COVID-19 and tobacco cessation: lessons from India.

OBJECTIVES: The Government of India prohibited the sale of tobacco products during the COVID-19 lockdown to prevent the spread of the SARS-CoV-2 virus. This study assessed the tobacco cessation behaviour and its predictors among adult tobacco users during the initial COVID-19 lockdown period in India. METHODS: A cross-sectional study was conducted with 801 adult tobacco users (both smoking and smokeless tobacco) in two urban metropolitan cities of India over a 2-month period (July to August 2020). The study assessed complete tobacco cessation and quit attempts during the lockdown period. Logistic and negative binomial regression models were used to study the correlates of tobacco cessation and quit attempts, respectively. RESULTS: In total, 90 (11.3%) tobacco users reported that they had quit using tobacco after the COVID-19 lockdown period. Overall, a median of two quit attempts (interquartile range 0-6) was made by tobacco users. Participants with good knowledge on the harmful effects of tobacco use and COVID-19 were significantly more likely to quit tobacco use (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.2-4.0) and reported more quit attempts (incidence risk ratio 5.7; 95% CI 2.8-11.8) compared to those with poor knowledge. Participants who had access to tobacco products were less likely to quit tobacco use compared to those who had no access (OR 0.3; 95% CI 0.2-0.5]. CONCLUSIONS: Access restrictions and correct knowledge on the harmful effects of tobacco use and COVID-19 can play an important role in creating a conducive environment for tobacco cessation among users.

A unique case of light chain (AL) amyloidosis masquerading as hypophosphatemic osteomalacia.

Light chain (AL) amyloidosis is the result of a clonal plasma cell disorder which causes organ damage by deposition of misfolded light chains. Kidney is a common site of amyloid deposition. Proteinuria, usually in nephrotic range and unexplained renal insufficiency are the main manifestations of renal injury. We report a unique case of renal involvement by AL amyloidosis masquerading as metabolic bone disease. 38 year old male patient presented with progressively increasing diffuse bony pains, low backache and proximal weakness of both lower limbs since two years. On investigation, he was detected to have hypophosphatemic osteomalacia due to renal phosphate loss which was fibroblast growth factor 23 (FGF23)- independent. He also had nephrotic range low molecular weight proteinuria. Renal biopsy to ascertain the aetiology revealed deposition of amyloid fibrils in the glomerular mesangium on electron microscopy. Its characterization by immunofluorescence (IF) was consistent with immunoglobulin light chain (AL) amyloidosis. In the absence of a demonstrable plasma cell clone on bone marrow biopsy, we made a diagnosis of monoclonal gammopathy of renal significance (MGRS). He was treated with chemotherapy following which there was symptomatic improvement and reduction in phosphaturia. This case describes a unique presentation of renal injury due to AL amyloidosis masquerading as hypophosphatemic osteomalacia. The aim of this report is to highlight that hypophosphatemia in adults is usually acquired and treatment of underlying etiology results in cure, unlike in children where genetic counseling and phosphate replacement is the mainstay of treatment.

Language prediction mechanisms in human auditory cortex.

Spoken language, both perception and production, is thought to be facilitated by an ensemble of predictive mechanisms. We obtain intracranial recordings in 37 patients using depth probes implanted along the anteroposterior extent of the supratemporal plane during rhythm listening, speech perception, and speech production. These reveal two predictive mechanisms in early auditory cortex with distinct anatomical and functional characteristics. The first, localized to bilateral Heschl's gyri and indexed by low-frequency phase, predicts the timing of acoustic events. The second, localized to planum temporale only in language-dominant cortex and indexed by high-gamma power, shows a transient response to acoustic stimuli that is uniquely suppressed during speech production. Chronometric stimulation of Heschl's gyrus selectively disrupts speech perception, while stimulation of planum temporale selectively disrupts speech production. This work illuminates the fundamental acoustic infrastructure-both architecture and function-for spoken language, grounding cognitive models of speech perception and production in human neurobiology.

High burden of cardiometabolic risk factors in spouses of Indian women with hyperglycaemia in pregnancy.

AIM: To evaluate the burden and association of cardiometabolic risk factors in the spouses of women with and without hyperglycaemia in pregnancy. METHODS: Women with (n = 204) and without (n = 197) hyperglycaemia in pregnancy, along with their spouses, participated in this cross-sectional study. The hyperglycaemia in pregnancy group included women with gestational diabetes and diabetes in pregnancy. A detailed questionnaire was completed for all participants (men and women), documenting relevant personal and medical history, along with biochemical investigations (men). RESULTS: A total of 401 couples were evaluated at the time point during the pregnancy of 24.7 ± 5.2 gestational weeks (mean ± sd). Dysglycaemia (prediabetes or diabetes), overweight/obesity (BMI ≥25 kg/m2 ) and metabolic syndrome were detected in 120 (58.9%), 123 (60.3%) and 98 spouses (48.3%) of women with hyperglycaemia in pregnancy, respectively. In the fully adjusted model, an increased risk of dysglycaemia [odds ratio 1.43 (95% CI 0.95-2.17); P = 0.088], overweight/obesity [odds ratio 1.49 (95% CI 0.98-2.27); P = 0.064] and metabolic syndrome [odds ratio 2.00 (95% CI 1.30-3.07); P = 0.001] was seen in the spouses of women with hyperglycaemia in pregnancy. The prevalence of these metabolic conditions was higher in spouses of women with diabetes in pregnancy compared to spouses of women with gestational diabetes mellitus. CONCLUSIONS: A high burden of cardiometabolic risk factors was observed in the spouses of women with hyperglycaemia in pregnancy. The opportunity provided by pregnancy could be used by the healthcare system not only to improve the health of the woman and her offspring, but also her spouse.

Effect of a multicomponent intervention on achievement and improvements in quality-of-care indices among people with Type 2 diabetes in South Asia: the CARRS trial.

AIMS: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care. METHODS: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol. RESULTS: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]. CONCLUSIONS: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps.

Isolated HbA1c identifies a different subgroup of individuals with type 2 diabetes compared to fasting or post-challenge glucose in Asian Indians: The CARRS and MASALA studies.

AIMS: Guidelines recommend hemoglobin A1c (HbA1c) as a diagnostic test for type 2 diabetes, but its accuracy may differ in certain ethnic groups. METHODS: The prevalence of type 2 diabetes by HbA1c, fasting glucose, and 2 h glucose was compared in 3016 participants from Chennai and Delhi, India from the CARRS-2 Study to 757 Indians in the U.S. from the MASALA Study. Type 2 diabetes was defined as fasting glucose ≥ 7.0 mmol/L, 2-h glucose ≥ 11.1 mmol/L, or HbA1c ≥ 6.5%. Isolated HbA1c diabetes was defined as HbA1c ≥ 6.5% with fasting glucose < 7.0 mmol/L and 2 h glucose < 11.1 mmol/L. RESULTS: The age, sex, and BMI adjusted prevalence of diabetes by isolated HbA1c was 2.9% (95% CI: 2.2-4.0), 3.1% (95% CI: 2.3-4.1), and 0.8% (95% CI: 0.4-1.8) in CARRS-Chennai, CARRS-Delhi, and MASALA, respectively. The proportion of diabetes diagnosed by isolated HbA1c was 19.4%, 26.8%, and 10.8% in CARRS-Chennai, CARRS-Delhi, and MASALA respectively. In CARRS-2, individuals with type 2 diabetes by isolated HbA1c milder cardio-metabolic risk than those diagnosed by fasting or 2-h measures. CONCLUSIONS: In Asian Indians, the use of HbA1c for type 2 diabetes diagnosis could result in a higher prevalence. HbA1c may identify a subset of individuals with milder glucose intolerance.

A lifestyle intervention programme for the prevention of Type 2 diabetes mellitus among South Asian women with gestational diabetes mellitus [LIVING study]: protocol for a randomized trial.

AIM: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. METHODS: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness. DISCUSSION: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939).

Acceptability of a decision-support electronic health record system and its impact on diabetes care goals in South Asia: a mixed-methods evaluation of the CARRS trial.

AIMS: To describe physicians' acceptance of decision-support electronic health record system and its impact on diabetes care goals among people with Type 2 diabetes. METHODS: We analysed data from participants in the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, who received the study intervention (care coordinators and use of a decision-support electronic health record system; n=575) using generalized estimating equations to estimate the association between acceptance/rejection of decision-support system prompts and outcomes (mean changes in HbA1c , blood pressure and LDL cholesterol) considering repeated measures across all time points available. We conducted in-depth interviews with physicians to understand the benefits, challenges and value of the decision-support electronic health record system and analysed physicians' interviews using Rogers' diffusion of innovation theory. RESULTS: At end-of-trial, participants with diabetes for whom glycaemic, systolic blood pressure, diastolic blood pressure and LDL cholesterol decision-support electronic health record prompts were accepted vs rejected, experienced no reduction in HbA1c [mean difference: -0.05 mmol/mol (95% CI -0.22, 0.13); P=0.599], but statistically significant improvements were observed for systolic blood pressure [mean difference: -11.6 mmHg (95% CI -13.9, -9.3); P ≤ 0.001], diastolic blood pressure [mean difference: -5.2 mmHg (95% CI -6.5, -3.8); P ≤ 0.001] and LDL cholesterol [mean difference: -0.7 mmol/l (95% CI -0.6, -0.8); P ≤0.001], respectively. The relative advantages and compatibility of the decision-support electronic health record system with existing clinic set-ups influenced physicians' acceptance of it. Software complexities and data entry challenges could be overcome by task-sharing. CONCLUSION: Wider adherence to decision-support electronic health record prompts could potentially improve diabetes goal achievement, particularly when accompanied by assistance from a non-physician health worker.

Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation.

Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1-p67phox interaction prevents platelet activation. Pharmacologic targeting of Rac1-NOX2 axis can be a viable approach for antithrombotic therapy. SUMMARY: Background Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. Objective We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac-p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1-/- mice or human platelets treated with NSC23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP. Treatment of platelets with Phox-I inhibited diverse CRP-induced responses, including: (i) ROS generation; (ii) release of P-selectin; (iii) secretion of ATP; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox-I inhibited thrombin-induced: (i) secretion of ATP; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox-I inhibited: (i) collagen-induced platelet aggregation without affecting the tail bleeding time and (ii) in vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss. Conclusions Small molecule targeting of the Rac1-p67phox interaction may present an antithrombosis regimen by preventing GPVI- and non-GPVI-mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time.

Prevalence of vitamin B12 deficiency in healthy Indian school-going adolescents from rural and urban localities and its relationship with various anthropometric indices: a cross-sectional study.

BACKGROUND: Micronutrient deficiency is a global health burden, especially among developing countries. The present cross-sectional study aimed to determine the prevalence of vitamin B12 deficiency in healthy Indian school-going adolescents, based on area of residence, sex and body mass index (BMI). Furthermore, the relationship of serum B12 concentration with dietary vitamin B12 intake and anthropometric indices was assessed among adolescents from rural and urban India. METHODS: A total of 2403 school-going adolescents (11-17 years) from National Capital Region and rural areas of Haryana, India were selected. Serum B12 concentrations were estimated using an electrochemiluminescence immunoassay. Dietary assessments were conducted on 65% of total participants (n = 1556) by two 24-h diet recalls. RESULTS: The prevalence of vitamin B12 deficiency in the total study population was 32.4% (rural: 43.9% versus urban: 30.1%, P < 0.001; male: 34.4% versus female: 31.0%, P < 0.05; normal weight: 28.1%, versus overweight: 39.8%, versus obese: 51.2%, P < 0.001). More than half (51.2%) of obese adolescents were vitamin B12 deficient. On multiple linear regression analysis, serum B12 in rural adolescents was associated with age (ß = -0.12, P < 0.05). Among urban adolescents, serum B12 was associated with BMI (ß = -0.08, P < 0.05) and adjusted dietary vitamin B12 intake (ß = 0.14, P < 0.001). Serum vitamin B12 levels were found to be lower in rural females (ß = -0.12, P = 0.030) and urban males (ß: 0.11, P < 0.001) compared to their respective contemporaries. CONCLUSIONS: Vitamin B12 deficiency was higher among rural school-going adolescents. Boys had a higher B12 deficiency than girls. Inverse associations of serum B12 with adiposity indices were observed. Serum B12 levels were positively associated with dietary vitamin B12 intake.

Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains.

Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ⩾5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.

Epidermal growth factor receptor positive lung cancer: The nontrial scenario.

PURPOSE: The aim of this study was to report the median overall survival (OS) in epidermal growth factor receptor (EGFR) mutation-positive patients who were managed out of a clinical trial. METHODS: Nonsmall cell lung cancer patients harboring activating EGFR mutations who were either ineligible or refused participation in a clinical trial were selected for this analysis. The reason for not participating in trial, staging, treatment, and outcome details were obtained from a prospective lung cancer database. The Kaplan-Meier method was used to estimate OS. Log-rank test and Cox proportion hazard model were used for univariate and multivariate analysis, respectively. RESULTS: We included 225 patients in this analysis. The median age of the cohort was 56 years (range 29-85 years). A compromised Eastern Cooperative Oncology Group performance status (PS) of >2 was the major reason (83 patients, 36.9%) for ineligibility of patients in a clinical trial. The major reason provided by eligible patients for refusal to participate in a clinical trial was long distance of travel and inability to comply with the study-mandated follow-up visits (65 patients, 28.9%). The median OS in patients with PS 0-2 was 18.17 months (95% confidence interval [CI]: 15.6-20.8 months) and it was 12.1 months (95% CI: 9.0-15.2 months) in patients with PS 3-4 (hazard ratio - 0.579 [95% CI: 0.398-0.843] P = 0.004). CONCLUSION: EGFR positive patients who were ineligible for a clinical trial due to poor PS had lower survival; however, patients with good PS treated off-trial had similar OS to that reported in multiple clinical trials.

The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study: Design and methods to address mental healthcare gaps in India.

INTRODUCTION: Depression and diabetes are highly prevalent worldwide and often co-exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly-controlled diabetes and depression in diabetes clinics in India. MATERIALS AND METHODS: Adults with diabetes, depressive symptoms (Patient Health Questionnaire-9 score≥10), and ≥1 poorly-controlled cardiometabolic indicator (either HbA1c≥8.0%, SBP≥140mmHg, and/or LDL≥130mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (≥50% reduction in Symptom Checklist score from baseline) AND one or more of: ≥0.5% reduction in HbA1c, ≥5mmHg reduction in SBP, or ≥10mg/dl reduction in LDL-c at 24months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost-effectiveness. RESULTS: The study trained seven care coordinators. Participant recruitment is complete - 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites. CONCLUSIONS: The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India (clinicaltrials.gov number: NCT02022111).

Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.

Autologous stem cell transplantation (ASCT) is an important treatment modality in light chain (AL) amyloidosis. Use of reduced-dose melphalan conditioning is common, given the associated organ and functional decline. The impact of full-intensity melphalan conditioning (n=314) was compared to reduced-dose conditioning (n=143). Patients in the full-intensity group were younger, with better performance status, fewer involved organs, lower tumor burden and lower Mayo stage. Full-dose conditioning was associated with higher rate of very good partial response or better (79% vs 62%; P<0.001), complete response rate (53% vs 37%; P=0.003) and organ response rate (74% vs 59%; P=0.002) as compared to reduced-dose conditioning. PFS was superior in the full-intensity group compared to the reduced-dose group (4-year PFS 55% vs 31%; P<0.001) as well as a longer overall survival (OS) 4-year OS (86% vs 54%; P<0.001). In addition, the OS and PFS were significantly lower in the reduced-dose group compared to the full-intensity group in Mayo stage III/IV as well as stage I/II. A multivariate analysis confirmed an independent impact for conditioning dose on PFS/OS. This study calls for re-assessment of the use of reduced-dose conditioning in ASCT for AL amyloidosis.

Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma.

We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III (P<0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III (P<0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.

Conversion of gestational diabetes mellitus to future Type 2 diabetes mellitus and the predictive value of HbA1c in an Indian cohort.

AIM: To investigate the distribution of and risk factors for dysglycaemia (Type 2 diabetes and prediabetes) in women with previous gestational diabetes mellitus in India. METHODS: All women (n = 989) from two obstetric units in New Delhi and Hyderabad with a history of gestational diabetes were invited to participate, of whom 366 (37%) agreed. Sociodemographic, medical and anthropometric data were collected and 75-g oral glucose tolerance test were carried out. RESULTS: Within 5 years (median 14 months) of the pregnancy in which they were diagnosed with gestational diabetes, 263 (72%) women were dysglycaemic, including 119 (32%) and 144 (40%) with Type 2 diabetes and prediabetes, respectively. A higher BMI [odds ratio 1.16 per 1-kg/m2 greater BMI (95% CI 1.10, 1.28)], presence of acanthosis nigricans [odds ratio 3.10, 95% CI (1.64, 5.87)], postpartum screening interval [odds ratio 1.02 per 1 month greater screening interval 95% CI (1.01, 1.04)] and age [odds ratio 1.10 per 1-year older age 95% CI (1.04, 1.16)] had a higher likelihood of having dysglycaemia. The American Diabetes Association-recommended threshold HbA1c value of ≥ 48 mmol/mol (6.5%) had a sensitivity and specificity of 81.4 and 90.7%, respectively, for determining the presence of Type 2 diabetes postpartum. CONCLUSION: The high post-pregnancy conversion rates of gestational diabetes to diabetes reported in the present study reinforce the need for mandatory postpartum screening and identification of strategies for preventing progression to Type 2 diabetes. Use of the American Diabetes Association-recommended HbA1c threshold for diabetes may lead to significant under-diagnosis.

Evolving management of insulinoma: Experience at a tertiary care centre.

BACKGROUND & OBJECTIVES: Since our previous study in 2006, several new modalities for localization of cause of endogenous hyperinsulinemic hypoglycaemia such as multiphasic computed tomography (CT), multiphasic magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), intraoperative ultrasound, and intra-arterial calcium infusion with arterial stimulation venous sampling (ASVS) have become available. Therefore, to evaluate the relative usefulness of various imaging modalities to guide future management in terms of diagnosis and patient care, we analyzed presentation and management of patients of endogenous hyperinsulinemic hypoglycaemia. METHODS: In this retrospective study, medical records of patients admitted with endogenous hyperinsulinemic hypoglycaemia were retrieved. Data pertaining to clinical features, diagnosis, imaging, surgery and patient outcome were extracted. The localization of insulinoma by preoperative imaging techniques was compared with the findings at surgery to assess the accuracy of localization. RESULTS: Fasting hypoglycaemia was present in all, and post-prandial hypoglycaemia (plasma glucose ≤50 mg/dl within four hours of meal) in 25.8 per cent. Mean duration of symptoms before reaching a diagnosis of hyperinsulinemic hypoglycaemia was 3.9 years. Mean duration of provocative fast was 21.8 h (range 6-48 h). Among the currently used imaging modalities, the sensitivity of localizing tumour was 79.3 per cent for multiphasic CT, 85 per cent for multiphasic MRI and 95 per cent for EUS. EUS detected tumour missed by both CT and MRI. All, except one of the operated patients, were cured by surgery. INTERPRETATION & CONCLUSIONS: Our results suggest that patients with insulinoma have a varied presentation. Multiphasic contrast-enhanced MRI/CT scan, EUS and ASVS may be complimentary in pre-operative localization.

CTLA4+49G allele associates with early onset of type 1 diabetes in North Indians.

Type 1 diabetes (T1D) is a complex autoimmune disease with strong genetic influence. In this study, we investigated +49A/G SNP (rs 231775) in exon 1 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) by PCR-RFLP and its influence as a risk factor for the disease in the North Indian population. This polymorphism at codon 17 results in an amino acid substitution (Thr/Ala) in the leader peptide of the molecule. The study included 232 patients with T1D (age at onset of disease (AOD): 0.5-37 years) and 305 ethnically matched healthy controls. The DNA obtained from these 537 individuals was amplified using a set of specific primers followed by restriction enzyme digestion with Fnu4HI. The +49G allele as well as its homozygous genotype G/G was observed to be significantly higher in patients as compared to the healthy controls {(37.3% vs. 25.6%, P = 4.96E(-05) , OR = 1.73; 95%CI = 1.33-2.25) (15.52% vs. 6.6%, P = 0.001, OR = 2.62; 95% CI = 1.48-4.63) respectively}. The frequency of G/G genotype was significantly higher in patients with early age at onset of disease (AOD:<12 years) as compared to that in the late-onset patients with AOD: ≥12 years (21.1% vs. 10.6%, P = 0.042, OR = 2.26; 95% CI = 1.09-4.67) as well as to that in the healthy controls (21.1% vs. 6.6%, P = 0.00004, OR = 3.8; 95% CI = 2.01-7.2). Further analysis revealed that the median AOD significantly reduced (P = 0.049) from 14 years in patients with A/A genotype to 11 and 10 years in those with A/G and G/G genotypes, respectively. These results suggest that CTLA4+49G allele, particularly in homozygous G/G condition, associates with early onset of T1D.

Pituitary volume and clinical trajectory in young relatives at risk for schizophrenia.

BACKGROUND: Stress and vulnerability likely interact to play a major role in psychosis. While much has been written about the neural diathesis-stress model in psychosis and its clinical risk states, little is known about HPA axis biomarkers in non-help-seeking individuals at familial high risk (FHR). We sought to prospectively measure pituitary volume (PV) in adolescents and young adults at FHR for schizophrenia and to follow their emerging sub-clinical psychotic symptoms and clinical trajectories. METHOD: Forty healthy controls and 38 relatives of patients with schizophrenia or schizoaffective disorder were identified in Pittsburgh, USA. PV was derived from baseline 1.5 T magnetic resonance imaging. Chapman's schizotypy scales were acquired at baseline, and structured clinical interviews for DSM-IV-TR Axis I diagnoses were attempted annually for up to 3 years. RESULTS: Seven individuals converted to psychosis. PV did not differ between FHR and control groups overall. Within the FHR group, PV was positively correlated with Chapman's positive schizotypy (Magical Ideation and Perceptual Aberration) scores, and there was a significant group × PV interaction with schizotypy. PV was significantly higher in FHR subjects carrying any baseline Axis I diagnosis (p = 0.004), and higher still in individuals who went on to convert to psychosis (p = 0.0007). CONCLUSIONS: Increased PV is a correlate of early positive schizotypy, and may predict trait vulnerability to subsequent psychosis in FHR relatives. These preliminary findings support a model of stress-vulnerability and HPA axis activation in the early phases of psychosis.

Liraglutide pharmacokinetics and dose-exposure response in Asian subjects with Type 2 diabetes from China, India and South Korea.

AIMS: To investigate the population pharmacokinetics and exposure-response relationship of liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue, in Asian subjects with Type 2 diabetes mellitus. METHODS: Data were derived from a published 16-week, randomized, double-blind, double-dummy, active-controlled, parallel-group trial of liraglutide in China, India and South Korea. The analysis utilized 2061 pharmacokinetic (PK) samples from 605 subjects exposed to liraglutide 0.6, 1.2 or 1.8 mg once daily. Demographic factors (body weight, age, gender, country) of importance for liraglutide clearance were evaluated. An exploratory exposure-response analysis was conducted to investigate effects on glycated haemoglobin (HbA1c) and body weight. RESULTS: Estimated liraglutide exposure (area under the curve; AUC) appeared to increase proportionally with increasing liraglutide dose (0.6-1.8 mg). The covariate analysis confirmed previous findings in a global clinical trial. Body weight was a predictor of liraglutide exposure; compared to a reference subject of 67 kg, exposure was 32% lower for maximum (115 kg) and 54% higher for minimum (37 kg) observed body weights. Gender, age and country had no relevant effect on exposure. Exposure-response analysis supported the use of 1.2mg as maintenance dose with the option of individual dose escalation to 1.8 mg to optimize treatment outcomes. CONCLUSIONS: Exposure appeared to increase proportionally with increasing liraglutide dose in Asian subjects with Type 2 diabetes mellitus. The only PK relevant predictor of exposure was body weight. The exposure-response relationships for HbA1c and body weight in Asian subjects were similar to observations in global populations.