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Aims: To describe health-related quality of life (HRQoL) and identify associated factors in patients with type 2 diabetes mellitus (T2DM) treated with oral glucose-lowering drugs (OGLDs)., Methods: This retrospective, cross-sectional analysis included adults with T2DM from 11 Asian countries/regions prospectively enrolled in the Joint Asian Diabetes Evaluation (JADE) Register (2007-2019) with available EuroQol-5D (EQ-5D-3L) data., Results: Of 47,895 included patients, 42,813 were treated with OGLDs + lifestyle modifications (LSM) and 5,082 with LSM only. Among those treated with OGLDs, 60% received sulphonylureas (SUs), of whom 47% received gliclazide. The OGLD + LSM group had a lower mean EQ-5D-3L index score than the LSM-only group (p < 0.001). The most affected EQ-5D-3L dimensions in OGLD + LSM-treated patients were pain/discomfort (26.2%) and anxiety/depression (22.6%). On multivariate analysis, good HRQoL was positively associated with male sex, education level, balanced diet and regular exercise, and negatively with complications/comorbidities, self-reported hypoglycaemia, smoking, HbA1c, age, body mass index and disease duration. Patients receiving gliclazide vs non-gliclazide SUs had lower HbA1c and better HRQoL in all dimensions (p < 0.001)., Conclusions: Demographic, physical and psychosocial-behavioural factors were associated with HRQoL in patients with T2DM. Our real-world data add to previous evidence that gliclazide is an effective OGLD, with most treated patients reporting good HRQoL. A plain language summary of this manuscript is available here., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Lee-Ling Lim reports receiving grants and/or honoraria for consultancy or giving lectures from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Roche, Sanofi, Servier, Viatris Pharmaceutical and Zuellig Pharma. Eric S.H. Lau reports no conflicts of interest. Siew Pheng Chan reports receiving grants and/or honoraria for consultancy or giving lectures from Abbott, AstraZeneca, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Servier and Zuellig Pharma. Linong Ji reports receiving consulting and lecture fees from Eli Lilly, Novo Nordisk, Merck, Sanofi-Aventis, MSD, Servier and Boehringer Ingelheim. Soo Lim has been a member of advisory boards or has consulted for Merck, Sharp & Dohme, NovoNordisk and Servier, has received grant support from AstraZeneca, Merck, Sharp & Dohme and Astellas, and has served on the speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, CKD Pharmaceutical and NovoNordisk. Sirinart Sirinvaravong reports receiving honoraria for giving lectures from Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi, Servier and Zuellig Pharma. A. G. Unnikrishnan reports receiving grants via affiliated institutions, advisory board and speaker contracts from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Sanofi, Serdia, Servier, Novo Nordisk and Roche. Andrea O.Y. Luk reports receiving grants and/or honoraria for consultancy or giving lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Lee's Pharmaceutical, Roche and Sanofi. The proceeds have been donated to CUHK, the ADA and other charity organizations to support diabetes research and education. Viviana Cortese and Alexandra Durocher are employees of Servier. Juliana C.N. Chan reports receiving research grants through her affiliated institutions, honoraria and speakers' fees from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Hua Medicine, Powder Pharmaceuticals, Lilly, Merck Sharp & Dohme, Merck Serono, Pfizer, Sanofi, Servier, Viatris Pharmaceutical and Zuellig Pharma, holds patents of genetic markers for predicting diabetes and its complications, and is a cofounder of a biotechnology start-up company, GemVCare, with partial support from the Hong Kong Government Innovation and Technology Commission for providing precision diabetes care and Chief Executive Officer of Asia Diabetes Foundation on a pro bono basis.]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To explore the patterns of use of oral glucose-lowering drugs (OGLDs) in Asian patients with type 2 diabetes (T2D), focusing on sulphonylureas (SUs), and to describe patient profiles according to treatment regimen., Methods: We conducted a cross-sectional analysis of data from adults with T2D from 11 Asian countries/regions with structured assessment enrolled in the prospective Joint Asia Diabetes Evaluation (JADE) register between November 2007 and December 2019. Patients receiving insulin and/or injectable glucagon-like peptide-1 receptor agonists were excluded., Results: Amongst 62 512 patients (mean ± standard deviation age: 57.3 ± 11.8 years; 53.6% men), 54 783 (87.6%) were treated with OGLDs at enrolment. Most received one (37.5%) or two (44.2%) OGLDs. In the entire cohort, 59.4% of treated patients received SU-based therapy with variations amongst countries/regions. Overall, 79.5% of SU regimens were based on SUs plus metformin, and 22.1% on SUs plus dipeptidyl peptidase-4 inhibitors. Among SU users, gliclazide was most commonly prescribed (46.7%), followed by glimepiride (40.0%) and glibenclamide (8.1%). More gliclazide users entered the cohort with glycated haemoglobin levels <53 mmol/mol (7%) than non-gliclazide SU users (odds ratio [OR] 1.09, 95% CI 1.02-1.17), with less frequent self-reported hypoglycaemia in the 3 months before registration (OR 0.81, 95% CI 0.72-0.92; adjusted for sociodemographic factors, cardiometabolic risk factors, complications, use of other OGLDs, country/region and year of registration)., Conclusion: In Asia, SUs are a popular OGLD class, often combined with metformin. Good glycaemic control and safety profiles associated with the use of SUs, including gliclazide, support their position as a key treatment option in patients with T2D., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Little information is available about experimental inoculation of leptospirosis in horses and the pathogenicity of Leptospira interrogans serovar Bratislava in this host., Objectives: To determine the serological, clinical, pathological and haematological responses of horses to L. interrogans serovar Bratislava strain PigK151., Study Design: Randomised controlled in vivo experiment., Methods: Ten seronegative female foals were divided into 2 groups, control (n = 4) and challenged (n = 6). The challenged group received 1 × 10 9 leptospires divided equally between topical ocular and intraperitoneal injections. Blood and urine samples were analysed. The temperature was recorded daily for the first 9 days, then weekly. Sera were tested by microscopic agglutination test (MAT). Automated complete blood count, differential and chemistry panel were performed. Histopathological analysis was performed on sections of liver, kidney, urinary bladder, uterine body and pineal gland. Sample culturing was performed from blood, urine, liver, kidney, reproductive tract and vitreous humour., Results: No pyrexia was noted. PCR and culture were negative from all samples. Differences between groups were found in CBC, differential counts and serum biochemistry panel (or profile), suggesting that leptospiral challenge triggered an inflammatory response. No evidence of leptospirosis was found from histopathological analysis. All challenged foals developed a humoral response. The MAT allowed the confirmation of the infecting serovar at a later stage, but it also revealed cross-reactive results that were further explained by genomic analysis., Main Limitations: This experimental challenge had two main limitations: (a) the results might have varied if another strain from the same serovar had been used and (b) the use of another route of infection and a higher bacterial dose might have achieved colonisation., Conclusions: Based on these findings, it may suggest that L. interrogans serovar Bratislava is neither pathogenic nor host-adapted serovar for horses, although these results might have varied if another strain from the same serovar had been used instead., (© 2021 EVJ Ltd.)

Introduction: To analyse the safety and effectiveness of gliclazide modified release (MR) in adults with type 2 diabetes mellitus participating in Ramadan from three geographically and culturally different regions of the world included in the DIA-RAMADAN study., Methods: DIA-RAMADAN was a real-world, observational, international, non-comparative study. The global study population was divided into three regional subgroups, with data gathered at inclusion 6-8 weeks prior to Ramadan (V0), during Ramadan (4.5 weeks) and 4-6 weeks after Ramadan (V1). Primary endpoint was the proportion of patients reporting ≥ 1 symptomatic hypoglycaemic events (HE), which were collected using a patient diary along with other adverse events., Results: Patient numbers from the three regions were n = 564 (46.5%; Indian sub-continent), n = 354 (29.1%; Middle East) and n = 296 (24.4%; South-East Asia). Patient baseline characteristics, demographics, fasting habits and antidiabetic treatments varied between regions. There were similar proportions of symptomatic HE between regions, with no severe HE. Significant weight reductions were observed in all regions following Ramadan, along with reductions in HbA 1c and fasting plasma glucose., Conclusion: These real-world study data indicate that gliclazide MR is safe and effective for management of type 2 diabetes during Ramadan in all three regions studied as part of DIA-RAMADAN., Trial Registration: Clinicaltrials.gov identifier NCT04132934. INFOGRAPHIC.

Aims: To compare the effectiveness and safety of gliclazide modified release (MR) to sitagliptin as type 2 diabetes mellitus (T2D) treatments in a real-world patient population., Materials and Methods: This retrospective cohort study used records from the UK Clinical Practice Research Datalink. The cohort consisted of adult patients with T2D newly treated with either gliclazide MR or sitagliptin as second-line treatment added to metformin and with a glycated haemoglobin (HbA1c) level of ≥7.0% (53 mmol/mol). Patients were 1:1 matched using high-dimensional propensity score matching and followed to determine the time taken to reach an HbA1c <7.0%. Secondary outcomes included time to HbA1c ≤6.5% (48 mmol/mol), time to ≥1% (11 mmol/mol) HbA1c reduction from baseline, treatment persistence and durability, and hypoglycaemic events., Results: Among the 1986 patients included, those on gliclazide MR more likely achieved an HbA1c <7.0% [hazard ratio (HR): 1.35; 95% confidence interval (CI): 1.15-1.57], HbA1c ≤6.5% (HR: 1.51; 95% CI: 1.19-1.92) or had an HbA1c reduction ≥1% from baseline (HR: 1.11; 95% CI: 1.00-1.24) compared with patients on sitagliptin. Durability (log-rank P = .135) and persistence (P = .119) were similar between the two groups. Hypoglycaemic events were uncommon (23 total severe and non-severe events; incidence rate, 3.7 per 1000 patient years), with 4.7 and 2.6 events per 1000 patient years with gliclazide MR and sitagliptin treatment, respectively., Conclusions: In this real-world study, second-line gliclazide MR was more effective than sitagliptin in reducing HbA1c, with similar durability and persistence and low rates of hypoglycaemic events, in individuals with T2D on metformin treatment and HbA1c above the target of 7.0%., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: With improvement in methods, mortality after duodeno-cefalo pancreatectomy (DCP) has decreased to 5% even if complication rate is still high (30-50%). The pancreatic fistula still occurs in 25-50% of cases. Various methods of treating pancreatic stump have been proposed aimed to improve this rate., Patients and Methods: The AA, surgeons of suburban hospital, have performed in five years, 2009-2013, 12 DCP. The pancreatic anastomosis has been in all cases an end-to-end duct-to-mucosa pancreatic-jejunostomy., Results: The prevalence of fistula has been 33% (4 cases, 3 grade A and 1 grade B according with ISGPF score)., Conclusions: Soft pancreas and small size of pancreatic duct are recognized as the mayor factor of risk for pancreatic fistula. In these cases are usually preferred pancreatic-jejunostomy (PJ) and pancreatic-gastro-anastomosis (PG). Both techniques show advantages and disadvantages: some randomized and prospective studies have demonstrated the absence of significative differences respect to the prevalence of pancreatic fistulas. Whipple method has been the most often used reconstructive method: a single loop with bile-pancreatic anastomosis and gastro-pancreatic anastomosis in sequence. A careful evaluation of pancretic tissue and Wirsung size with the aim of choosing the most suitable technique and an accurate execution are the most effective methods to prevent pancreatic fistula,even considering particular setting as elderly patient or HIV infection.

Nineteen open heifers or cows were vaccinated 45 days prior to breeding with a modified-live bovine viral diarrhea virus (BVDV) vaccine. An additional six animals were not vaccinated and served as controls. All 25 animals were estrus-synchronized and bred. At 75 days of gestation, the 25 pregnant animals were experimentally infected with a type II isolate of BVDV by intranasal inoculation. At 75 days after inoculation, the animals were euthanized and each fetus was removed and retained for sampling. Virus isolation was accomplished from fetal tissues (spleen, thymus, and small intestine). Type II BVDV was isolated from the fetuses collected from all six unvaccinated control animals and from eight of 19 fetuses from vaccinated animals, which were determined to be persistently infected following experimental challenge.

Objective: To determine the effect of maternally derived antibodies on induction of protective immune responses against bovine viral diarrhea virus (BVDV) type II in young calves vaccinated with a modified-live bovine viral diarrhea virus (BVDV) type I vaccine., Design: Blinded controlled challenge study., Animals: 24 neonatal Holstein and Holstein-cross calves that were deprived of maternal colostrum and fed pooled colostrum that contained a high concentration of (n = 6) or no (18) antibodies to BVDV., Procedure: At 10 to 14 days of age, 6 seropositive and 6 seronegative calves were given a combination vaccine containing modified-live BVDV type I. All calves were kept in isolation for 4.5 months. Six calves of the remaining 12 untreated calves were vaccinated with the same combination vaccine at approximately 4 months of age. Three weeks later, all calves were challenged intranasally with a virulent BVDV type II., Results: Seronegative unvaccinated calves and seropositive calves that were vaccinated at 2 weeks of age developed severe disease, and 4 calves in each of these groups required euthanasia. Seronegative calves that were vaccinated at 2 weeks or 4 months of age developed only mild or no clinical signs of disease., Conclusions and Clinical Relevance: Results indicate that a single dose of a modified-live BVDV type-I vaccine given at 10 to 14 days of age can protect susceptible young calves from virulent BVDV type II infection for at least 4 months, but high concentrations of BVDV-specific maternally derived antibodies can block the induction of the response.

The efficacy of modified-live (MLV) bovine respiratory syncytial virus (BRSV) vaccines and the correlates of vaccine-induced immunity were investigated in calves using a virulent experimental infection. Clinical disease and pulmonary pathology were significantly reduced, relative to unvaccinated controls, in calves vaccinated according to label directions with commercial multivalent MLV BRSV vaccines. In vitro assays of cellular immunity were more consistent correlates of vaccine associated protection than presence of post vaccination serum antibody. Most vaccinated calves shed virus, but peak virus titre was suppressed compared to unvaccinated controls, with clearance coincident with the simultaneous appearance of mucosal antibody, cytotoxic cells in the lung and anamnestic or primary serum antibody responses. Virus clearance in unvaccinated calves was coincident with the appearance of BRSV specific cytotoxic cells, before mucosal antibody was detected.

Objective: To evaluate the potential synergy between bovine respiratory syncytial virus (BRSV) and 3-methylindole (3MI) in inducing respiratory disease in cattle., Animals: 20 mixed-breed beef calves., Procedure: A 2 X 2 factorial design was used, with random assignment to the following 4 treatment groups: unchallenged control, BRSV challenge exposure (5 X 10(4) TCID50 by aerosolization and 5.5 X 10(5) TCID50 by intratracheal inoculation), 3MI challenge exposure (0.1 g/kg of body weight, PO), and combined BRSV-3MI challenge exposure. Clinical examinations were performed daily. Serum 3MI concentrations, WBC counts, PCV, total plasma protein, and fibrinogen concentrations were determined throughout the experiment. Surviving cattle were euthanatized 7 days after challenge exposure. Pulmonary lesions were evaluated at postmortem examination., Results: Clinical respiratory disease was more acute and severe in cattle in the BRSV-3MI challenge-exposure group than in cattle in the other groups. All 5 cattle in this group and 3 of 5 cattle treated with 3MI alone died or were euthanatized prior to termination of the experiment. Mean lung displacement volume was greatest in the BRSV-3MI challenge-exposure group. Gross and histologic examination revealed that pulmonary lesions were also most severe for cattle in this group., Conclusions and Clinical Relevance: Feedlot cattle are commonly infected with BRSV, and 3MI is produced by microflora in the rumen of all cattle. Our results suggest that there is a synergy between BRSV and 3MI. Thus, controlling combined exposure may be important in preventing respiratory disease in feedlot cattle.

Objective: To determine efficacy of a modified-live type-I isolate of bovine viral diarrhea virus (BVDV) vaccine in protecting calves from infection with a virulent type-II isolate, and to determine which type of immune response (i.e., humoral or cellular) correlates with protection., Design: Prospective study., Animals: 28 neonatal Holstein and Holstein-cross calves., Procedure: Within 18 hours of birth, calves received maternal colostrum or were fed pooled colostrum. On days 7 to 10 after birth, calves were determined to be seropositive (n = 16) or seronegative (12) for antibodies to BVDV on the basis of ELISA and virus neutralization test results. Seropositive and seronegative 10- to 14-day-old calves were then given a combined vaccine that contained a modified-live type-I isolate of BVDV or a similar vaccine that lacked protection against bovine viral diarrhea. All calves were inoculated intranasally approximately 21 days after vaccination with a virulent type-II isolate of BVDV. Clinical and immunologic variables, including clinical scores, rectal temperatures, results of CBC with lymphocyte subset analysis, antibody responses, and cell-mediated immune responses, were monitored for 14 days after inoculation., Results: Seronegative-unvaccinated calves developed severe disease and required euthanasia. Vaccination of seronegative calves with a modified-live type-I isolate had a disease-sparing effect as did passive transfer of colostral antibodies to BVDV. Clinical scores were not significantly different between seropositive-vaccinated and seropositive-unvaccinated calves after viral inoculation., Clinical Implications: A single dose of a modified-live type-I isolate of BVDV vaccine protects young calves from clinical signs of disease associated with type-II isolates.

During the past several years, acute infections with bovine viral diarrhea virus (BVDV) have been causally linked to hemorrhagic and acute mucosal disease-like syndromes with high mortality. The majority of BVDVs isolated in such cases have been classified as type II on the basis of genetic and antigenic characteristics. It was our objective to examine clinical disease, lesions and potential sites of viral replication, following experimental BVDV type II infection in young calves. On approximately day 35 after birth, calves that had received BVDV-antibody-negative colostrum were infected by intranasal inoculation of 5 x 10(5) TCID50 of BVDV type II isolate 24,515 in 5 mL of tissue culture fluid (2.5 mL/nostril). Calves were monitored twice daily for signs of clinical disease. Approximately 48-72 h after infection, all calves developed transient pyrexia (39.4-40.5 degrees C) and leukopenia. Beginning on approximately day 7 after infection, all calves developed watery diarrhea, pyrexia (40.5-41.6 degrees C), marked leukopenia (> or = 75% drop from preinoculation values), variable thrombocytopenia, and moderate to severe depression. Calves were euthanized on days 10, 11, or 12 after infection due to severe disease. Gross and histological lesions consisted of multifocal bronchointerstitial pneumonia (involving 10%-25% of affected lungs), bone marrow hypoplasia and necrosis, and minimal erosive lesions in the alimentary tract. Immunohistochemical staining for BVDV revealed widespread viral antigen usually within epithelial cells, smooth muscle cells and mononuclear phagocytes in multiple organs, including lung, Peyer's patches, gastric mucosa, thymus, adrenal gland, spleen, lymph nodes, bone marrow, and skin. This BVDV type II isolate caused rapidly progressive, severe multisystemic disease in seronegative calves that was associated with widespread distribution of viral antigen and few gross or histological inflammatory lesions.

Objective: To determine the duration for cross-neutralizing antibodies stimulated by administration of a single dose of a modified-live vaccine against bovine viral diarrhea virus (BVDV) to seronegative cattle., Animals: 23 Angus cows seronegative to BVDV., Procedure: Cows were randomly assigned to control (unvaccinated) or test (vaccinated) groups. Eighteen BVDV-seronegative Angus cattle were vaccinated via IM injection with a modified-live BVDV (NADL strain) vaccine and commingled with 5 unvaccinated seronegative cows. Serum was obtained from the cows before vaccination, on the day of vaccination, and 1.5, 3, 6, 9, 12, and 18 months after vaccination. Serum neutralizing antibody tests were performed on samples obtained at each point after vaccination, using a panel of 12 strains of BVDV that, on the basis of reactivity with monoclonal antibodies, were identified as heterologous., Results: Antibodies against all 12 strains of BVDV (which we tested) were detected by use of viral neutralization testing in samples obtained from vaccinated cattle 18 months after vaccination; however, concentration of antibody for some of the strains was low. Nonvaccinated cattle remained seronegative throughout the 18-month study period., Clinical Implications: Analysis of these data indicated that modified-live BVDV vaccines could stimulate an antibody response in seronegative cows that was detectable for at least 18 months after vaccination. These antibodies were able to cross neutralize 12 antigenically diverse strains of BVDV.

Objective: To assess the effect of vaccination against bovine respiratory syncytial virus on milk production, reproductive performance, and health in lactating dairy cows., Design: Prospective randomized block design., Animals: 385 Holstein dairy cows and heifers., Procedure: Cows were grouped by lactation number, season of calving, and previous mature equivalent 305-day milk production (where appropriate). Prior to parturition, cows and heifers were randomly assigned to be vaccinated i.m. against infectious bovine rhinotracheitis, bovine viral diarrhea, and parainfluenza 3 viruses by use of a three-way vaccine, or to be vaccinated against those viruses as well as bovine respiratory syncytial virus, using a four-way vaccine. Milk production was measured daily through 305 days of lactation. Reproductive and medical records were reviewed to obtain insemination dates and record medical problems of cows in each vaccine treatment group., Results: Compared with the three-way vaccine, administration of the four-way vaccine was associated with higher milk production (1.39 kg [3.06 lb] more milk/d) in first-parity cows during the first 21 weeks of lactation. Vaccination did not have any effect on milk production after the first 21 weeks of lactation in cows of any parity. Conception rates at first insemination were higher for four-way vaccinated first-parity cows than for three-way vaccinated first-parity cows (54.6 vs 32.7%). Compared with second-parity cows that received the three-way vaccine, first insemination conception rate was improved for second-parity cows vaccinated with the four-way vaccine (28.9 vs 47.8%, respectively). In cows of third or greater parity, first insemination conception rate was not different between the 2 vaccine treatment groups., Clinical Implications: Vaccination of heifers against bovine respiratory syncytial virus prior to partrition may increase milk production and first insemination conception rates.

Objective: To examine the effects of perinatal vaccination on cellular and humoral responses in cows and on passive transfer of antibodies and cells to calves, and to assess the role of maternal antibodies in vaccination responses of neonatal calves., Design: Prospective randomized control trial., Animals: 52 beef cows and their calves., Procedures: Assigned cows were vaccinated twice during the last month of gestation. Assigned calves were vaccinated at day 10 after birth. Antibody concentrations and cellular responses to bovine respiratory syncytial virus (BRSV) and bovine herpesvirus type 1 (BHV-1) were measured in blood and colostrum of cows and in blood of calves. Calves were assessed for passive transfer of lymphocytes., Results: At parturition, serum antibody concentrations to BRSV as well as BHV-1- and BRSV-specific blastogenic responses were significantly higher in vaccinated cows. After birth, calves from vaccinated cows had significantly higher concentrations of BRSV-specific serum antibodies, but not BHV-1 specific antibodies. Calves did not develop delayed-type hypersensitivity responses to BRSV. At weaning, lymphocytes from neonatally vaccinated calves had significantly higher values for virus-specific proliferation than did lymphocytes from unvaccinated calves; however, significant differences were not detected between groups after vaccination at weaning., Clinical Implications: Administration of modified-live viral vaccines can boost systemic humoral and cellular responses to BRSV and BHV-1 in cows. Neonatal calves can be immunologically primed by vaccination with modified-live virus vaccines. Virus-specific memory cells persist in most calves until weaning.