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Background: Neutrophil extracellular traps (NETs) being one of the predominant activities of neutrophils has become its key defense mechanism owing to its extensive role in inflammation and infection. However, the mechanisms regulating NET formation or NETosis still remains to be better understood. Our earlier whole genome transcriptomic data revealed two G-protein couple receptors (GPCRs) - complement component 5a receptor 1 (C5aR1) and leukotriene B4 receptor 1 (LTB4R1) were downregulated in term low birth weight (tLBW) newborns with deficient NET formation abilities. Neutrophils employ C5aR1 and LTB4R1 for mediating their immune responses, inflammation and antimicrobial activity. Hence, this study was aimed to explore the role of two GPCRs, C5aR1 and LTB4R1 including their downstream signaling molecules in NETs induction and regulation., Methods: The validation of the transcriptomic data for C5aR1 and LTB4R1 was done using quantitative real time PCR. Pharmacological inhibition of C5aR1 and LTB4R1 using W-54011 and LY223982 on neutrophils of adults and newborns' was done to study their impact on NETosis. Extracellular DNA release, Reactive oxygen species (ROS) generation, expression of NET proteins, and signaling molecules downstream to C5aR1 and LTB4R1 were quantified using plate reader based assay, immunofluorescence, and western blotting. Myeloperoxidase (MPO)-DNA quantified by flow cytometry. Knockdown studies using siRNA against C5aR1 and LTB4R1 were done in HL-60 cells derived surrogate neutrophils and expression of downstream molecules of the two GPCRs, C5aR1 and LTB4R1 signaling axis along with NET proteins was quantified by western blotting., Results: The expression of C5aR1 and LTB4R1, extracellular DNA, ROS and NET associated proteins (NE, CitH3, PAD4 and MPO) was notably increased upon NET induction in healthy adults and normal birth weight (NBW) newborns' neutrophils. Pharmacological inhibition of these two GPCRs led to substantial reduction in NETosis, extracellular DNA, ROS generation, and expression of NET associated proteins like CitH3, NE, PAD4, MPO along with downstream signaling molecules Rap1a, B-Raf and pERK. Our observations suggest a precise role of C5aR1 and LTB4R1 on induction of NETs via Rap1a/B-Raf/ERK signaling axis., Conclusion: The C5aR1 and LTB4R1 signaling via Rap1a/B-Raf/ERK axis acts as a signal-relay mechanism to regulate NET formation in neutrophils. Further, C5aR1 and LTB4R1 signaling cascade along with NET-associated proteins are remarkably downregulated in tLBW newborns' neutrophils leading to impaired NETosis in them. Therefore, C5aR1 and LTB4R1 and their signaling molecules could provide an effective therapeutic target for compromised NETosis like tLBW newborns., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Health system resilience refers to the capacity of a health system to effectively anticipate, assimilate, adjust to and recuperate from unforeseen disruptions and pressures. Evidence indicates that low- and middle-income countries (LMICs) have a double burden of dealing with the existing shortage of health resources in managing both non-emergency care and emergency care during epidemics. Intersectoral collaboration plays a pivotal role in managing crises such as pandemics. The World Health Organization has emphasized that effective intersectoral collaboration is vital for uninterrupted essential services during a pandemic. The study aimed to look at the collaborations entered into at various levels for managing the COVID-19 pandemic, taking as an example the municipal corporation in Ahmedabad, India. We undertook a qualitative study that involved conducting 52 in-depth interviews with officials from the health department, and other departments at the Ahmedabad Municipal Corporation (AMC), including firefighting, estate, engineering and education, as well as private stakeholders. Many diverse observations were documented in this study as collaboration varied across the sectors. A lack of hospital beds and shortage of essential drugs and oxygen posed challenges for healthcare providers and provided an opportunity to collaborate with private stakeholders. Mandatory COVID testing and mobile units such as the Sanjivani van and Vadil ghar seva were examples of some of the initiatives taken by the AMC to manage the pandemic that were instigated and implemented with support from various departments such as education, engineering, tax, estate, animal husbandry and firefighting. Proper communication between public and private entities will result in unfragmented efforts to combat emergencies. Thus, a resilient health system is necessary as well as systematic intersectoral collaboration to ensure the uninterrupted delivery of essential health services during health emergencies., (© The Author(s) 2024. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Background: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology., Objective: To investigate the immunomodulatory effects of Dexamethasone-primed Wharton's jelly (WJ) derived MSCs CM (DW) and IFN-γ-primed WJ-MSCs-CM (IW) on NETosis and associated protein markers in SLE patients' LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein., Methods: We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing ex vivo and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β)., Results: Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs., Conclusion: Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Priya, Thacker, Chaubey, Rai, Singh, Rawat, Giri, Mohanty and Rai.)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been used for almost a decade and have proven to be effective not only in managing Type 2 diabetes (T2D), but their cardio and renal protective features make them very useful in managing patients with risk of multiple comorbidities. This systematic review was undertaken by the authors because there is no evidence currently available in India that has studied the suitability of SGLT2i as a first-line agent in patients newly diagnosed with T2D in India., Materials and Methods: First, literature was searched to identify features that are considered important when deciding on a first-line agent for managing T2D. A total of 5 broad topics were identified-glycemic control, extra glycemic effects, antihyperglycemic combination therapy, safety, and cost-effectiveness. These domains had further subheadings, and a total of 16 domains were identified. Metformin is the drug of choice as a first-line agent in such situations and has been considered the gold standard for evaluating the effects of SGLT2i across these domains. A systematic literature review on each domain was conducted to compare SGLT2i with the gold standard in Indian patients newly diagnosed with T2D. Evidence was graded (levels of evidence (LoE)-A, B, and C), and recommendations (class of recommendation (CoR)-I, II, and III) were classified by the expert group as defined in the methodology., Results: According to the systematic reviews conducted, 11 domains had Level A evidence, 2 domains (impact on lipids and gut microbiome) had Level B, and 3 domains had Level C (β-cell function, renal protection, and glycemic variability) evidence. Based on evidence and expert opinion, the authors recommend SGLT2i as a first-line agent for managing newly diagnosed patients with T2D with a Class I recommendation for 13 domains and Class II for the remaining 3 (impact on lipids, gut microbiome, and β-cell function). Although a poorer level of evidence (Level C) was available for the glycemic variability domain, the authors still reported this as Class I recommendations according to their expert opinion and consensus., Conclusion: This article advocates adopting SGLT2 inhibitors as the primary treatment choice for treating patients with newly diagnosed T2D in India., (© Journal of the Association of Physicians of India 2023.)

Introduction: LANDMARC (CTRI/2017/05/008452), a prospective, observational real-world study, evaluated the occurrence of diabetes complications, glycemic control and treatment patterns in people with type 2 diabetes mellitus (T2DM) from pan-India regions over a period of 3 years., Methods: Participants with T2DM (≥25 to ≤60 years old at diagnosis, diabetes duration ≥2 years at the time of enrollment, with/without glycemic control and on ≥2 antidiabetic therapies) were included. The proportion of participants with macrovascular and microvascular complications, glycemic control and time to treatment adaptation over 36 months were assessed., Results: Of the 6234 participants enrolled, 5273 completed 3 years follow-up. At the end of 3-years, 205 (3.3%) and 1121 (18.0%) participants reported macrovascular and microvascular complications, respectively. Nonfatal myocardial infarction (40.0%) and neuropathy (82.0%) were the most common complications. At baseline and 3-years, 25.1% (1119/4466) and 36.6% (1356/3700) of participants had HbA1c <7%, respectively. At 3-years, population with macrovascular and microvascular complications had higher proportion of participants with uncontrolled glycemia (78.2% [79/101] and 70.3% [463/659], respectively) than those without complications (61.6% [1839/2985]). Over 3-years, majority (67.7%-73.9%) of the participants were taking only OADs (biguanides [92.2%], sulfonylureas [77.2%] and DPP-IV inhibitors [62.4%]). Addition of insulin was preferred in participants who were only on OADs at baseline, and insulin use gradually increased from 25.5% to 36.7% at the end of 3 years., Conclusion: These 3-year trends highlight the burden of uncontrolled glycemia and cumulative diabetes-related complications, emphasizing the importance of optimizing diabetes management in India., (© 2023 Sanofi and The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Introduction: There are limited data on the real-world management of diabetes in the Indian population. In this 2-year analysis of the LANDMARC study, the management of type 2 diabetes mellitus (T2DM) and related complications were assessed., Method: This multicenter, observational, prospective study included adults aged ≥25 to ≤60 years diagnosed with T2DM (duration ≥2 years at enrollment) and controlled/uncontrolled on ≥2 anti-diabetic agents. This interim analysis at 2 years reports the status of glycaemic control, diabetic complications, cardiovascular (CV) risks and therapy, pan-India including metropolitan and non-metropolitan cities., Results: Of the 6234 evaluable patients, 5318 patients completed 2 years in the study. Microvascular complications were observed in 17.6% of patients (1096/6234); macrovascular complications were observed in 3.1% of patients (195/6234). Higher number of microvascular complications were noted in patients from non-metropolitan than in metropolitan cities (p < .0001). In 2 years, an improvement of 0.6% from baseline (8.1%) in mean glycated haemoglobin (HbA1c) was noted; 20.8% of patients met optimum glycaemic control (HbA1c < 7%). Hypertension (2679/3438, 77.9%) and dyslipidaemia (1776/3438, 51.7%) were the predominant CV risk factors in 2 years. The number of patients taking oral anti-diabetic drugs in combination with insulin increased in 2 years (baseline: 1498/6234 [24.0%] vs. 2 years: 1917/5763 [33.3%]). While biguanides and sulfonylureas were the most commonly prescribed, there was an evident increase in the use of dipeptidyl peptidase-IV inhibitors (baseline: 3049/6234, 48.9% vs. 2 years: 3526/5763, 61.2%)., Conclusion: This longitudinal study represents the control of T2DM, its management and development of complications in Indian population., Clinical Trial Registration Number: CTRI/2017/05/008452., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: Work-related musculoskeletal disorders (WMSDs) are the second most common cause of disability, accounting for 17% of all Years lived with a disability (YLDs) worldwide. Healthcare professionals, especially dentists, are known to be at a higher risk of WMSDs. Therefore, this study aims to determine the point and period prevalence of WMSDs among dentists and to assess the risk factors for WMSDs, including workstation analysis., Methods: This cross-sectional study was conducted among 120 dentists from three dental colleges in Gujarat (Ahmedabad and Gandhinagar), India. A structured questionnaire was used to collect sociodemographic and occupational history along with pre-validated standardized tools such as the Nordic Musculoskeletal Questionnaire (NMQ), Rapid Entire Body Assessment (REBA) score sheet and Quick Exposure Checklist (QEC). Data analysis was performed using SPSS version 20., Results: The period prevalence of MSDs and WMSDs were 85% and 75.8% respectively, and the point prevalence was 39.2% and 23.3% respectively. Prosthodontists reported the highest prevalence of WMSDs. The neck (64.7%) was the most commonly affected area. A statistically significant result was obtained between MSDs and BMI (P = 0.02), qualification (P = 0.01) and between WMSDs and duration of work in the sitting posture (P = 0.03)., Conclusions: The prevalence of both MSDs and WMSDs was found to be high. Dentists with higher BMI, higher qualifications, lack of breaks, having poor workstations and higher REBA and QEC scores, whose job tasks involve continuous inspection, frequent bending of elbow joints, frequent repetitive motions, tasks that require them to reach distances greater than 20 inches and tasks that involve twisting of the waist are at a higher risk of developing MSDs., Competing Interests: None

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion-inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.

Introduction: Longitudinal data on management and progression of type 2 diabetes mellitus (T2DM) in India are scarce. LANDMARC (CTRI/2017/05/008452), first-of-its-kind, pan-India, prospective, observational study aimed to evaluate real-world patterns and management of T2DM over 3 years., Methods: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrolment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. The first-year trends for glycaemic control, therapy and diabetic complications, including those from metropolitan and non-metropolitan cities are reported here., Results: Of 6236 enrolled participants, 5654 completed 1 year in the study. Although the overall mean glycated haemoglobin (HbA1c) improved by 0.5% (baseline: 8.1%) at 1 year, only 20% of the participants achieved HbA1c <7%. Participants from metropolitan and non- metropolitan cities showed similar decrease in glycaemic levels (mean change in HbA1c: -0.5% vs. -0.5%; p = .8613). Among diabetic complications, neuropathy was the predominant complication (815/6236, 13.1% participants). Microvascular complications (neuropathy, nephropathy and retinopathy) were significantly (p < .0001) higher in non-metropolitan than metropolitan cities. Hypertension (2623/6236, 78.2%) and dyslipidaemia (1696/6236, 50.6%) continued to be the most commonly reported cardiovascular risks at 1 year. After 1 year, majority of the participants were taking only oral anti-diabetic drugs (OADs) (baseline: 4642/6236 [74.4%]; 1 year: 4045/6013 [67.3%]), while the proportion of those taking insulin along with OADs increased (baseline: 1498/6236 [24.0%] vs. 1 year: 1844/6013 [30.7%]). Biguanides and sulfonylureas were the most used OADs. The highest increase in use was seen for dipeptidyl peptidase-IV inhibitors (baseline: 3047/6236 [48.9%]; 1 year: 3529/6013 [58.7%]). Improvement in all glycaemic parameters was significantly (p < .0001) higher in the insulin vs. the insulin-naïve subgroups; in the insulin-naïve subgroup, no statistical difference was noted in those who received >3 vs. ≤3 OADs., Conclusions: First-year trends of the LANDMARC study offer insights into real-world disease progression, suggesting the need for controlling risk factors and timely treatment intensification in people with T2DM., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Introduction: Longitudinal data on progression, complications, and management of type 2 diabetes mellitus (T2DM) across India are scarce. LANDMARC (CTRI/2017/05/008452), the first pan -India, longitudinal, prospective, observational study, aims to understand the management and real-world outcomes of T2DM over 3 years., Methods: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrollment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. Baseline characteristics were analyzed using descriptive statistics., Results: Of the 6279 recruited participants, 6236 were eligible for baseline assessment (56.6% [ n / N  = 3528/6236] men; mean ± SD age: 52.1 ± 9.2 years, diabetes duration: 8.6 ± 5.6 years). mean ± SD HbA1c, fasting plasma glucose, and postprandial glucose values were 64 ± 17 mmol/mol (8.1 ± 1.6%), 142.8 ± 50.4 mg/dl, and 205.7 ± 72.3 mg/dl, respectively. Only 25.1% ( n / N  = 1122/6236) participants had controlled glycemia (HbA1c < 53 mmol/mol, <7%). Macrovascular and microvascular complications were prevalent in 2.3% ( n / N  = 145/6236) and 14.5% ( n / N  = 902/6236) participants, respectively. Among those with complications, non-fatal myocardial infarction ( n / N  = 74/145, 51.0%) and neuropathy ( n / N  = 737/902, 81.7%) were the most reported macrovascular and microvascular complication, respectively. Hypertension ( n / N  = 2566/3281, 78.2%) and dyslipidemia ( n / N  = 1635/3281, 49.8%) were the most reported cardiovascular risks. Majority (74.5%; n / N  = 4643/6236) were taking oral anti-diabetic drugs (OADs) only, while 24.4% ( n / N  = 1522/6236) participants were taking OADs+insulin. Biguanides ( n / N  = 5796/6236, 92.9%) and sulfonylureas ( n / N  = 4757/6236, 76.3%) were the most reported OADs. Basal ( n / N  = 837/6236, 13.4%) and premix ( n / N  = 684/6236, 11.0%) insulins were the most reported insulins., Conclusions: Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM., Competing Interests: AKD, AM, AGU, and NR received honoraria from Sanofi and other pharmaceutical companies. KMPK is on the advisory board of Sanofi and received honorarium for his talks. SJ received speaker/advisory/research grants from Abbott, Astrazeneca, Biocon, Boehringer Ingelheim, Eli Lilly, Franco Indian, Glenmark, Lupin, Marico, MSD, Novartis, Novo Nordisk, Roche, Sanofi, Serdia, Twinhealth, and Zydus. SK received honoraria/ speaker fees from Eli Lilly, Novo Nordisk, and Sanofi. HT received honoraria from MSD, Novartis, Sanofi and from other companies for advice and lectures. BS received honorarium from Aventis, Novo Nordisk, Eli Lilly, Boehringer Ingelheim (BI), and MSD. RG, AN, SM, SKM, VK, DC, VS, CT, and GC are employees of Sanofi. SC received honoraria/grants from Biocon, BI, Intas, Novartis, Sanofi, and Serdia. SKW has nothing to declare. AHZ received honoraria from Novo Nordisk, Eli Lilly, Johnson & Johnson, AstraZeneca, BI, and Sanofi., (© 2021 Sanofi. Published by John Wiley & Sons Ltd.)

Background: Hypertension is the biggest contributor to global burden of disease and mortality. Increasing compliance with antihypertensive treatment and achieving a wide BP control in the population represents a major challenge for clinical practice. The benefits of single pill combination versus free-equivalent combination has been demonstrated in several meta-analyses and is now strongly supported by the latest 2018 ESC/ESH guidelines. The RAAS blocker with CCB and thiazide like diuretic is proposed as the optimal combination in patients inadequately controlled by two drugs., Objective: To assess the blood pressure control rate, safety, tolerability and quality of life with triple-drug SPC in patients with grade II/ III hypertension., Methods: Hypertensive patients uncontrolled (BP ≥ 140/90 mmHg) on two-drug therapy were recruited in an open-label, phase III clinical trial conducted in outpatient setting in India with 6 months treatment period. No other antihypertensive medication except the study medication was received by the patients., Results: Out of 218 evaluable patients the observed average blood pressure reduction achieved from baseline to end of study at 6 months was Systolic Blood Pressure (SBP) 28.5 mm Hg / Diastolic Blood Pressure (DBP) 13.8 mm Hg. The quality of life (QoL) questionnaire demonstrated improvement in QoL for all patients., Conclusion: This study showed the clinical efficacy, safety and acceptability of the perindopril/indapamide/amlodipine SPC in patients with grade 2/3 hypertension inadequately controlled with two-drug therapy. The clinical effectiveness was observed in more than 96 % patients. The benefit of single-pill combination (SPC) therapy in hypertension control was reconfirmed in this study., (© Journal of the Association of Physicians of India 2011.)

Aim: India contributes towards a large part of the worldwide epidemic of diabetes and its associated complications. However, there are limited longitudinal studies available in India to understand the occurrence of diabetes complications over time. This pan-India longitudinal study was initiated to assess the real-world outcomes of diabetes across the country., Methods: The LANDMARC study is the first prospective, multicentre, longitudinal, observational study investigating a large cohort of people with type 2 diabetes mellitus across India over a period of 3 years. The primary objective of this ongoing study is to determine the proportion of people developing macrovascular diabetes complications over the duration of the study (36 months ± 45 days) distributed over seven visits; the secondary objective is to evaluate microvascular diabetes complications, glycaemic control and time-to-treatment adaptation or intensification. Overall, 6300 participants (aged 25-60 years) diagnosed with type 2 diabetes for at least 2 years will be included from 450 centres across India. Data will be recorded for baseline demographics, comorbidities, glycaemic measurements, use of anti-hyperglycaemic medications and any cardiovascular or other diabetes-related events occurring during the observational study period., Conclusions: The LANDMARC study is expected to reveal the trends in complications associated with diabetes, treatment strategies used by physicians, and correlation among treatment, control and complications of diabetes within the Indian context. The findings of this study will help to identify the disease burden, emergence of early-onset complications and dose titration patterns, and eventually develop person-centred care and facilitate public health agencies to invest appropriate resources in the management of diabetes. (Trial Registration No: CTRI/2017/05/008452)., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor., Objective: Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control., Methods: A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remogliflozin etabonate 250 mg BID (group 2, n = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatment-emergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated., Results: Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was - 0.72 ± 0.09, - 0.77 ± 0.09, and - 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (- 0.14%, 90% confidence interval [CI] - 0.38 to 0.10) and group 2 versus group 3 (- 0.19%; 90% CI - 0.42 to 0.05) was noninferior to that in group 3 (p < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported., Conclusion: This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM., Trial Registration: CTRI/2017/07/009121.

Diabetes is a chronic disease and is one of the leading causes of morbidity and mortality worldwide. Being an ancient disease, many individuals follow complementary and alternative medicinal (CAM) therapies for either the cure or prevention of the disease. The popularity of these practices among the general public is in no way a testimony to their safety and efficacy. Due to the possibility of undesirable interactions with conventional medicines, it is imperative that patients are asked about CAM use during patient assessment. Patient- and physician-targeted awareness programs on various aspects of CAM use must be initiated to create a better understanding of evidence-based use of these practices. In addition, there should be guidelines in place based on clinical trial outcomes, and stricter regulations need to be enforced on CAM practices to ensure their safety and effectiveness.

We report the first closed-loop operation of a 100 Gbps polarization-insensitive, 4-channel wavelength-tracking WDM receiver in silicon photonics platform. Error-free operation is achieved with input polarization scrambling over input wavelength change of 4.5 nm using efficient thermal tuning of Si microring demux, corresponding to greater than 60°C fluctuation in temperature.

Background: Diabetes is endemic with developing economies contributing to the bulk of this pandemic. Despite the evidence of incremental benefit of glycemic control starting early in life, acceptance of and adherence to modern medications remain suboptimal., Aims: To determine the hemoglobin A1c (HbA1c)-lowering efficacy and safety of nutritional supplement, PreCrea(®), in adult Indians with newly diagnosed hyperglycemia., Materials and Methods: Double-blind, randomized study conducted in six diabetes centers in India. A total of 193 treatment-naïve subjects with newly diagnosed hyperglycemia and fasting plasma glucose (FPG) >100 mg/dL were randomized into either PreCrea(®) 600 mg (n = 90) or matched placebo (n = 89) capsules twice daily, along with lifestyle modification, for 12 weeks. The main outcomes were changes in HbA1c and FPG levels, attainment of the American Diabetes Association (ADA)-defined goals for HbA1c, and clinical and biochemical measures of safety., Results: At 12 weeks, mean HbA1c in PreCrea(®) group reduced by 0.91% compared with 0.08% increase in the placebo group (P < .001). The reductions in the mean FPG at week 4 (P < .001) and week 12 (P = 0.04) were significant compared to the baseline. ADA goal of HbA1c <7% increased from 15.5% at the baseline to 35.6% at week 12 in PreCrea(®) subjects. Clinical safety and biochemical safety did not change. Hypoglycemia and weight gain were not observed with PreCrea(®)., Conclusions: Nearly 1% point reduction in HbA1c at week 12 with PreCrea(®) is comparable with most first-line glucose-lowering drugs. The safety and tolerability of PreCrea(®) highlights its potential as a first-line therapy in newly detected hyperglycemia.

Plants provide fundamental support systems for life on Earth and are the basis for all terrestrial ecosystems; a decline in plant diversity will be detrimental to all other groups of organisms including humans. Decline in plant diversity has been hard to quantify, due to the huge numbers of known and yet to be discovered species and the lack of an adequate baseline assessment of extinction risk against which to track changes. The biodiversity of many remote parts of the world remains poorly known, and the rate of new assessments of extinction risk for individual plant species approximates the rate at which new plant species are described. Thus the question 'How threatened are plants?' is still very difficult to answer accurately. While completing assessments for each species of plant remains a distant prospect, by assessing a randomly selected sample of species the Sampled Red List Index for Plants gives, for the first time, an accurate view of how threatened plants are across the world. It represents the first key phase of ongoing efforts to monitor the status of the world's plants. More than 20% of plant species assessed are threatened with extinction, and the habitat with the most threatened species is overwhelmingly tropical rain forest, where the greatest threat to plants is anthropogenic habitat conversion, for arable and livestock agriculture, and harvesting of natural resources. Gymnosperms (e.g. conifers and cycads) are the most threatened group, while a third of plant species included in this study have yet to receive an assessment or are so poorly known that we cannot yet ascertain whether they are threatened or not. This study provides a baseline assessment from which trends in the status of plant biodiversity can be measured and periodically reassessed.

We report on a packaged prototype of a WDM photonic transceiver. It is an all-solid state hybrid assembly based on 130nm SOI photonic circuitry integrated with a 40nm CMOS VLSI driver. Our prototype supports eight tunable WDM channels operating at 10Gb/s, each capable of both transmitting and receiving data on the same chip. We discuss two options to close the link using the optical fiber or a waveguide bridge chip. We provide integration details and supporting link measurement data to describe packaged photonic module and its power efficient functionality with its on-chip power per channel averaging 1.3pJ/bit, excluding off-chip laser electrical power.

DRESS Syndrome is caused by exposure to certain medications that may cause fever, rash, inflammation of internal organs, lymphadenopathy and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia and atypical lymphocytosis. We herein report a case of DRESS syndrome who presented with fever and rash, secondary to sulfasalazine ingestion. Diagnosis of DRESS is often delayed, as several diseases have clinical and laboratory features similar to DRESS syndrome.

We report the first complete 10G silicon photonic ring modulator with integrated ultra-efficient CMOS driver and closed-loop wavelength control. A selective substrate removal technique was used to improve the ring tuning efficiency. Limited by the thermal tuner driver output power, a maximum open-loop tuning range of about 4.5nm was measured with about 14mW of total tuning power including the heater driver circuit power consumption. Stable wavelength locking was achieved with a low-power mixed-signal closed-loop wavelength controller. An active wavelength tracking range of > 500GHz was demonstrated with controller energy cost of only 20fJ/bit.

We demonstrate the first germanium-silicon C-band electro-absorption based waveguide modulator array and echelle-grating-based silicon wavelength multiplexer integrated with a digital CMOS driver circuit. A 9-channel, 10Gbps SiGe electro-absorption wavelength-multiplexed modulator array consumed a power of 5.8mW per channel while being modulated at 10.25Gbps by 40nm CMOS drivers delivering peak-to-peak voltage swings of 2V, achieving a modulation energy-efficiency of ~570fJ/bit including drivers. Performance up to 25Gbps on a single-channel SiGe modulator and CMOS driver is also reported.

We demonstrate a hybrid III-V/SOI laser by vertically coupling a III-V RSOA chip with a SOI-CMOS chip containing a tunable wavelength selective reflector. We report a waveguide-coupled wall-plug-efficiency of 5.5% and output power of 10 mW. A silicon resistor-based microheater was integrated to thermally tune a ring resonator for precise lasing wavelength control. A high tuning efficiency of 2.2 nm/mW over a range of 18 nm was achieved by locally removing the SOI handler substrate. C-band single mode lasing was confirmed with a side mode suppression ratio of 35 dB. This grating coupler based vertical integration approach can be scaled up in two dimensions for efficient multi-wavelength sources in silicon photonics.

Background: Postmenopausal women have shown proactive willingness to take responsibility for their changing health care needs. The example of osteoporosis is a model that when educated of their bone health status, this cohort follows through with prevention and treatment regimens. Postmenopausal status is considered to be a risk factor for periodontitis. It is known that up to 50% of periodontal disease goes undiagnosed. The goal of periodontal therapy is to prevent tooth loss., Objective: Is there a need, then to educate and inform postmenopausal women of their periodontal status? Can dentists provide a greater service to this cohort by increasing education and information?, Materials and Methods: The current study compares patient perception to actual clinical findings in 94 postmenopausal women. Patients are informed of their diagnosis, and educated about the disease, its risk factors and preventive and treatment modalities. Detailed interviews examine the patient intentions to follow up on preventive and treatment regimens suggested., Results: Although 97.8% of participants reported having "healthy gums", 36.2% had severe periodontitis in at least one site. Interviews reveal that patients associated disease with abscess, and would be likely to follow prevetive and treatment regimens when they were informed of their diagnosis and educated on the topic., Conclusion: The findings suggest a need to make education a priority when treatment postmenopausal women.

We report design improvements for evanescently coupled Germanium photodetectors grown at low temperature. The resulting photodetectors with 10 μm Ge length manufactured in a commercial CMOS process achieve >0.8 A/W responsivity over the entire C-band, with a device capacitance of <7 fF based on measured data.

We report optical waveguides up to one meter long with 0.026 dB/cm loss fabricated in a 300nm thick SOI CMOS process. Combined with tight bends and compact interlayer grating couplers, we demonstrate a complete toolbox for ultralow-loss, high-density waveguide routing for macrochip interconnects.

We show enhanced optical bistability induced by free carrier absorption from junction doping in substrate-removed silicon ring modulators. Such linear thermal effects dominate the loss in high-speed depletion silicon ring modulators. Optical bistability was observed with about 100 μW of input optical power. We further show that such thermal interactions causes data-dependent ring resonance shifts, and consequently severely degrade the data modulation quality at low speeds. The frequency response of this effect was measured to be about 100~200 kHz.

We report a high-speed ring modulator that fits many of the ideal qualities for optical interconnect in future exascale supercomputers. The device was fabricated in a 130 nm SOI CMOS process, with 7.5 μm ring radius. Its high-speed section, employing PN junction that works at carrier-depletion mode, enables 25 Gb/s modulation and an extinction ratio >5 dB with only 1V peak-to-peak driving. Its thermal tuning section allows the device to work in broad wavelength range, with a tuning efficiency of 0.19 nm/mW. Based on microwave characterization and circuit modeling, the modulation energy is estimated ~7 fJ/bit. The whole device fits in a compact 400 μm2 footprint.

Using low parasitic microsolder bumping, we hybrid integrated efficient photonic devices from different platforms with advanced 40 nm CMOS VLSI circuits to build ultra-low power silicon photonic transmitters and receivers for potential applications in high performance inter/intra-chip interconnects. We used a depletion racetrack ring modulator with improved electro-optic efficiency to allow stepper optical photo lithography for reduced fabrication complexity. Integrated with a low power cascode 2 V CMOS driver, the hybrid silicon photonic transmitter achieved better than 7 dB extinction ratio for 10 Gbps operation with a record low power consumption of 1.35 mW. A received power penalty of about 1 dB was measured for a BER of 10(-12) compared to an off-the-shelf lightwave LiNOb3 transmitter, which comes mostly from the non-perfect extinction ratio. Similarly, a Ge waveguide detector fabricated using 130 nm SOI CMOS process was integrated with low power VLSI circuits using hybrid bonding. The all CMOS hybrid silicon photonic receiver achieved sensitivity of -17 dBm for a BER of 10(-12) at 10 Gbps, consuming an ultra-low power of 3.95 mW (or 395 fJ/bit in energy efficiency). The scalable hybrid integration enables continued photonic device improvements by leveraging advanced CMOS technologies with maximum flexibility, which is critical for developing ultra-low power high performance photonic interconnects for future computing systems.

Agenesis or hypoplasia of the right or left pulmonary arteries are among the rarest pulmonary artery anomalies with left sided anomalies being reported even less frequently. Pulmonary artery agenesis should be suspected in asymptomatic patients if a plain chest X-ray shows asymmetric lung fields, lung hypoplasia, or hyperinflation of the contralateral lung. It must be considered as a rare cause of recurrent lower respiratory tract infections in childhood and in subjects with a low threshold for or recurrent "High Altitude Pulmonary Edema".

Objective: The aim of this study was to compare the periodontium of postmenopausal women with known low bone mineral density who are receiving long-term bisphosphonate therapy with those who are not., Methods: The periodontal status of 28 white postmenopausal women with low bone density using bisphosphonate therapy for at least 2 years was compared with that of a matching group not using such therapy. All women underwent a cone-beam CT scan of the jaw and a complete periodontal examination evaluating for plaque score, periodontal probing depth, clinical attachment loss, bleeding on probing, and alveolar bone height., Results: Bisphosphonate users had higher plaque score, lower probing depth, and lesser clinical attachment loss compared with the controls. These differences were determined to be significant by both t test and Wilcoxon's tests. Bleeding on probing was lower and the alveolar bone height was higher in the bisphosphonate group than in controls, but these differences were not statistically significant. Linear models showed no significant interactions between plaque score and bisphosphonate use, suggesting that the association of periodontal status and outcome measures was constant across all levels of plaque scores. Bisphosphonate use was a significant factor for probing depth but was not significant for the other parameters when adjusted for plaque score., Conclusions: Long-term bisphosphonate use seems to have some beneficial effects on the periodontium of postmenopausal women with low bone density, across all levels of plaque score.

Species and biotype distribution was determined in 44 bovine viral diarrhea virus- (BVDV-) positive samples submitted to the Animal Disease Diagnostic Laboratory (ADDL) in Indiana during 2006-2008. BVDV RNA was detected in the 5'-untranslated region and N(pro) region using reverse transcriptase PCR followed by sequencing analysis of the PCR product. Additionally, cases were classified into one of six categories according to history and/or lesions: acute symptomatic, hemorrhagic, respiratory distress, reproductive, persistent infection (PI), and mucosal disease (MD). Of 44 BVDV-positive samples, 33 were noncytopathic (ncp), 10 were cytopathic (cp), and one presented both ncp and cp biotypes. Sequencing analysis demonstrated that all samples belonged to BVDV-1a, BVDV-1b, or BVDV-2. The most common isolate was ncp BVDV-1b, (44%) followed by ncp BVDV-2a (24%). Among the six categories, respiratory clinical signs were the most common (36%) followed by PI (25%) and MD (16%).

We demonstrate spectral tunability for microphotonic add-drop filters manufactured as ring resonators in a commercial 130 nm SOI CMOS technology. The filters are provisioned with integrated heaters built in CMOS for thermal tuning. Their thermal impedance has been dramatically increased by the selective removal of the SOI handler substrate under the device footprint using a bulk silicon micromachining process. An overall ~20x increase in the tuning efficiency has been demonstrated with a 100 µm radius ring as compared to a pre-micromachined device. A total of 3.9 mW of applied tuning power shifts the filter resonant peak across one free spectral node of the device. The Q-factor of the resonator remains unchanged after the co-integration process and hence this device geometry proves to be fully CMOS compatible. Additionally, after the cointegration process our result of 2π shift with 3.9 mW power is among the best tuning performances for this class of devices. Finally, we examine scaling the tuning efficiency versus device footprint to develop a different performance criterion for an easier comparison to evaluate thermal tuning. Our criterion is defined as the unit of power to shift the device resonance by a full 2π phase shift.

We report the first compact silicon CMOS 1x4 tunable multiplexer/ demultiplexer using cascaded silicon photonic ring-resonator based add/drop filters with a radius of 12 microm, and integrated doped-resistor thermal tuners. We measured an insertion loss of less than 1 dB, a channel isolation of better than 16 dB for a channel spacing of 200 GHz, and a uniform 3 dB pass band larger than 0.4 nm across all four channels. We demonstrated accurate channel alignment to WDM ITU grid wavelengths using integrated silicon heaters with a tuning efficiency of 90 pm/mW. Using this device in a 10 Gbps data link, we observed a low power penalty of 0.6 dB.

We report the first sub-picojoule per bit (400fJ/bit) operation of a silicon modulator intimately integrated with a driver circuit and embedded in a clocked digital transmitter. We show a wall-plug power efficiency below 400microW/Gbps for a 130nm SOI CMOS carrier-depletion ring modulator flip-chip integrated to a 90nm bulk Si CMOS driver circuit. We also demonstrate stable error-free transmission of over 1.5 petabits of data at 5Gbps over 3.5 days using the integrated modulator without closed-loop ring resonance tuning. Small signal measurements of the CMOS ring modulator, sans circuit, showed a 3dB bandwidth in excess of 15GHz at 1V of reverse bias, indicating that further increases in transmission rate and reductions of energy-per-bit is possible while retaining compatibility with CMOS drive voltages.

We report ultra-low-power (690fJ/bit) operation of an optical receiver consisting of a germanium-silicon waveguide detector intimately integrated with a receiver circuit and embedded in a clocked digital receiver. We show a wall-plug power efficiency of 690microW/Gbps for the photonic receiver made of a 130nm SOI CMOS Ge waveguide detector integrated to a 90nm Si CMOS receiver circuit. The hybrid CMOS photonic receiver achieved a sensitivity of -18.9dBm at 5Gbps for BER of 10(-12). Enabled by a unique low-overhead bias refresh scheme, the receiver operates without the need for DC balanced transmission. Small signal measurements of the CMOS Ge waveguide detector showed a 3dB bandwidth of 10GHz at 1V of reverse bias, indicating that further increases in transmission rate and reductions of energy-per-bit will be possible.

From September 2005 through October 2006, fibromatosis was diagnosed in 2 red squirrels (Tamiasciurus hudsonicus) and 1 gray squirrel (Sciurus carolinensis). All 3 squirrels had multifocal to coalescing, tan, firm alopecic cutaneous nodules. Two squirrels also had pulmonary nodules. Histologically, the cutaneous nodules had marked epidermal hyperplasia, with ballooning degeneration of keratinocytes, spongiosis, and eosinophilic cytoplasmic inclusions. The dermis was expanded by proliferation of atypical mesenchymal cells with cytoplasmic inclusions. Additional findings included pulmonary adenomatous hyperplasia with cytoplasmic inclusions, renal tubular epithelial hyperplasia with cytoplasmic inclusions, atypical mesenchymal proliferation in the liver, and atypical mesenchymal proliferation with cytoplasmic inclusions in the seminal vesicles. Ultrastructurally, poxviral particles were observed in skin scrapings and sections of cutaneous and pulmonary nodules. Polymerase chain reaction targeting the highly conserved Leporipoxvirus DNA polymerase gene was positive using DNA extracted from the cutaneous lesions of all 3 squirrels. Nucleotide sequence of the 390 base PCR amplicons was closely related to that of other members of the genus Leporipoxvirus. To the authors' knowledge, this is the first report of cutaneous and systemic poxviral disease in American red squirrels with molecular characterization of the squirrel fibroma virus.

Bovine viral diarrhea (BVD) is one of the economically important diseases of cattle. For many years, different types of vaccines have been commercially available, yet this disease is hard to control in high-density population areas. Detection and isolation of bovine viral diarrhea virus (BVDV) from any potential reservoir is vital, especially when considering virus eradication from a herd or locale. One potential source is wild ruminants. Ear notches and lymph nodes were collected from the wild population of white-tailed deer (Odocoileus virginianus) during deer hunting season in Indiana and tested for BVDV with a commercial BVD antigen capture enzyme-linked immunosorbent assay. Two samples out of 745 collected samples were positive, and subsequently cp and ncp BVDV was isolated from 1 ear notch and 1 lymph node. These isolates were genotyped as type 1a and 1b based on sequence analysis of the 5' untranslated region (UTR). The results of the present study indicate that the prevalence of BVDV in the white-tailed deer population of Indiana is about 0.3%. Wild ruminants infected with BVDV should be taken into consideration during an eradication program of BVDV from the livestock population.

Mesial temporal lobe epilepsy (MTLE), the most common epilepsy in adults, is generally intractable and is suspected to be the result of recurrent excitation or inhibition circuitry. Recurrent excitation and the development of seizures have been associated with aberrant mossy fiber sprouting in the hippocampus. Of the animal models developed to investigate the pathogenesis of MTLE, post-status epilepticus models have received the greatest acceptance because they are characterized by a latency period, the development of spontaneous motor seizures, and a spectrum of lesions like those of MTLE. Among post-status epilepticus models, induction of systemic kainic acid or pilocarpine-induced epilepsy is less labor-intensive than electrical-stimulation models and these models mirror the clinicopathologic features of MTLE more closely than do kindling, tetanus toxin, hyperthermia, post-traumatic, and perinatal hypoxia/ischemia models. Unfortunately, spontaneous motor seizures do not develop in kindling or adult hyperthermia models and are not a consistent finding in tetanus toxin-induced or perinatal hypoxia/ischemia models. This review presents the mechanistic hypotheses for seizure induction, means of model induction, and associated pathology, especially as compared to MTLE patients. Animal models are valuable tools not only to study the pathogenesis of MTLE, but also to evaluate potential antiepileptogenic drugs.

Toxoplasmosis was diagnosed in a woodchuck (Marmota monax) and 2 American red squirrels (Tamiasciurus hudsonicus). The woodchuck was euthanized by a wildlife rescue organization in New York after progressive clinical signs of head tilt, circling, and rapid weight loss. Necropsy examination revealed acute subdural hemorrhage over the right cerebral hemisphere. Histologic lesions included meningoencephalitis, myocarditis, and hepatitis. Protozoal cysts were present in affected and unaffected neuroparenchyma. The squirrels were found dead, emaciated, and moderately infested with fleas near a park in northern Indiana. In both squirrels, the lungs were consolidated with numerous nodules up to 2 mm in diameter. Histologically, pneumonia and encephalitis were associated with intracellular and free protozoa. Additional histologic lesions included multifocal lymphoplasmacytic encephalitis with intralesional protozoa in both squirrels. The protozoa were positive with Toxoplasma gondii-specific immunohistochemistry and had ultrastructural features consistent with T. gondii in both squirrels. A real-time polymerase chain reaction test using T. gondii-specific probes demonstrated protozoal DNA in the lung, brain, and kidney of the squirrels and in the brain and heart of the woodchuck. To the authors' knowledge, this is the first report of toxoplasmosis in woodchucks or American red squirrels. Because rodents are common near urban settlements, this finding underscores their role as important intermediate hosts for T. gondii.

Purpose: To explore attitudes and perceptions of obesity, and identify preferences for weight-management interventions by African-American and Caucasian women who were followed in general internal medicine clinics., Procedure: Surveys exploring these issues were mailed to African-American (n=240) and Caucasian (n=240) women with a BMI of > or =30., Main Findings: Caucasian women felt past weight-loss efforts were helped by weight-loss programs significantly more than African-American women (P<0.001); African-American women were more likely to feel that their cultural background contributed to their weight gain than did Caucasian women (P=0.001). African-American women expressed a higher need for one-on-one counseling with their physician (P<0.001) as well as group meetings with the dietician, physician and other women (P=0.004) than did Caucasian women. African-American women also felt it was more important for weight-loss programs to have information on food common to their culture than did Caucasian women (P<0.001)., Conclusions: Differences in cultural background and preferences about weight loss interventions have important policy implications for how the U.S. healthcare system provides care to an ever-increasing multicultural population with a national epidemic such as obesity.

Designing culturally relevant weight-reduction programs requires understanding of ethnic variations and illness beliefs. Preliminary data on the values and beliefs about obesity and weight reduction were obtained from women of different ethnic/racial backgrounds. Purposive sampling was used to recruit African American (AA) and Caucasian (C) women with a body mass index (BMI)>or= 30 from the general internal medicine clinics of a large tertiary care facility. Four focus groups (2 with AA women and 2 with C women) consisting of a total of 20 subjects were conducted in a 2-month period. AA women cited culture specific barriers to weight loss more so than did C women. AA women and C women also differed on how health care professionals could help them with weight loss. These findings have implications for nursing's role in the design of culturally relevant weight-loss programs.

Monkeypox with extensive lesions was diagnosed in a prairie dog that was involved in a recent human outbreak of monkeypox in the Midwestern United States. Gross lesions included oral ulcers, pulmonary consolidation, enlarged cervical and thoracic lymph nodes, and multifocal, small, white umbilicated plaques in the gastrointestinal wall. Microscopic lesions were extensive in the lungs and consisted of fibrinonecrotic bronchopneumonia with vasculitis and poorly defined eosinophilic intracytoplasmic inclusion bodies in cells thought to be alveolar epithelial cells, histiocytes, and fibroblasts. Multifocal necrotizing lesions, often accompanied by myxedema, were also present in most of the other examined organs. Aggregates of pox viral particles were observed within lesions by transmission electron microscopy. Monkeypox virus infection was confirmed by real-time polymerase chain reaction and virus culture at the Centers for Disease Control and Prevention. This report highlights the difficulties of rapid diagnosis of exotic or emerging diseases and further substantiates the prairie dog as an animal model of monkeypox.

Objective: To describe an outbreak of encephalomyelitis caused by West Nile virus (WNV) in horses in northern Indiana., Design: Case series., Animals: 170 horses., Procedures: Horses with clinical signs suggestive of encephalomyelitis caused by WNV were examined. Date, age, sex, breed, and survival status were recorded. Serum samples were tested for anti-WNV antibodies, and virus isolation was attempted from samples of brain tissue. Climate data from local weather recording stations were collected. An epidemic curve was constructed, and case fatality rate was calculated., Results: The most common clinical signs were ataxia, hind limb paresis, and muscle tremors and fasciculations. Eight horses had been vaccinated against WNV from 2 to 21 days prior to the appearance of clinical signs. West Nile virus was isolated from brain tissue of 2 nonvaccinated horses, and anti-WNV IgM antibodies were detected in 132 nonvaccinated horses; in 2 other nonvaccinated horses, anti-WNV antibodies were detected and WNV was also isolated from brain tissue. Thirty-one (22.8%) horses died or were euthanatized. The peak of the outbreak occurred on September 6, 2002. Ambient temperatures were significantly lower after the peak of the outbreak, compared with prior to the peak., Conclusions and Clinical Relevance: The peak risk period for encephalomyelitis caused by WNV in northern Indiana was mid-August to mid-September. Reduction in cases coincided with decreasing ambient temperatures. Because of a substantial case fatality rate, owners of horses in northern Indiana should have their horses fully protected by vaccination against WNV before June. In other regions of the United States with a defined mosquito breeding season, vaccination of previously nonvaccinated horses should commence at least 4 months before the anticipated peak in seasonal mosquito numbers, and for previously vaccinated horses, vaccine should be administered no later than 2 months before this time.

Objective: To determine whether the increasing prevalence of feline hyperthyroidism is the result of aging of the cat population and whether consumption of canned foods at various times throughout life is associated with increased risk of hyperthyroidism., Design: Retrospective and case-control studies., Study Population: Medical records of 169,576 cats, including 3,570 cats with hyperthyroidism, evaluated at 9 veterinary school hospitals during a 20-year period, and 109 cats with hyperthyroidism (cases) and 173 cats without hyperthyroidism (controls)., Procedure: Age-adjusted hospital prevalence of hyperthyroidism was calculated by use of Veterinary Medical Database records. On the basis of owners' questionnaire responses, logistic regression was used to evaluate associations between consumption of canned food and development of hyperthyroidism., Results: Age-specific hospital prevalence of feline hyperthyroidism increased significantly from 1978 to 1997. Overall, consumption of pop-top canned (vs dry) food at various times throughout life and each additional year of age were associated with greater risk of developing hyperthyroidism. In female cats, increased risk was associated with consumption of food packaged in pop-top cans or in combinations of pop-top and non-pop-top cans. In male cats, increased risk was associated with consumption of food packaged in pop-top cans and age., Conclusions and Clinical Relevance: These findings suggest that the increasing prevalence of feline hyperthyroidism is not solely the result of aging of the cat population and that canned foods may play a role.

Sephacryl S-1000 size-exclusion chromatography was used to purify turkey coronavirus (TCoV) from infected turkey embryo. TCoV was propagated in the 22-day-old turkey embryos. Intestines and intestinal contents of infected embryos were harvested and homogenized. After low speed centrifugation, the supernatant was concentrated by ultracentrifugation through a cushion of 30 or 60% sucrose solution, or by ammonium sulfate precipitation. The purification methods included sucrose gradient and Sephacryl S-1000 size-exclusion chromatography. Ultracentrifugation through a cushion of 60% sucrose solution was better than the other two methods for concentration of TCoV from intestinal homogenate. The most effective method for purifying TCoV and removing extraneous materials was size-exclusion chromatography as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. More spike-rich particles were observed in the sample purified by chromatography than those purified by sucrose gradient as examined by electron microscopy. Differentiation of turkey anti-TCoV antiserum from normal turkey serum was better achieved by ELISA plates coated with TCoV preparation purified by size-exclusion chromatography than that purified by sucrose density gradient. The results indicated that Sephacryl S-1000 chromatography was useful for purification of TCoV.

The present study was to characterize turkey coronavirus associated with turkey poult enteritis and mortality. Intestinal contents or intestines from affected turkey poults and inoculated turkey embryos contained coronaviruses as revealed by electron microscopy or were positive for turkey coronavirus by immunofluorescent antibody assay. Sucrose density gradient ultracentrifugation of the virus-containing intestinal homogenate yielded two opalescent bands corresponding to the buoyant densities of 1.14-1.15 and 1.18-1.20 g/ml, respectively. Coronaviral particles from intestinal contents or the sucrose density gradient preparation were mainly spherical in shape and had envelope and central depression. They were surrounded by a fringe of regularly spaced petal-shaped projections attached to the particles by a short stalk. Purified viruses hemagglutinated rabbit erythrocytes with a titer of 16. Major protein bands of purified viruses analyzed by SDS-PAGE were located at 200, 100-110, 50-60, and 30-35 kDa. The patterns of protein bands were consistent with those of Minnesota or Quebec turkey coronavirus isolates. A 568 bp nucleotide fragment of turkey coronavirus spike protein gene was amplified from RNA of inoculated turkey embryo intestine or purified virus. Sequence analysis of the 568 bp PCR product revealed high degree of identity with the corresponding spike protein gene sequence of human and bovine coronaviruses. The results indicated that turkey coronavirus was associated with turkey poults with acute enteritis.

The objective of the present study was to elucidate the kinetics of humoral and cellular immune responses of turkey poults infected with turkey coronavirus (TCV). Turkey poults were orally inoculated with TCV at 10 d of age, and the immune responses were analyzed at 1, 3, 7, 14, 21, 28, 42, and 63 d postinfection (PI) in three different experiments. Total Ig to TCV was initially detected at 7 and 14 d PI in Experiments 1 and 3. In addition, Ig gradually increased from 7 to 21 d PI and remained at 80 immunofluroescent antibody assay (IFA) titers or more thereafter. Lymphocyte proliferation responses of spleen cells to concanavalin A were higher in TCV-infected turkeys than in noninfected control turkeys with significant differences (P < 0.05) being noted at 14 and 63 d PI in Experiment 2 and at 3 and 28 d PI in Experiment 3. Strong IFA staining response to TCV antigen was observed in intestines of turkeys at 1, 3, and 7 d PI, and the response declined from 14 to 28 d PI in Experiment 3. In Experiment 3, the IgG isotype antibody response to TCV was markedly increased after 21 d PI and remained high until 63 d PI. The IgM isotype antibody response to TCV was 1.40 and 0.91 at 7 and 14 d PI, respectively. The IgA isotype antibody response to TCV was very low as detected at 7 (0.13), 14 (0.20), and 21 (0.17) d PI. Turkeys infected with TCV had significantly higher (P < 0.05) antibody response to sheep erythrocytes than noninfected controls at 7 d PI. Virus-specific lymphocyte proliferation response of spleen cells was significantly stimulated (P < 0.05) at 63 d PI in Experiment 3. The proportion of the CD4+ subpopulation of T lymphocytes was significantly increased (P < 0.05) at 1, 7, and 21 d PI in Experiment 3. The results indicate that humoral and cellular immunities to TCV are elicited in turkeys following infection with TCV.

Decisions to begin or continue hormone replacement therapy (HRT) are individualized, depending on a woman's anticipated benefits and risks from HRT. Estrogen, especially when begun early in menopause, has been shown to be beneficial in the prevention and treatment of osteoporosis. Potential risks of HRT include gallbladder disease, thromboembolism, and breast cancer. Systemic or topical estrogen can improve postmenopausal vaginal atrophy, vasomotor symptoms, and cervical cytologic changes. Treatment of other urogynecologic changes, such as vulval dystrophy and urinary incontinence, can relieve symptoms and improve the older woman's quality of life.