Context:Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS.Methods:One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four–hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded.Results:As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance.Conclusions:We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

Context:Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS.Methods:We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index–matched healthy controls, complemented by in vitro experiments.Results:PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis.Conclusions:These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS.

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.

Pembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication.

The knowledge of etiology and antibiotic resistance pattern of the organisms causing urinary tract infection is essential. This study was taken up to determine the presentation and risk factors associated with community-acquired urinary tract infection (CA-UTI). The distribution of bacterial strains isolated from these patients and their resistance pattern were also studied. This multidisciplinary prospective observational study was conducted in M. S. Ramaiah Hospital, Bangalore, between January and December, 2008. Patients who had CA-UTI confirmed by positive urine culture reports were included in the study. Statistical analysis was done using the SPSS version 16. Symptomatology and others risk factors for CA-UTI were studied in these patients and the causative organisms and their resistance patterns were recorded. Of the total 510 patients included, 57% belonged to the elderly age group (50–79 years). Fever and dysuria were the most common clinical presentation, but were not specific in predicting CA-UTI. Escherichia coli (66.9%) was the most common organism causing CA-UTIs with extended spectrum beta lactamase (ESBL) resistance seen in nearly two-thirds of these cases (42.2%). The organisms recorded least resistance against carbapenems (3.9%). A high resistance rate was seen for fluoroquinolones (74.1%). In conclusion, a high rate of ESBL-positive organisms and their resistance to commonly used antibiotics brings a concern for future options in treating these conditions.

Objective: COVID-19 in people with diabetes is associated with a disproportionately worse prognosis. DKA is an acute complication of diabetes with a mortality rate of approximately 0.67%. Little is known about the natural history of DKA in the presence of COVID-19. This study aimed to explore the effects of COVID-19 on presentation, clinical course and outcome in patients presenting with DKA. Design: Retrospective cohort study. Methods: All patients treated for DKA between 1 March 2020 and 30 May 2020 were included. Patients were categorised as COVID-positive or COVID-negative based on swab test. A pre-COVID group was established using data from 01 March 2019 to 30 May 2019 as external control. Data regarding demographics, diabetes type, pH, bicarbonate, lactate, glucose, DKA duration, complications and outcome were collected. Results: A total of 88 DKA episodes were included in this study. There was no significant difference in the severity or duration of DKA between the three groups. COVID-positive T1DM were more hyperglycaemic on admission compared to COVID-negative and pre-COVID patients. There was an over representation of T2DM in COVID-positive patients with DKA than in pre-COVID or COVID-negative groups. Conclusion: COVID-19 appears to influence the natural history of DKA differently in T1DM and T2DM. Patients with T1DM and COVID-19 presented with more hyperglycaemia (60mmol/l (35.9-60.0) vs. 31.4mmol/l (28.0-39.1) vs. 24mmol/l (20.2-33.75), respectively). Patients with T2DM were unusually presenting in DKA when infected with COVID-19 with greater ICU need and higher mortality rates. A collaborative, multi-centre study is needed to provide more definitive results.

Context:Rapid treatment of sepsis is of crucial importance for survival of patients. Specific and rapid markers of bacterial infection have been sought for early diagnosis of sepsis. One such measurement, Procalcitonin (PCT), has recently become of interest as a possible marker of the systemic inflammatory response to infection.Aims:This study was done to find out the common sources of sepsis and to evaluate the diagnostic value of PCT, its predictive value and its relation with Sepsis-related Organ Failure Assessment (SOFA) scores and mortality in various stages of sepsis.Settings and Design:The prospective study was conducted at our tertiary care center from October 2006 to December 2008. A total of 100 patients were included in the study. The study sample included all patients aged above 18 years presenting consecutively to our center during the study period with acute sepsis. They were divided into three groups: sepsis, severe sepsis and septic shockbased on standardized criteria.Materials and Methods:PCT and various other relevant factors were measured in all study subjects. These parameters were compared among the three study groups. The statistical analyses were done using Student “t” test and two-way analysis of variance (ANOVA).Results:Respiratory tract infection was the most common source of sepsis. PCT proved to be an excellent indicator of sepsis with sensitivity of 94%. There was a significant association between serum PCT and SOFA scores (P < 0.05). Serum PCT levels did not predict mortality in the present study.Conclusions:PCT is among the most promising sepsis markers, capable of complementing clinical signs and routine lab parameters suggestive of severe infection.

To investigate the relationship between social deprivation and incident diabetesrelated foot disease (DFD) in newly diagnosed patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A population-based open retrospective cohort study using The Health ImprovementNetwork (1 January 2005 to 31 December 2019) was conducted. Patients with type 2 diabetes free of DFD at baseline were stratified by Townsend deprivation index, and risk of developing DFD was calculated. DFD was defined as a composite of foot ulcer (FU), Charcot arthropathy, lower-limb amputation (LLA), peripheral neuropathy (PN), peripheral vascular disease (PVD), and gangrene. RESULTSA total of 176,359 patients were eligible (56% men; mean age 62.9 [SD 13.1] years). After excluding 26,094 patients with DFD before/within 15 months of type 2 diabetes diagnosis, DFD incidentally developed in 12.1% of the study population over 3.27 years (interquartile range 1.41-5.96). Patients in the most deprived Townsend quintile had increased risk of DFD compared with those in the least deprived (adjusted hazard ratio [aHR] 1.22; 95% CI 1.16-1.29) after adjusting for sex, age at type 2 diabetes diagnosis, ethnicity, smoking, BMI, HbA 1c , cardiovascular disease, hypertension, retinopathy, estimated glomerular filtration rate, insulin, glucose/lipid-lowering medication, and baseline foot risk. Patients in the most deprived Townsend quintile had higher risk of PN