diagnosis of adrenal insufficiency.

BACKGROUND: Synacthen stimulated salivary cortisol has been previously evaluated and found beneficial in the diagnosis of adrenal insufficiency (AI), especially in situations with altered cortisol-binding protein (CBG) levels. Unfortunately, Synacthen is not marketed in many parts of the world whereas porcine sequence corticotrophin (Acton Prolongatum) is readily available. This study aimed to find the diagnostic accuracy of Acton prolongatum stimulated salivary cortisol test (APSST) compared to the short synacthen test (SST). METHODS: Consecutive outpatients with suspected AI underwent SST initially, followed by APSST after 3 days. For APSST, saliva was collected at 0, 60 and 120 minutes after administering 30 units Acton Prolongatum intramuscularly. Serum and salivary cortisol were estimated using electrochemiluminescence assay. (Cobas e 411, Elecsys Cortisol II kits) RESULTS: Sixty-seven patients with clinically suspected AI were enrolled for the study. Based on SST, 35 patients were classified as having AI [primary AI (n=19) and secondary AI (n=16)] whereas 32 had normal glucocorticoid reserve. The area under receiver operator curve of 0.99 and 0.98 was observed for salivary cortisol values at 60 and 120 minutes, respectively, for APSST. A cut-off value of 18.5 nmol/L (0.67 µg/dL) and 29.3 nmol/L (1.06 µg/dL) at 60 and 120 minutes, respectively, had a sensitivity as well as specificity of 93%-100% in diagnosing AI. CONCLUSION: Salivary cortisol estimation following stimulation using intramuscular porcine ACTH (Adrenocorticotrophic hormone) (30 units) is an economical and accurate alternative to SST in the diagnosis of AI, m and its level of 30 nmol/L or more at 2 hours confirms adrenal sufficiency.

Late-Night Salivary Cortisol in Healthy, Community-Dwelling Asian Indians Assessed by Second-Generation ECLIA.

BACKGROUND: Late-night salivary cortisol (LNSC) is used as a screening test for Cushing syndrome (CS), but there is no community-derived normative data for the normal upper limit in the South Asian population. This study aimed to determine the upper limit of normal (97.5th percentile) for LNSC in an Asian Indian population using a commercially available second-generation electrochemiluminiscence immunoassay (ECLIA). METHODS: LNSC in apparently healthy community-dwelling individuals was assessed by multistage cluster sampling. Healthy individuals age 18 to 60 years from 8 urban and 8 rural clusters of Thiruvananthapuram district were studied. Thirty people from an approximate population of 1000 individuals from each cluster participated in the study. A saliva sample was collected between 11 PM and 12 midnight and analyzed using Roche COBAS-e-411 and ultrasensitive Cortisol II kits the next day. RESULTS: Cortisol values from 474 salivary samples were available for final analysis after exclusion of improperly collected samples. The 97.5th percentile of the LNSC concentrations was 0.25 µg/dL (6.89 nmol/L) (90% CI, 0.23-0.27 µg/dL; ie, 6.34-7.45 nmol/L). In postmenopausal women, median LNSC was significantly higher but the 90% CI for the upper limit of their LNSC (0.28µg/dL or 7.72 nmol/L) overlapped with that of premenopausal women. CONCLUSIONS: This study establishes the normal value of LNSC estimated by second-generation ECLIA in healthy community-dwelling Asian Indian individuals for the first time. Salivary cortisol at 11 pm to 12 am is less than 0.25µg/dL (6.89 nmol/L) in the general Asian Indian population. Menopause causes a significant increase in LNSC and may lead to overdiagnosis of CS if not interpreted carefully.

Thoracoscopic Esophagectomy for a Huge Leiomyosarcoma.

Esophageal leiomyosarcoma is the commonest of all esophageal sarcomas but yet has a very low incidence. These tumors have been resected by the open approach so far. We describe the steps and challenges involved in the thoracoscopic excision of a huge leiomyosarcoma of the esophagus.

Alteration in the phosphorylation status of NMDA receptor GluN2B subunit by activation of both NMDA receptor and L-type voltage gated calcium channel.

Calcium influx through N-methyl-D-aspartate receptors (NMDAR) and voltage-gated calcium channels (VGCC) play major roles in postsynaptic signaling mechanisms. NMDAR subunit GluN2B is phosphorylated at Ser1303. Phosphorylation at this site is a prominent event in cell culture systems as well as in vivo. However, the functional significance of phosphorylation at this site is not completely understood. In this study, we compared the effect of calcium signaling through NMDAR and VGCC on the phosphorylation status of GluN2B-Ser1303 in the rat in vivo. VGCC was activated by intraperitoneal (IP) injection of the activator, BayK8644 and NMDAR was activated by intracerebroventricular (ICV) injection of NMDA in separate experimental groups. We found that the level of phospho-GluN2B-Ser1303 in the cortex and in the hippocampus increased in response to activation of either channel. The effects could be prevented by prior ICV administration of the specific blockers of these channels such as MK-801 for NMDAR and nifedipine for VGCC. The effect was also blocked by pretreatment with ICV administration of KN-93 indicating that it is mediated through CaM kinase. Both during NMDAR activation and VGCC activation, cell survival associated signals such as phospho-AKT and phospho-CREB showed decrease, consistent with activation of cell death pathways during these treatments. We conclude that under in vivo conditions, calcium influx through either NMDAR or VGCC activates CaM kinase, which in turn phosphorylates GluN2B-Ser1303.