Expert eValuation of Efficacy and Rationality of Vildagliptin "EVER-Vilda": An Indian Perspective.

Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor is effective in reducing HbA1c levels in patients with type 2 diabetes (T2DM) when administered as monotherapy, dual or triple combination therapy. In India, Vildagliptin is commonly prescribed in T2DM patients because it reduces mean amplitude of glycemic excursion (MAGE), has lower risk of hypoglycemia and is weight neutral. Early combination therapy with vildagliptin and metformin is effective and well-tolerated in patients with T2DM, regardless of age or ethnicity. In view of already existing data on vildagliptin and the latest emerging clinical evidence, a group of endocrinologists, diabetologists and cardiologists convened for an expert group meeting to discuss the role and various combinations of vildagliptin in T2DM management. This practical document aims to guide Physicians and Specialists regarding the different available strengths and formulations of vildagliptin for the initiation and intensification of T2DM therapy.

Multinational primary health care experiences from the initial wave of the COVID-19 pandemic: A qualitative analysis.

OBJECTIVE: To learn from primary health care experts' experiences from the COVID-19 pandemic across countries. METHODS: We applied qualitative thematic analysis to open-text responses from a multinational rapid response survey of primary health care experts assessing response to the initial wave of the COVID-19 pandemic. RESULTS: Respondents' comments focused on three main areas of primary health care response directly influenced by the pandemic: 1) impact on the primary care workforce, including task-shifting responsibilities outside clinician specialty and changes in scope of work, financial strains on practices, and the daily uncertainties and stress of a constantly evolving situation; 2) impact on patient care delivery, both essential care for COVID-19 cases and the non-essential care that was neglected or postponed; 3) and the shift to using new technologies. CONCLUSIONS: Primary health care experiences with the COVID-19 pandemic across the globe were similar in their levels of workforce stress, rapid technologic adaptation, and need to pivot delivery strategies, often at the expense of routine care.

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.

Integrating primary care and public health to enhance response to a pandemic.

Primary health care (PHC) includes both primary care (PC) and essential public health (PH) functions. While much is written about the need to coordinate these two aspects, successful integration remains elusive in many countries. Furthermore, the current global pandemic has highlighted many gaps in a well-integrated PHC approach. Four key actions have been recognized as important for effective integration.A survey of PC stakeholders (clinicians, researchers, and policy-makers) from 111 countries revealed many of the challenges encountered when facing the pandemic without a coordinated effort between PC and PH functions. Participants' responses to open-ended questions underscored how each of the key actions could have been strengthened in their country and are potential factors to why a strong PC system may not have contributed to reduced mortality.By integrating PC and PH greater capacity to respond to emergencies may be possible if the synergies gained by harmonizing the two are realized.

Primary care perspectives on pandemic politics.

While the COVID-19 pandemic now affects the entire world, countries have had diverse responses. Some responded faster than others, with considerable variations in strategy. After securing border control, primary health care approaches (public health and primary care) attempt to mitigate spread through public education to reduce person-to-person contact (hygiene and physical distancing measures, lockdown procedures), triaging of cases by severity, COVID-19 testing, and contact-tracing. An international survey of primary care experts' perspectives about their country's national responseswas conducted April to early May 2020. This mixed method paper reports on whether they perceived that their country's decision-making and pandemic response was primarily driven by medical facts, economic models, or political ideals; initially intended to develop herd immunity or flatten the curve, and the level of decision-making authority (federal, state, regional). Correlations with country-level death rates and implications of political forces and processes in shaping a country's pandemic response are presented and discussed, informed by our data and by the literature. The intersection of political decision-making, public health/primary care policies and economic strategies is analysed to explore implications of COVID-19's impact on countries with different levels of social and economic development.

Rapid quantitative determination of fat-soluble vitamins and coenzyme Q-10 in human serum by reversed phase ultra-high pressure liquid chromatography with UV detection.

We are presenting the first ultra-high pressure LC (UHPLC) method for rapid quantitative measurement of vitamin A, E (alpha- and gamma-tocopherol), beta-carotene and CoQ(10) from human serum. The chromatography was performed on Shield RP(18) UHPLC column with UV detection. The method was validated based on linearity, accuracy, matrix effects study, precision and stability. The calibration was linear over the following range: 0.09-10.0 for retinol and gamma-tocopherol, 0.05-5 for beta-carotene, 0.9-100 for alpha-tocopherol and 0.14-15 mg/L for CoQ(10). The limit of detection and quantitation for retinol, gamma-tocopherol, beta-carotene, alpha-tocopherol and CoQ(10) were as follows 0.07/0.024, 0.018/0.06, 0.004/0.12, 0.078/0.261, 0.008/0.028 mg/L. The recoveries were above 85%. The inter- and intra-assay precision was below 10%. Reference intervals were established for children and adults. Because of its low cost, extremely short analysis time (2 min) and excellent chromatographic reproducibility this UHPLC method can easily be adopted for high-throughput clinical and pharmacokinetics studies.

Utility of single luteinizing hormone determination 3 h after depot leuprolide in monitoring therapy of gonadotropin-dependent precocious puberty.

To determine utility of luteinizing hormone (LH) estimation, post intramuscular (IM) depot leuprolide in comparison with subcutaneous leuprolide stimulation test. Test for monitoring therapy in patients with gonadotropin dependent precocious puberty (GDPP). In seven patients of GDPP, who were treated with 11.25 mg depot leuprolide, the LH peak after subcutaneous (sc) test was compared with LH at hourly interval for 4 h after IM depot leuprolide for 13 tests and 3rd hour value for next ten tests. These two values were compared both before and after therapy. Before therapy, the mean +/- SD LH peak after subcutaneous leuprolide stimulation test was 20.6 +/- 7.85 IU/l (range 9.64-30.4 IU/l), and it was 27.3 +/- 12.21 IU/l 3 h after the first depot leuprolide injection (range 10.5-45.4 IU/l). During therapy, the mean +/- SD of LH peak after sc stimulation test was 1.96 +/- 0.75 IU/l (range 1.1-3.1 IU/l), and it was 2.58 +/- 0.54 IU/l (range 1.4-3.4 IU/l) 3 h after depot leuprolide injection. Three-hour LH value following IM depot leuprolide injection (11.25 mg) can be used for monitoring therapy in patients with GDPP because of its convenience and cost effectiveness.

Analysis of urinary aromatic acids by liquid chromatography tandem mass spectrometry.

The separation and detection of 11 urinary aromatic acids was developed using HPLC-MS/MS. The method features a simple sample preparation involving a single-step dilution with internal standard and a rapid 8 min chromatographic separation. The accuracy was evaluated by the recovery of known spikes between 87 and 110%. Inter- and intra-assay precision (CV) was below 11% in all cases and the analytes were observed to be stable for up to 8 weeks when stored at -20 degrees C. The method was validated based upon linearity, accuracy, precision and stability and was used to establish reference intervals for children and adults.

Quantification of urinary zwitterionic organic acids using weak-anion exchange chromatography with tandem MS detection.

A rapid and accurate quantitative method was developed and validated for the analysis of four urinary organic acids with nitrogen containing functional groups, formiminoglutamic acid (FIGLU), pyroglutamic acid (PYRGLU), 5-hydroxyindoleacetic acid (5-HIAA), and 2-methylhippuric acid (2-METHIP) by liquid chromatography tandem mass spectrometry (LC/MS/MS). The chromatography was developed using a weak anion-exchange amino column that provided mixed-mode retention of the analytes. The elution gradient relied on changes in mobile phase pH over a concave gradient, without the use of counter-ions or concentrated salt buffers. A simple sample preparation was used, only requiring the dilution of urine prior to instrumental analysis. The method was validated based on linearity (r2>or=0.995), accuracy (85-115%), precision (C.V.<12%), sample preparation stability (

High performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) assay for chiral separation of lactic acid enantiomers in urine using a teicoplanin based stationary phase.

A novel method for the separation and simultaneous determination of urinary D- and L-lactic acid enantiomers by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) is presented. The chiral separation was optimized on a Chirobiotic teicoplanin aglyocone (TAG) column. Most interestingly, the addition of water in small volume fraction to the polar organic mobile phase was found to significantly improve the chromatography. Calibration curves were linear (r2>0.9950) over the range 3-1000 mg/L for L-lactic acid and 0.5-160.8 mg/L for D-lactic acid. The limit of detection (LOD) (S/N=3) and limit of quantification (LOQ) (S/N=10) were determined experimentally (n=3) to be 0.2 and 0.5mg/L for L-lactic acid and 0.4 and 1.3 mg/L for D-lactic acid, respectively. The normal patient range of L-lactic acid was 1-20 microg/mg creatinine with an elevated value of 85 microg/mg creatinine. For D-lactic acid, the range of normal values were between 0 and 5 microg/mg creatinine with an elevated value of 40 microg/mg creatinine. Finally, the validated method allows for rapid analysis with a total run time of 7.5 min.

Direct analysis of un-derivatized asymmetric dimethylarginine (ADMA) and L-arginine from plasma using mixed-mode ion-exchange liquid chromatography-tandem mass spectrometry.

A high-throughput analytical method was developed for the measurement of asymmetric dimethylarginine (ADMA) and L-arginine (ARG) from plasma using LC/MS/MS. The sample preparation was simple and only required microfiltration prior to analysis. ADMA and ARG were assayed using mixed-mode ion-exchange chromatography which allowed for the retention of the un-derivatized compounds. The need for chromatographic separation of ADMA from symmetric dimethylarginine (SDMA) was avoided by using an ADMA specific product ion. As a result, the analytical method only required a total run time of 2 min. The method was validated by linearity, with r2>or=0.995 for both compounds, and accuracy, with no more than 7% deviation from the theoretical value. The estimated limit of detection and limit of quantification were suitable for clinical evaluations. The mean values of plasma ADMA and ARG taken from healthy volunteers (n=15) were 0.66+/-0.12 and 87+/-35 microM, respectively; the mean molar ratio of ARG to ADMA was 142+/-81.

Drugs and thyroid.

Drugs can affect thyroid functional status in numerous ways. They may influence thyroid homeostasis at any level from their synthesis, secretion, transport or end-organ action resulting in hypothyroidism or hyperthyroidism. Amiodarone is an important drug in this group. The effects of amiodarone on thyroid function result from iodine release and intrinsic drug properties. Both amiodarone-induced thyrotoxicosis (AIT) and amiodarone -induced hypothyroidism (AIH) may develop in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Treatment of AIH consists of thyroxine replacement while continuing or discontinuing amiodarone therapy. In type I AIT the main medical treatment consists of simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. It is important to evaluate patients before and during amiodarone therapy. The list of drugs affecting thyroid function is long with new drugs being added. Some of them are clinically important while others just produce diagnostic dilemmas. The possible effect of drugs on the results of thyroid-function tests should always be considered while making decisions regarding patient care.

Anatomy, biomechanics, and surgical approach to synovial folds within the joints of the foot.

The presence of synovial folds in various joints of the foot has been previously documented. The function and clinical significance of these structures within the joint have not been established. Histologically they are considered anatomically different from a meniscus primarily owing to their makeup of loose connective tissue with nerve fibrils and several synovial cell layers. We hypothesize that the function of these folds is similar to that of the menisci: to increase joint congruity and stability. We further hypothesize that these folds will be present in joints of the foot that require greater stability. To demonstrate this, 41 fixated cadaveric feet were sectioned in the sagittal plane and the incidence and locations of the synovial folds were documented. Three fixated cadaveric feet were evaluated using a materials testing machine. The first metatarsophalangeal joint was incised, and the presence of the synovial fold was documented. The joint was then taken through its range of motion with and without the synovial fold while data on the force and displacement were collected. The steps were then repeated for the ankle joint. The results showed statistically stiffer ankle and first metatarsophalangeal joints with the synovial fold present, as determined by the stress-strain curve. On the basis of the presence and location of these synovial folds, we demonstrated arthroscopic surgical approaches to many of the documented joints that contain these folds. Because the folds contain synovial cells and vascular tissue, damage to them can result in considerable pain. In such cases, arthroscopic surgery would be of benefit. Further research may indicate whether they need to be salvaged during joint procedures to facilitate normal joint function or should be removed to reduce postoperative complications.

Cushing disease in children and adolescents: twenty years' experience in a tertiary care center in India.

OBJECTIVE: To analyze the clinical presentation, diagnostic evaluation, treatment modalities, and follow-up of pediatric patients with Cushing disease. METHODS: In this retrospective analysis, we reviewed records of children (younger than 20 years) with Cushing disease who had undergone transsphenoidal adenomectomy in a tertiary health care center in India during the period of 1988 to 2008. Endogenous hypercortisolism was identified by a serum cortisol value ≥1.8 µg/dL during a low-dose dexamethasone suppression test (LDDST) with or without elevated midnight serum cortisol (≥3.2 µg/dL). Corticotropin dependence was defined by a basal plasma corticotropin concentration ≥5 pg/mL. Patients with normal pituitary imaging underwent bilateral inferior petrosal sinus sampling (BIPSS). Those with persistent or recurrent disease after surgery were treated with second-line interventions on a case-by-case basis. RESULTS: Twenty-nine boys and 19 girls were included. Mean age was 14.85 (±2.5) years. Weight gain (98%), round facies (98%), and growth arrest (83%) were the most common manifestations. LDDST and midnight cortisol had 100% sensitivity for detecting endogenous hypercortisolism, while midnight corticotropin measurement had 100% sensitivity for defining corticotropin dependence. Magnetic resonance imaging and unstimulated BIPSS had 71% and 89% sensitivity, respectively, for diagnosing Cushing disease. Twenty-seven patients (56%) achieved remission after the first transsphenoidal operation with higher remission rates in those with microadenoma (75%). Basal serum cortisol <5 mg/dL on the fifth postoperative day predicted cure. Eight patients received postoperative radiotherapy, with 4 achieving remission. CONCLUSIONS: Clinical presentation and diagnostic yield with various tests were similar to those previously reported in the literature. Remission rates were poor after first transsphenoidal operation in patients with macroadenoma and outcome was dismal with a second transsphenoidal operation. Serum cortisol concentration <5 mg/dL on the fifth postoperative day predicted cure.

Primary hyperparathyroidism in children and adolescents.

OBJECTIVE: Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. Awareness should improve in order to lower threshold for screening and allow intervention before serious and permanent sequelac occur. METHODS: A retrospective analysis of 15 children and adolescents with PHPT (age <20 yr) seen in our clinic between 1993 and 2006. RESULTS: Mean age of patients was 17.73 yr (Range - 13-20, Male-3: Female-12). Average duration of symptoms was 18.87 (range: 0-48) mo. Clinical features at presentation included bone pain (86.67%), proximal myopathy (46.67%), bony deformities (53.33%), fractures (60%), palpable osteitis fibrosa cystica (33.3%), renal calculi (40%), palpable neck swelling (13.3%) and acute pancreatitis (6.67%). None had positive family history or features suggestive of multiple endocrine neoplasia (MEN). After biochemical confirmation, tumor was localised in all prior to surgery. Histopathology confirmed adenoma in all cases. Post-operative hungry bone syndrome occurred in 33.3%. CONCLUSION: PHPT is more common in females. Presentation of the disease is similar to their adult counterparts except for more severe bone disease and less severe renal disease. MEN and familial non-MEN PHPT do not constitute a major cause of pediatric PHPT as against to worldwide data. The incidence of hyperplasia as a cause of PHPT is rare in our pediatric population.

Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy.

OBJECTIVE: To evaluate the efficacy of cabergoline therapy in patients with Cushing disease who remained uncured (had persistent or recurrent disease) after a pituitary surgical procedure with or without radiotherapy. METHODS: We undertook a prospective, open-label, single-arm study, with short-term (5 months) and longterm (1 year) evaluations. In 20 patients with uncured Cushing disease, treatment was initiated with cabergoline at a dosage of 1 mg/wk, with a monthly increment of 1 mg, until midnight serum cortisol (MNSC) or low-dose dexamethasone suppression serum cortisol (LDSC) (or both) normalized or a maximal dosage of 5 mg/wk was reached. RESULTS: Overall, 5 of 18 patients (28%) responded in terms of LDSC or MNSC (or both) at a mean dosage of 3.6 mg/wk (range, 2 to 5). When the response was defined with use of either LDSC or MNSC level as an isolated criterion, it was achieved in 4 of 16 patients (25%) and 3 of 18 patients (17%), respectively. Four patients were treated for 1 year, and the response was persistent in 2 and 3 patients on the basis of MNSC and LDSC levels, respectively. Lower baseline serum cortisol (basal, MNSC, and LDSC) values were predictive of a therapeutic response. CONCLUSION: Cabergoline was an effective therapy in 28%, 25%, and 17% of patients with uncured Cushing disease in terms of LDSC or MNSC (or both), LDSC alone, and MNSC alone, respectively. Further studies are needed to address the persistence of the drug response and the effects on the dynamics of the hypothalamic-pituitary-adrenal axis.

Prevalence of hypogonadism in patients with type 2 diabetes mellitus in an Asian Indian study group.

OBJECTIVE: To determine the prevalence of hypogonadism in Asian Indian patients with type 2 diabetes mellitus (T2DM) and to correlate it with components of the metabolic syndrome and microvascular complications of T2DM. METHODS: One hundred consecutive male patients with T2DM between 25 and 50 years of age and 50 age-matched healthy adults without diabetes underwent assessment. Calculated free testosterone was derived by using serum total testosterone and sex hormone-binding globulin. Those patients with 2 calculated free testosterone values less than 64.8 pg/mL were diagnosed as having hypogonadism. RESULTS: Of the 100 patients with T2DM, 15 (15%) were found to have hypogonadism-7 of 29 (24%) between 31 and 40 years of age and 8 of 67 (12%) between 41 and 50 years old. None of the 4 patients between 25 and 30 years old had hypogonadism. Eleven patients (73%) had hypogonadotropic hypogonadism, and 4 (27%) had hypergonadotropic hypogonadism. Among the control subjects, the prevalence of hypogonadism was 10%. In comparison with Western data, we found a higher prevalence of hypogonadism in patients with T2DM, especially in those in the 4th decade of life. The prevalence of hypogonadism was higher in obese patients, although it did not reach statistical significance. No statistically significant correlation was observed between hypogonadism and age, duration of diabetes, glycemic control, androgen deficiency symptoms, or microvascular complications. CONCLUSION: The prevalence of hypogonadism was higher in the patients with diabetes than in the control subjects, although the difference did not reach statistical significance. There was no correlation of hypogonadism with components of the metabolic syndrome or microvascular complications of diabetes mellitus.

Bone mineral density and disorders of mineral metabolism in chronic liver disease.

AIM: To estimate the prevalence and identify the risk factors for metabolic bone disease in patients with cirrhosis. METHODS: The study was performed on 72 Indian patients with cirrhosis (63 male, nine female; aged < 50 years). Etiology of cirrhosis was alcoholism (n = 37), hepatitis B (n = 25) and hepatitis C (n = 10). Twenty-three patients belonged to Child class A, while 39 were in class B and 10 in class C. Secondary causes for metabolic bone disease and osteoporosis were ruled out. Sunlight exposure, physical activity and dietary constituents were calculated. Complete metabolic profiles were derived, and bone mineral density (BMD) was measured using dual energy X ray absorptiometry. Low BMD was defined as a Z score below -2. RESULTS: Low BMD was found in 68% of patients. Lumbar spine was the most frequently and severely affected site. Risk factors for low BMD included low physical activity, decreased sunlight exposure, and low lean body mass. Calcium intake was adequate, with unfavorable calcium: protein ratio and calcium: phosphorus ratio. Vitamin D deficiency was highly prevalent (92%). There was a high incidence of hypogonadism (41%). Serum estradiol level was elevated significantly in patients with normal BMD. Insulin-like growth factor (IGF) 1 and IGF binding protein 3 levels were below the age-related normal range in both groups. IGF-1 was significantly lower in patients with low BMD. Serum osteocalcin level was low (68%) and urinary deoxypyridinoline to creatinine ratio was high (79%), which demonstrated low bone formation with high resorption. CONCLUSION: Patients with cirrhosis have low BMD. Contributory factors are reduced physical activity, low lean body mass, vitamin D deficiency and hypogonadism and low IGF-1 level.