Risk of diabetes and expected years in life without diabetes among adults from an urban community in India: findings from a retrospective cohort.

BACKGROUND: Diabetes prevalence has increased over the past few decades, and the shift of the burden of diabetes from the older population to the younger population has increased the exposure of longer durations in a morbid state. The study aimed at ascertaining the likelihood of progression to diabetes and to estimate the onset of diabetes within the urban community of Mumbai. METHODS: This study utilized an observational retrospective non-diabetic cohort comprising 1629 individuals enrolled in a health security scheme. Ten years of data were extracted from electronic medical records, and the life table approach was employed to assess the probability of advancing to diabetes and estimate the expected number of years lived without a diabetes diagnosis. RESULTS: The study revealed a 42% overall probability of diabetes progression, with age and gender variations. Males (44%) show higher probabilities than females (40%) of developing diabetes. Diabetes likelihood rises with age, peaking in males aged 55-59 and females aged 65-69. Males aged 30-34 exhibit a faster progression (10.6 years to diagnosis) compared to females (12.3 years). CONCLUSION: The study's outcomes have significant implications for the importance of early diabetes detection. Progression patterns suggest that younger cohorts exhibit a comparatively slower rate of progression compared to older cohorts.

Incidence of needlestick injury among healthcare workers in western India.

BACKGROUND OBJECTIVES: Injuries occurring from contaminated sharps are a major occupational health hazard. It carries a risk of transmitting blood-borne diseases such as human immunodeficiency virus (HIV), hepatitis B and hepatitis C. Healthcare workers (HCWs), including personnel handling biomedical waste, are at risk. The objective of this study was to determine the incidence and details of needlestick injury (NSI) among HCWs. METHODS: We analyzed data of all HCWs who reported NSI over the past three years. Demographic details, type and source of injury, use of personal protective equipment (PPE), immediate post-exposure measures, hepatitis B vaccination status and HCWs and source's HIV, hepatitis B and hepatitis C serological status were studied. RESULTS: Fifty-six cases of NSI were recorded over three years, accounting for an incidence of 10.4/100 occupied beds per year. Maximum cases (73.2%) occurred between the 20 and 40 yr age group. The distribution among the work category was doctors (37.5%), nursing staff (26.8%), phlebotomy technicians (12.5%), housekeeping/subordinate staff (12.5%) and others (10.7%). Appropriate PPE was donned by 66 per cent of the HCWs. The majority of cases (46.4%) occurred in wards and operating rooms (23.2%). Phlebotomy (35.7%), followed by procedures, such as hemoglucotest (HGT) measurement, intravenous cannula insertion and operative procedures (33.9%), were the most common situation during which HCWs suffered NSI. While 64.2 per cent HCWs were vaccinated for hepatitis B, only 5.4 per cent of the HCWs completed post-exposure anti-retroviral regimen. INTERPRETATION CONCLUSIONS: We conclude that a relative lack of awareness towards preventive measures and inexperience among HCWs may be contributory to high occurrence of NSI events. This study emphasizes upon ensuring active hospital-wide hepatitis B vaccination of all HCWs and supportive therapy to improve compliance towards post-exposure prophylaxis.

Quantitative Metabolic Volumetric Product on 18Fluorine-2fluoro-2-deoxy-D-glucose-positron Emission Tomography/Computed Tomography in Assessing Treatment Response to Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Multiparametric Analysis Integrating American College of Rheumatology/European League Against Rheumatism Criteria.

The purpose of this study was to assess the role of fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in the evaluation of treatment response evaluation to disease-modifying antirheumatic drug (DMARD) therapy in patients of rheumatoid arthritis (RA). A total of ten patients with proven diagnosis of RA as per the 2010 American College of Rheumatology/European League against Rheumatism (EULAR) criteria were prospectively evaluated. All patients underwent clinical and biochemical evaluation and a baseline FDG-PET/CT with assessment of maximum standardized uptake value and metabolic volumetric product (MVP) values. DMARD therapy was started with a combination of hydroxychloroquine and sulfasalazine. On follow-up at 3 and 6 months, the response to treatment was assessed by clinical, biochemical, and FDG-PET/CT parameters. These parameters were analyzed in a combined manner, and the patients were grouped into 4 categories as per response to DMARD therapy - complete response, good response, mixed response, and no response. Evaluation of treatment response in ten patients at 3rd month and in nine patients at 6 months showed (a) agreement for MVP, biochemical parameters with clinical symptomatic assessment in all patients, (b) while agreement for EULAR score was noted in only three patients and disagreement in seven patients with clinical symptoms Response EULAR (rEULAR) (0.37) and at 6 months in only three patients and disagreement in six patients, rEULAR (0.52). The correlation factors at 3rd month and 6th months were, respectively, as follows: rMVP (0.67 and 0.75), response RA factor (0.54 and 0.74), response erythrocyte sedimentation rate (0.81 and 0.73), response C-reactive protein (0.78 and 0.51), and response anti-cyclic citrullinated peptide antibodies (0.33 and 0.54). The overall response to DMARD therapy at 3 months was assessed with results showing good response by four cases (40%), mixed response by 1 (10%), no response by 5 (50%), and complete response by none (0%). Step-up therapy at 3 months was initiated in four patients showing nonresponse/progression on clinical symptomatic assessment; of these, two patients showed a good response, one mixed response, and the remaining one continued to show nonresponse at 6 months follow-up. One patient who had a minimal response at 3 months on PET-CT (only 5.96% reduction of MVP) was continued on the same DMARD in view of clinical symptomatic good response (at 3 months) but ultimately had disease progression in all scales and worsening of symptom (at 6 months). FDG-PET/CT-based assessment of inflammatory activity noted in the joints of RA with quantitative parameters can be a promising approach for the whole body assessment of RA disease activity and treatment response assessment, especially in inconclusive cases and correlates well with other parameters. MVP can be used as a useful objective and adjunct parameter for assessing response to treatment.

Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation.

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation.

Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.

Differential diagnosis of lung cancer, its metastasis and chronic obstructive pulmonary disease based on serum Vegf, Il-8 and MMP-9.

Chronic obstructive pulmonary disease (COPD) patients are at higher risk of developing lung cancer and its metastasis, but no suitable biomarker has been reported for differential diagnosis of these patients. Levels of serum biomarkers (VEGF, IL-8, MMP-9 and MMP-2) were analyzed in these patients, which were compared with healthy donors (HD). Levels of VEGF (P < 0.005) and MMP-9 (P < 0.05) were significantly higher in COPD patients than HD. Compared to HD, a decrease in IL-8 (~8.1 folds; P < 0.0001) but an increase in MMP-9 (~1.6 folds; P < 0.05) levels were observed in the lung cancer patients. Cancer patients showed significantly (P < 0.005) lower levels of serum VEGF (1.9 folds) and IL-8 (~9 folds) than the COPD patients. VEGF level was significantly higher (2.6 folds; P < 0.0005) in metastatic than non-metastatic cancer patients. However, MMP-2 didn't show significant variation in these patients. The Youden's index (YI) values for lung cancer diagnosis in HD using IL-8 was 0.55 with 83.3% overall accuracy. VEGF was able to diagnose COPD in HD with better YI (0.38) and overall accuracy (70.6%). IL-8 was able to diagnose cancer in COPD patients and HD with YI values of 0.35, 0.55 with 71% and 83.3% overall accuracy, respectively.

18F-FDG PET and PET/CT in diagnosis and treatment monitoring of pyrexia of unknown origin due to tuberculosis with prominent hepatosplenic involvement.

The potential of (18)F-FDG PET/CT in the diagnosis and treatment response monitoring of fever of unknown origin (resulting from hepatosplenic tuberculosis) is demonstrated in this report. The patient was a 32-y-old woman who had presented to us with a history of pyrexia of unknown origin for the past 2 mo. On investigation, she was found to have hepatic and splenic granulomas, with whole-body (18)F-FDG PET demonstrating abnormal (18)F-FDG-avid foci in the liver and spleen. Ultrasonography-guided liver biopsy was suggestive of granulomatous hepatitis. The patient was clinically nonresponsive to first-line antitubercular drugs, and second-line antitubercular medications were added subsequently in view of clinical nonresponse. The patient responded well to the treatment. The repeated CT scan at 11 mo demonstrated persistence of the splenic granulomas; however, follow-up (18)F-FDG PET/CT at the same time showed resolution of (18)F-FDG-concentrating active disease foci with suggestion of complete metabolic response, commensurate with the patient's clinical improvement.

Discovery of a potent and selective small molecule hGPR91 antagonist.

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.