130 results on '"T. George"'
Search Results
2. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA‐REG OUTCOME trial
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Anne Pernille Ofstad, Afshin Salsali, Erich Bluhmki, Martin Schumacher, Christoph Wanner, John M. Lachin, Silvio E. Inzucchi, Stefan Hantel, Kristin Ohneberg, Jyothis T. George, Claudia Schmoor, David Fitchett, Faiez Zannad, Bernard Zinman, St. Michael's Hospital, Yale University School of Medicine, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], University Hospital of Würzburg, University of Freiburg [Freiburg], Clinical Trials Center, Freiburg University Medical Center, Boehringer Ingelheim Norway KS, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Boehringer Ingelheim International GmbH, Biostatistics Center, The George Washington University, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), This analysis was funded by Boehringer Ingelheim. TheEMPA-REG OUTCOME trial was funded by BoehringerIngelheim and Eli Lilly., Yale School of Medicine [New Haven, Connecticut] (YSM), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), and BOZEC, Erwan
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medicine.medical_specialty ,Population ,Empagliflozin ,Renal function ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Glucosides ,Diabetes mellitus ,Internal medicine ,Heart rate ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Humans ,030212 general & internal medicine ,Benzhydryl Compounds ,education ,Heart Failure ,education.field_of_study ,business.industry ,Proportional hazards model ,Diabetes ,SGLT2 inhibitor ,Original Articles ,medicine.disease ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,Diabetes Mellitus, Type 2 ,chemistry ,RC666-701 ,Heart failure ,Cardiology ,Mediation analysis ,Uric acid ,Original Article ,Cardiology and Cardiovascular Medicine ,business - Abstract
International audience; Aims: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death.Methods and results: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated.Conclusions: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.
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- 2021
3. Design and rationale of the EMPA‐VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure
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Eleanor Wicks, Hanan Lamlum, Jyothis T. George, Olorunsola F. Agbaje, Christopher T. Rodgers, Rury R. Holman, Oliver J Rider, Ladislav Valkovič, Heiko G. Niessen, Rolf Grempler, Stefan Neubauer, Moritz Hundertmark, Joanne E. Milton, Jisoo Lee, Ruth L. Coleman, Masliza Mahmod, Rodgers, Christopher [0000-0003-1275-1197], and Apollo - University of Cambridge Repository
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31P-MRS ,Trial design ,medicine.medical_specialty ,Study Designs ,Empagliflozin ,Heart failure ,Placebo ,31P‐MRS ,Glucosides ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Diseases of the circulatory (Cardiovascular) system ,Benzhydryl Compounds ,Study Design ,Ejection fraction ,business.industry ,Diabetes ,Type 2 Diabetes Mellitus ,medicine.disease ,Clinical trial ,Diabetes Mellitus, Type 2 ,RC666-701 ,Cohort ,Cardiology ,Quality of Life ,Cardiology and Cardiovascular Medicine ,business ,SGLT2 inhibitors - Abstract
Aims Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). Methods and results The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31Phosphorus-MRS. Conclusions EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).
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- 2021
4. Impact of polyvascular disease with and without co‐existent kidney dysfunction on cardiovascular outcomes in diabetes: A post hoc analysis of <scp>EMPA‐REG OUTCOME</scp>
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Odd Erik Johansen, Christoph Wanner, Isabella Zwiener, Subodh Verma, Javed Butler, Jyothis T. George, Bernard Zinman, Silvio E. Inzucchi, C. David Mazer, and Anne Pernille Ofstad
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medicine.medical_specialty ,kidney dysfunction ,Endocrinology, Diabetes and Metabolism ,Population ,empagliflozin ,Renal function ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Kidney ,Cardiovascular System ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Empagliflozin ,Humans ,Benzhydryl Compounds ,education ,Heart Failure ,education.field_of_study ,business.industry ,Proportional hazards model ,Hazard ratio ,kidney outcomes ,Original Articles ,medicine.disease ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Heart failure ,Cardiology ,Original Article ,CV outcomes ,type 2 diabetes ,business ,polyvascular disease - Abstract
Aim To determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA‐REG OUTCOME population, and the relationship of kidney dysfunction co‐existent with polyvascular disease on CV/heart failure (HF) outcomes. Materials and Methods Patients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m2) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all‐cause mortality (ACM) and 3‐point major adverse CV events (3P‐MACE) were assessed using multivariable Cox regression models. Results Baseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P‐MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m2) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P‐MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups. Conclusions Polyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status.
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- 2021
5. Empagliflozin treatment effects across categories of baseline <scp>HbA1c</scp> , body weight and blood pressure as an add‐on to metformin in patients with type 2 diabetes
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Isabella Zwiener, Naveed Sattar, Jyothis T. George, Prabhav Trivedi, Silvio E. Inzucchi, Kamlesh Khunti, Melanie J. Davies, and Odd Erik Johansen
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Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,empagliflozin ,Urology ,Blood Pressure ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Body weight ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Double-Blind Method ,Glucosides ,Internal Medicine ,medicine ,Empagliflozin ,Humans ,Hypoglycemic Agents ,In patient ,Benzhydryl Compounds ,Adverse effect ,Aged ,Glycated Hemoglobin ,business.industry ,Body Weight ,SGLT2 inhibitor ,Original Articles ,Middle Aged ,medicine.disease ,Metformin ,Treatment Outcome ,glycaemic control ,Blood pressure ,Diabetes Mellitus, Type 2 ,Drug Therapy, Combination ,Female ,Original Article ,type 2 diabetes ,business ,medicine.drug - Abstract
Aim To investigate the association of different categories of baseline cardio‐metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second‐line therapy to metformin in patients with type 2 diabetes (T2D). Materials and Methods Patients aged 18 years or older with HbA1c 7.0%‐10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c 90 kg, SBP 140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio‐metabolic factors. Results In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P < .0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models: .0290/.1431 and .0004/.0042, respectively) and in BW (P interaction .1340/.0012 and .0202/
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- 2020
6. Early benefits of empagliflozin in patients with or without heart failure: findings from EMPA‐REG OUTCOME
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Pierpaolo Pellicori, Bernard Zinman, Anne Pernille Ofstad, Jyothis T. George, Martina Brueckmann, Christoph Wanner, JoAnn Lindenfeld, Cordula Zeller, and David Fitchett
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medicine.medical_specialty ,Randomization ,Short Communication ,Short Communications ,Empagliflozin ,Heart failure ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Placebo ,Trial ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,medicine ,Diseases of the circulatory (Cardiovascular) system ,030212 general & internal medicine ,EMPA‐REG OUTCOME ,Adverse effect ,business.industry ,Diabetes ,medicine.disease ,Blood pressure ,RC666-701 ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims:\ud The EMPA‐REG OUTCOME trial demonstrated reductions in cardiovascular (CV) death and heart failure (HF) outcomes with empagliflozin, a sodium–glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes and established CV disease over a study period of 3 years. We aimed to investigate the early benefit–risk profile of empagliflozin in patients enrolled in the EMPA‐REG OUTCOME trial according to HF status at baseline.\ud \ud Methods and results:\ud The effects of treatments on glycated haemoglobin, systolic blood pressure and body weight, and on the HF endpoints of hospitalization for HF (HHF), HHF or CV death, and HHF or all‐cause mortality were evaluated at 12 weeks, 6 months, and 1 year after randomization. Occurrence of adverse events (AEs) during these time points was also evaluated. Compared with placebo, empagliflozin lowered glycated haemoglobin, systolic blood pressure, and body weight and rates of all the HF endpoints, as early as at 12 weeks, regardless of HF status at baseline. Favourable clinical and metabolic effects were maintained over time. AEs were generally higher in those with HF than without HF; however, compared with placebo, empagliflozin did not increase risk of developing AEs over the first year of treatment.\ud \ud Conclusions:\ud In the EMPA‐REG OUTCOME trial, the use of empagliflozin led to early and beneficial effects on clinical, metabolic, and HF outcomes in patients with type 2 diabetes with or without HF at baseline, which were already apparent within 12 weeks from initiation of treatment. Over the first year of treatment, no safety concern was detected with the use of empagliflozin.
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- 2020
7. Teduglutide Therapy in 2 Patients With Short‐Bowel Syndrome and Familial Adenomatous Polyposis
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Brian R. Boulay, Robert J. Carroll, Pierpaolo Di Cocco, Enrico Benedetti, and Alvin T. George
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medicine.medical_specialty ,Nutrition and Dietetics ,business.industry ,Medicine (miscellaneous) ,Short bowel syndrome ,medicine.disease ,Teduglutide ,Gastroenterology ,Organ transplantation ,Familial adenomatous polyposis ,chemistry.chemical_compound ,Parenteral nutrition ,chemistry ,Internal medicine ,Medicine ,business - Published
- 2020
8. Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy
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Matthew M. Riggs, Julio Rosenstock, Lori M. Laffel, Rena J. Eudy-Byrne, Ahmed Elmokadem, Jan Marquard, Bruce A. Perkins, Nima Soleymanlou, Valerie Nock, Dietmar Neubacher, Curtis K. Johnston, Karl Heinz Liesenfeld, Jay S. Skyler, and Jyothis T. George
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medicine.medical_specialty ,Diabetic ketoacidosis ,type 1 diabetes ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Population ,empagliflozin ,Urology ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,sodium‐glucose co‐transporter‐2 inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Double-Blind Method ,Glucosides ,Pharmacokinetics ,Internal Medicine ,Empagliflozin ,medicine ,Humans ,Hypoglycemic Agents ,Insulin ,Benzhydryl Compounds ,education ,Glycated Hemoglobin ,antidiabetic drug ,education.field_of_study ,Type 1 diabetes ,Dose-Response Relationship, Drug ,business.industry ,Low dose ,Original Articles ,medicine.disease ,Dose–response relationship ,Diabetes Mellitus, Type 1 ,dose–response relationship ,Drug Therapy, Combination ,Original Article ,business - Abstract
Aim To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses. Materials and methods Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses. Results The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks. Conclusions The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches.
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- 2020
9. Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: data from the EMPA‐REG OUTCOME trial
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Nikolaus Marx, Christoph Wanner, Anne Pernille Ofstad, Jonathan Slawik, Michaela Mattheus, Subodh Verma, Silvio E. Inzucchi, David Fitchett, Jyothis T. George, Michael Böhm, Martina Brueckmann, Bernard Zinman, and Stefan D. Anker
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medicine.medical_specialty ,030204 cardiovascular system & hematology ,Placebo ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Glucosides ,Internal medicine ,Diabetes mellitus ,Atrial Fibrillation ,Empagliflozin ,medicine ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Heart Failure ,business.industry ,Hazard ratio ,Atrial fibrillation ,medicine.disease ,Confidence interval ,Diabetes Mellitus, Type 2 ,Heart failure ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Atrial fibrillation (AF) is common in patients with diabetes and heart failure (HF) and increases the future risk of adverse cardiovascular (CV) outcomes. This analysis from the EMPA-REG OUTCOME trial explores CV and renal outcomes in patients with vs. without AF at baseline and assesses the benefits of empagliflozin. Methods and results Analyses were conducted on patients distinguished by the presence (n = 389) or absence (n = 6631) of AF at baseline. Outcome events were more frequent in patients with AF than those without AF. Empagliflozin compared to placebo reduced CV death or HF hospitalisation consistently in patients with AF [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.36-0.92] and without AF (HR 0.67, 95% CI 0.55-0.82, Pinteraction = 0.56). Similar results were observed for the components of this endpoint, all-cause mortality, new or worsening nephropathy, first introduction of loop diuretics, or occurrence of oedema. The absolute number of prevented events was higher in patients with AF, resulting in larger absolute treatment effects of empagliflozin. New loop diuretics or oedema were associated with increased rates of subsequent events, and rates appeared lower in those randomised to empagliflozin. Conclusions In patients with type 2 diabetes mellitus and established CV disease, those with AF at baseline had higher rates of adverse HF outcomes than those without AF. Irrespective of the presence of AF, empagliflozin reduced HF-related and renal events. The absolute number of prevented events is higher in patients with AF than without AF. Patients with diabetes, CV disease and AF may especially benefit from use of empagliflozin.
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- 2019
10. Author response for 'Effects of Empagliflozin on Insulin Initiation or Intensification in Patients with Type 2 Diabetes and Cardiovascular Disease: Findings from the EMPA‐REG OUTCOME ® Trial'
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Bernard Zinman, Christoph Wanner, Subodh Verma, Naveed Sattar, Michaela Mattheus, Anne Pernille Ofstad, Muthiah Vaduganathan, Silvio E. Inzucchi, Martina Brueckmann, Jyothis T. George, Javed Butler, and David Fitchett
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medicine.medical_specialty ,business.industry ,Insulin ,medicine.medical_treatment ,Type 2 diabetes ,Disease ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Empagliflozin ,Medicine ,In patient ,business ,EMPA - Published
- 2021
11. Author response for 'Effect of empagliflozin on cardiorenal outcomes and mortality according to body‐mass index: A subgroup analysis of the EMPA‐REG OUTCOME trial with a focus on Asia'
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Wataru Ogawa, Bernard Zinman, Linong Ji, Christoph Wanner, Koutaro Yokote, Yiming Mu, Isabella Zwiener, Odd Erik Johansen, Jiajun Zhao, Qiuhe Ji, Jyothis T. George, and Kohjiro Ueki
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Gerontology ,chemistry.chemical_compound ,Focus (computing) ,chemistry ,business.industry ,Empagliflozin ,Medicine ,Subgroup analysis ,business ,Body mass index ,Outcome (game theory) ,EMPA - Published
- 2021
12. Can the cardiovascular risk reductions observed with empagliflozin in the EMPA‐REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?
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Uli C. Broedl, Jyothis T. George, Ruth L. Coleman, Bernard Zinman, Alastair Gray, Hans-Juergen Woerle, David Fitchett, and Rury R. Holman
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Relative risk reduction ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Glucosides ,Risk Factors ,Internal medicine ,Heart rate ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Medicine ,Myocardial infarction ,Benzhydryl Compounds ,Risk factor ,business.industry ,medicine.disease ,Blood pressure ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Relative risk ,Heart failure ,Cardiology ,business - Abstract
Aim To perform post‐hoc analyses of the EMPA‐REG OUTCOME trial examining the degree to which empagliflozin‐induced changes in conventional cardiovascular (CV) risk factors might explain the observed CV benefits. Materials and methods We estimated 3‐year EMPA‐REG OUTCOME CV event rates using a type 2 diabetes‐specific clinical outcomes simulation model applied to annual patient‐level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL cholesterol, LDL cholesterol, systolic blood pressure, glycated haemoglobin, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate, and histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk reductions were compared. Results Model‐predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin‐associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for all‐cause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). Conclusions Empagliflozin‐associated changes in conventional CV risk factors in EMPA‐REG OUTCOME appear to explain only a small proportion of the CV and all‐cause death reductions observed. Alternative risk‐reduction mechanisms need to be explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug‐specific effect.
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- 2020
13. Author response for 'Can the Cardiovascular Risk Reductions Observed with Empagliflozin in the EMPA‐REG OUTCOME Trial be Explained by Concomitant Changes Seen in Conventional Cardiovascular Risk Factor Levels?'
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null Ruth L. Coleman, null Alastair M. Gray, null Uli C. Broedl, null David Fitchett, null Jyothis T. George, null Hans J. Woerle, null Bernard Zinman, and null Rury R. Holman
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- 2020
14. Author response for 'Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose‐lowering therapy?'
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David Fitchett, Christina Janista, Vincent Woo, Stefan Hantel, Dubravka Jurišić-Eržen, Jyothis T. George, Stefan Kaspers, Silvio E. Inzucchi, and Bernard Zinman
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Glucose lowering ,Kidney ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Internal medicine ,Empagliflozin ,medicine ,Cardiology ,business ,Baseline (configuration management) - Published
- 2019
15. Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial
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Akiko Sarashina, Kosuke Shiki, Ganghyuck Lee, Yusuke Taneda, Nima Soleymanlou, Akira Shimada, Atsutaka Yasui, Jan Marquard, Toshiaki Hanafusa, and Jyothis T. George
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Male ,type 1 diabetes ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,law.invention ,0302 clinical medicine ,Endocrinology ,Glucosides ,Japan ,Randomized controlled trial ,law ,randomized trial ,Insulin ,030212 general & internal medicine ,SGLT2 inhibitor ,Middle Aged ,Treatment Outcome ,Drug Therapy, Combination ,Female ,Original Article ,pharmacokinetics ,Adult ,medicine.medical_specialty ,Diabetic ketoacidosis ,empagliflozin ,Urology ,030209 endocrinology & metabolism ,Placebo ,Young Adult ,03 medical and health sciences ,Double-Blind Method ,Pharmacokinetics ,Glycosuria ,Weight Loss ,pharmacodynamics ,Internal Medicine ,medicine ,Empagliflozin ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Aged ,Type 1 diabetes ,Dose-Response Relationship, Drug ,business.industry ,Original Articles ,medicine.disease ,Hypoglycemia ,Diabetes Mellitus, Type 1 ,Pharmacodynamics ,business - Abstract
Aims This phase 2, double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin. Materials and methods Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment. Results PD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported. Conclusions Based on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.
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- 2018
16. Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial
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Yuki Miyamoto, Christopher Lee, Jyothis T. George, Fernando Solimando, Keiko Suzaki, Kosuke Shiki, Jisoo Lee, Ryuzo Kawamori, Masakazu Haneda, and Gang Cheng
- Subjects
linagliptin ,Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Fixed-dose combination ,empagliflozin ,Placebo-controlled study ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Linagliptin ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Double-Blind Method ,Glucosides ,Randomized controlled trial ,law ,Internal medicine ,randomized trial ,Internal Medicine ,Empagliflozin ,medicine ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Aged ,Glycated Hemoglobin ,business.industry ,Body Weight ,Original Articles ,Middle Aged ,medicine.disease ,phase III study ,Safety profile ,glycaemic control ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Original Article ,Drug Therapy, Combination ,Female ,type 2 diabetes ,business ,medicine.drug - Abstract
Aims This double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. Methods The trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. Results Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, −0.93% vs 0.21%; adjusted mean difference, −1.14%) and Week 52 (−1.16% vs 0.06%; adjusted mean difference, −1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations. Conclusions These results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.
- Published
- 2018
17. Empagliflozin reduces the risk of a broad spectrum of heart failure outcomes regardless of heart failure status at baseline
- Author
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Cordula Zeller, Mark C. Petrie, Christoph Wanner, João Pedro Ferreira, Anne Pernille Ofstad, David Fitchett, James L. Januzzi, Michael Böhm, Martina Brueckmann, Faiez Zannad, Sanjay Kaul, and Jyothis T. George
- Subjects
medicine.medical_specialty ,Cardiotonic Agents ,MEDLINE ,Comorbidity ,Broad spectrum ,Text mining ,Glucosides ,Internal medicine ,Diabetes mellitus ,medicine ,Empagliflozin ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Baseline (configuration management) ,Sodium-Glucose Transporter 2 Inhibitors ,Randomized Controlled Trials as Topic ,Heart Failure ,business.industry ,Hemodynamics ,medicine.disease ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Heart failure ,Cardiology and Cardiovascular Medicine ,business - Published
- 2019
18. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors
- Author
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Naveed Sattar, Afshin Salsali, Carolyn S.P. Lam, Alfred K. Cheung, Jennifer B. Green, Stuart J. Pocock, Nikolaus Marx, Javed Butler, Hans-Juergan Woerle, Cyrus R. Mehta, Carine E. Hamo, Julio Rosenstock, Gerasimos Filippatos, Subodh Verma, Benjamin M. Scirica, Sanjiv J. Shah, Richard A. Bernstein, Faiez Zannad, Gregory Y.H. Lip, Martina Brueckmann, Peter A. McCullough, Piotr Ponikowski, Christoph Wanner, Stefan D. Anker, James L. Januzzi, Sanjay Kaul, Jyothis T. George, and Hiroyuki Tsutsui
- Subjects
medicine.medical_specialty ,business.industry ,Public health ,Type 2 Diabetes Mellitus ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Diabetes mellitus ,Heart failure ,Internal medicine ,Empagliflozin ,Cardiology ,Medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Cardiovascular mortality - Abstract
Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate.
- Published
- 2017
19. Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans
- Author
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M. Hendrikse, Robert P. Millar, Johannes D. Veldhuis, Richard A. Anderson, Iain J. Clarke, and Jyothis T. George
- Subjects
Male ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Somatotropic cell ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gonadotropic cell ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Humans ,Medicine ,Kisspeptins ,Luteinizing hormone secretion ,business.industry ,Neuropeptides ,luteinizing hormone/choriogonadotropin receptor ,Luteinizing Hormone ,Middle Aged ,Gonadotropin secretion ,Postmenopause ,030104 developmental biology ,Hormone receptor ,Female ,business ,Hormone ,Endocrine gland - Abstract
SummaryBackground Gonadotropin-inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human. Objective We tested the hypotheses that exogenous GnIH inhibits LH secretion (i) in postmenopausal women and (ii) in men concurrently administered exogenous kisspeptin. Design Following in vitro and in vivo preclinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH: 1·5–150 μg/kg/h, iv for 3 h) was undertaken, and 50 μg/kg/h selected for further evaluation. Five postmenopausal women were administered 50 μg/kg/h iv infusion for 3 h or vehicle on two separate days. Four men were administered kisspeptin-10 (0·3 μg/kg iv bolus) with simultaneous infusion of GnIH (50 μg/kg/h, iv for 3 h) or vehicle. Participants Healthy postmenopausal women (mean age 58 ± 2 years, LH: 30·8 ± 2·9 IU/l, FSH: 78·7 ± 6·4 IU/l, oestradiol
- Published
- 2017
20. Cardiovascular outcome trials of glucose-lowering drugs in type 2 diabetes: 10 frequently asked questions
- Author
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Jyothis T. George
- Subjects
Glucose lowering ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Frequently asked questions ,Alternative medicine ,Type 2 diabetes ,medicine.disease ,Outcome (game theory) ,Diabetes mellitus ,Internal Medicine ,medicine ,business ,Intensive care medicine - Published
- 2015
21. HIV infection is associated with an increased prevalence of coronary noncalcified plaque among participants with a coronary artery calcium score of zero: Multicenter AIDS Cohort Study (MACS)
- Author
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Thomas S. Metkus, L. A. Kingsley, Richard T. George, Xiuhong Li, Frank J. Palella, Matthew J. Budoff, Wendy S. Post, Todd T. Brown, Lisa P. Jacobson, and Witt
- Subjects
education.field_of_study ,medicine.medical_specialty ,medicine.diagnostic_test ,Coronary artery calcium score ,business.industry ,Health Policy ,Population ,Cardiovascular risk factors ,Multicenter AIDS Cohort Study ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Confidence interval ,Surgery ,Infectious Diseases ,Internal medicine ,Angiography ,Cohort ,Cardiology ,Medicine ,Pharmacology (medical) ,business ,education - Abstract
Objectives HIV-infected individuals bear increased cardiovascular risk even in the absence of traditional cardiovascular risk factors. In the general population, coronary artery calcium (CAC) scanning is of value for cardiovascular risk stratification, but whether a CAC score of zero implies a low noncalcified coronary plaque burden in HIV-infected persons is unknown. Methods We assessed the prevalence of noncalcified coronary plaque and compared noncalcified coronary plaque burden between HIV-infected and HIV-uninfected participants who had CAC scores of zero in the Multicenter AIDS Cohort Study (MACS) using coronary computed tomography (CT) angiography. Results HIV infection was associated with the presence of noncalcified coronary plaque among these men with CAC scores of zero. In a model adjusted only for age, race, centre, and pre- or post-2001 cohort, the prevalence ratio for the presence of noncalcified plaque was 1.27 (95% confidence interval 1.04–1.56; P = 0.02). After additionally adjusting for cardiovascular risk factors, HIV infection remained associated with the presence of noncalcified coronary plaque (prevalence ratio 1.31; 95% confidence interval 1.07–1.6; P = 0.01). Conclusions Among men with CAC scores of zero, HIV infection is associated with an increased prevalence of noncalcified coronary plaque independent of traditional cardiovascular risk factors. This finding suggests that CAC scanning may underestimate plaque burden in HIV-infected men.
- Published
- 2015
22. Effects of Naltrexone on Neural and Subjective Response to Alcohol in Treatment-Seeking Alcohol-Dependent Patients
- Author
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Sara K. Blaine, Lishu Zhang, Kristie A. Diamond, Vijay A. Ramchandani, Markus Heilig, Primavera A. Spagnolo, Monte J. Phillips, Melanie L. Schwandt, Reza Momenan, David T. George, and Julie Usala
- Subjects
Adult ,Male ,medicine.drug_class ,Narcotic Antagonists ,Population ,Medicine (miscellaneous) ,Alcohol ,Craving ,Toxicology ,Placebo ,Article ,Naltrexone ,Young Adult ,chemistry.chemical_compound ,medicine ,Humans ,Infusions, Intravenous ,education ,Endogenous opioid ,education.field_of_study ,Ethanol ,business.industry ,Middle Aged ,Alcoholism ,Psychiatry and Mental health ,Treatment Outcome ,chemistry ,Anesthesia ,Ventral Striatum ,Female ,medicine.symptom ,business ,human activities ,Photic Stimulation ,Opioid antagonist ,medicine.drug - Abstract
Positively reinforcing properties of alcohol are in part mediated by activation of the ventral striatum (VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone (NTX) can block this cascade, but its ability to do so in treatment-seeking alcoholics has not been examined. Our objective was to study the effects of NTX on alcohol-induced VS activation and on amygdala response to affective stimuli in treatment-seeking alcohol-dependent inpatients.Sixty-three treatment-seeking alcoholics were randomized to receive NTX (50 mg) or placebo (PLC) daily. On Day 7, participants underwent an alcohol cue reactivity session, and craving was measured using the Penn Alcohol Craving Scale. On Day 9, participants received a saline infusion followed by an alcohol infusion and also viewed affective stimuli in a magnetic resonance scanner.Irrespective of medication treatment condition, the alcohol infusion did not activate the VS in the alcohol-dependent patients. Unexpectedly, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure, and increased subjective response to alcohol ("high" and "intoxicated") compared to PLC subjects. No significant effects of alcohol infusion on brain response to affective stimuli were in the NTX or PLC groups.Unlike previous findings in social drinkers, a moderate level of intoxication did not activate the VS in treatment-seeking alcoholics. This is likely to reflect tolerance to the positively reinforcing properties of alcohol in this clinical population. Our findings may help explain the efficacy of NTX to reduce heavy drinking, but not to maintain abstinence.
- Published
- 2014
23. Muscle activation varies with contraction mode in human spinal cord injury
- Author
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T. George Hornby, Christopher K. Thompson, and Hyosub E. Kim
- Subjects
medicine.medical_specialty ,Contraction (grammar) ,Physiology ,business.industry ,Muscle activation ,Isometric exercise ,Concentric ,medicine.disease ,Cellular and Molecular Neuroscience ,Physical medicine and rehabilitation ,Physiology (medical) ,medicine ,Eccentric ,Neurology (clinical) ,Spasticity ,medicine.symptom ,business ,Spinal cord injury ,Rehabilitation interventions - Abstract
Introduction: To better understand volitional force generation after chronic incomplete spinal cord injury (SCI), we examined muscle activation during single and repeated isometric, concentric, and eccentric knee extensor (KE) maximal voluntary contractions (MVCs). Methods: Torque and electromyographic (EMG) activity were recorded during single and repeated isometric and dynamic KE MVCs in 11 SCI subjects. Central activation ratios (CARs) were calculated for all contraction modes in SCI subjects and 11 healthy controls. Results: SCI subjects generated greater torque, KE EMG, and CARs during single eccentric vs. isometric and concentric MVCs (all P 25%) and concentric (>30%) MVCs. Conclusions: SCI subjects demonstrated greater muscle activation during eccentric MVCs vs. isometric and concentric MVCs. This pattern of activation contrasts with the decreased eccentric activation demonstrated by healthy controls. Such information may aid development of novel rehabilitation interventions. Muscle Nerve 51: 235–245, 2015
- Published
- 2014
24. Are the cardiovascular risk reductions seen with empagliflozin in the EMPA-REG OUTCOME trial explained by conventional cardiovascular risk factors?
- Author
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Ruth L. Coleman, D Fitchett, Bernard Zinman, Hans-Juergen Woerle, Alistair Gray, Rury R. Holman, Uli C. Broedl, and J T George
- Subjects
chemistry.chemical_compound ,medicine.medical_specialty ,chemistry ,business.industry ,Internal medicine ,Cardiovascular risk factors ,Empagliflozin ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Outcome (game theory) ,EMPA - Abstract
To estimate the degree to which cardiovascular risk reductions demonstrated with empagliflozin administration in the EMPA-REG OUTCOME trial might be explained by changes observed in conventional cardiovascular factors during the study.
- Published
- 2017
25. How does obesity affect fertility in men - and what are the treatment options?
- Author
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Jyothis T. George, Richard A. Anderson, and Victoria Stokes
- Subjects
Male ,Infertility ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Fertility ,Fertilization in Vitro ,Body Mass Index ,Clomiphene ,Endocrinology ,Erectile Dysfunction ,Estrogen Receptor Modulators ,Pregnancy ,Weight loss ,Internal medicine ,Odds Ratio ,medicine ,Humans ,Testosterone ,Obesity ,Spermatogenesis ,Infertility, Male ,Adiposity ,media_common ,Libido ,Aromatase Inhibitors ,business.industry ,Pregnancy Outcome ,Testosterone (patch) ,Overweight ,medicine.disease ,Metformin ,Clinical trial ,Treatment Outcome ,Erectile dysfunction ,Androgens ,Female ,medicine.symptom ,business ,Psychosocial - Abstract
Summary Adiposity is associated with reduced fertility in men. The aetiology is multifactorial, with obese men at greater risk of suffering from impaired spermatogenesis, reduced circulating testosterone levels, erectile dysfunction and poor libido. The diagnosis and treatment of reduced fertility observed in obese men therefore requires insight into the underlying pathology, which has hormonal, mechanical and psychosocial aspects. This article summarises the current epidemiological, experimental and clinical trial evidence from the perspective of a practicing clinician. The following conclusions and recommendations can be drawn: Obesity is associated with low serum testosterone concentrations, but treatment with exogenous testosterone is likely to adversely impact on fertility. It is important to discuss this with men prior to initiation of testosterone therapy. Obesity adversely affects sperm concentration and may affect sperm quality. However, whether or not weight loss will correct these factors remain to be established. Oestrogen receptor modulators (and aromatase inhibitors) are unlicensed in the treatment for male hypogonadism and/or infertility. These treatments should hence be considered experimental approach until ongoing clinical trials report their outcomes.
- Published
- 2014
26. Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes
- Author
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Laura E. Kwako, Vijay A. Ramchandani, Melanie L. Schwandt, Daniel W. Hommer, Markus Heilig, Joanna R. Sells, David T. George, and Rajita Sinha
- Subjects
Pharmacology ,medicine.medical_specialty ,Alcohol dependence ,Medicine (miscellaneous) ,Alcohol abuse ,Craving ,medicine.disease ,behavioral disciplines and activities ,Psychiatry and Mental health ,Distress ,Cue reactivity ,mental disorders ,Trier social stress test ,medicine ,Anxiety ,medicine.symptom ,Psychology ,Psychiatry ,Guided imagery ,Clinical psychology - Abstract
Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving.
- Published
- 2014
27. Identification of Cadherin 11 as a Mediator of Dermal Fibrosis and Possible Role in Systemic Sclerosis
- Author
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Minghua Wu, Robert Lafyatis, Sandeep K. Agarwal, Filemon K. Tan, Mesias Pedroza, Shervin Assassi, Michael B. Brenner, Anuh T. George, and Maureen D. Mayes
- Subjects
Pathology ,medicine.medical_specialty ,integumentary system ,medicine.diagnostic_test ,Immunology ,Transforming growth factor beta ,Biology ,Bleomycin ,medicine.disease ,Scleroderma ,chemistry.chemical_compound ,Rheumatology ,chemistry ,Fibrosis ,Biopsy ,Skin biopsy ,medicine ,biology.protein ,Immunology and Allergy ,cardiovascular diseases ,Myofibroblast ,Transforming growth factor - Abstract
Objective Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Methods Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11–deficient mice and anti–Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow–derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Results Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11–knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti–Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. Conclusion These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.
- Published
- 2014
28. ICSH guidelines for the verification and performance of automated cell counters for body fluids
- Author
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G, Bourner, B, De la Salle, T, George, Y, Tabe, H, Baum, N, Culp, and T B, Keng
- Subjects
Automation, Laboratory ,Quality Control ,Canada ,Standardization ,Computer science ,International Cooperation ,Biochemistry (medical) ,Clinical Biochemistry ,Reproducibility of Results ,Hematology ,General Medicine ,International working group ,Sensitivity and Specificity ,United Kingdom ,United States ,Blood Cell Count ,Body Fluids ,Japan ,Surveys and Questionnaires ,Systems engineering ,Proficiency testing ,Humans ,Laboratories - Abstract
Summary One of the many challenges facing laboratories is the verification of their automated Complete Blood Count cell counters for the enumeration of body fluids. These analyzers offer improved accuracy, precision, and efficiency in performing the enumeration of cells compared with manual methods. A patterns of practice survey was distributed to laboratories that participate in proficiency testing in Ontario, Canada, the United States, the United Kingdom, and Japan to determine the number of laboratories that are testing body fluids on automated analyzers and the performance specifications that were performed. Based on the results of this questionnaire, an International Working Group for the Verification and Performance of Automated Cell Counters for Body Fluids was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines to help laboratories plan and execute the verification of their automated cell counters to provide accurate and reliable results for automated body fluid counts. These guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus.
- Published
- 2014
29. Childhood Trauma Exposure and Alcohol Dependence Severity in Adulthood: Mediation by Emotional Abuse Severity and Neuroticism
- Author
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Vijay A. Ramchandani, Markus Heilig, Daniel W. Hommer, David T. George, and Melanie L. Schwandt
- Subjects
Adult ,Male ,medicine.medical_specialty ,Medicine (miscellaneous) ,Toxicology ,Impulsivity ,Effect Modifier, Epidemiologic ,Severity of Illness Index ,Article ,Young Adult ,Surveys and Questionnaires ,Severity of illness ,medicine ,Humans ,Child Abuse ,Child ,Psychological abuse ,Psychiatry ,Neuroticism ,Adult Survivors of Child Abuse ,Alcohol dependence ,Middle Aged ,Anxiety Disorders ,Alcoholism ,Psychiatry and Mental health ,Physical abuse ,Sexual abuse ,Case-Control Studies ,Female ,medicine.symptom ,Psychology ,Psychopathology - Abstract
Background Childhood trauma has been linked with a number of negative outcomes later in life, including alcohol dependence (AD). Previous studies have suggested a mediating role for neuroticism in the relationship between childhood trauma and psychopathology. In this study, we investigate the prevalence of multiple types of childhood trauma in treatment-seeking alcohol-dependent patients, and the associations between childhood trauma and AD severity using multiple mediation analysis. Methods The prevalence of 5 types of childhood trauma—emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect—was assessed in treatment-seeking alcohol-dependent patients (n = 280) and healthy controls (n = 137) using the Childhood Trauma Questionnaire. Multiple mediation analyses were used to model associations between childhood trauma measures and alcohol-related outcomes, primarily the severity of AD in the alcohol-dependent sample. Results Childhood trauma was significantly more prevalent and more severe in the alcohol-dependent subjects. In addition, childhood trauma was found to influence AD severity, an effect that was mediated by neuroticism. When individual trauma types were examined, emotional abuse was found to be the primary predictor of AD severity, both directly and through the mediating effects of the impulsivity subfacet of neuroticism. Physical abuse also had a moderate direct effect on AD severity. Mediation analysis did not reveal any association between childhood trauma and Alcohol Use Disorders Identification Test score in the nondependent control sample. Conclusions Childhood trauma is highly prevalent in treatment-seeking alcoholics and may play a significant role in the development and severity of AD through an internalizing pathway involving negative affect. Our findings suggest that alcoholics with a history of childhood emotional abuse may be particularly vulnerable to severe dependence.
- Published
- 2012
30. Patients with ‘interval’ colorectal cancers have worse outcomes compared with cancers in patients who decline the National Bowel Cancer Screening Programme - Results from a Multicentre Study
- Author
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A. T. George and A. Field
- Subjects
Gynecology ,medicine.medical_specialty ,Screen detected ,business.industry ,Colorectal cancer ,education ,Gastroenterology ,Early detection ,Improved survival ,Faecal occult blood ,medicine.disease ,digestive system diseases ,Screening programme ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,030211 gastroenterology & hepatology ,In patient ,business ,Mass screening - Abstract
We write to highlight a unique and inadvertent study finding, that patients on the national guaiac-based faecal occult blood testing (FOBT) screening programme, who developed interval colorectal cancers (IC) and in particular right-sided cancers, had a worse outcome compared with cancers in patients who declined to participate in the National FOBT screening process. This was identified as part of a UK-based multicentre study looking into FOBT and interval cancers in patients on incident rounds of screening(1). In the United Kingdom, colorectal cancer (CRC) is the second most common form of cancer-related mortality, with less than half surviving for more than 5 years. Biennial FOBT screening has reduced CRC mortality, mainly though the early detection and improved survival of screen detected cancers (2). This article is protected by copyright. All rights reserved.
- Published
- 2017
31. Smaller right amygdala in Caucasian alcohol-dependent male patients with a history of intimate partner violence: a volumetric imaging study
- Author
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Robert R. Rawlings, Reza Momenan, Joshua D. McKellar, Daniel W. Hommer, Lishu Zhang, Melanie L. Schwandt, David T. George, and Mike Kerich
- Subjects
Pharmacology ,medicine.medical_specialty ,Aggression ,Alcohol dependence ,Medicine (miscellaneous) ,Poison control ,Alcohol abuse ,social sciences ,medicine.disease ,Amygdala ,White matter ,Psychiatry and Mental health ,medicine.anatomical_structure ,mental disorders ,medicine ,Orbitofrontal cortex ,medicine.symptom ,Psychology ,Psychiatry ,Prefrontal cortex ,Clinical psychology - Abstract
Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men (n = 54), ages 24-55, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs (n = 27), non-violent ADs (n = 14) and HCs (n = 13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV. Language: en
- Published
- 2011
32. The Biometric Measurement of Alcohol Consumption
- Author
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Anders Helander, Boris Tabakoff, Lawrence D. Snell, Vijay A. Ramchandani, Lutz Pridzun, Markus Heilig, Laura Saba, Melanie L. Schwandt, Paula L. Hoffman, David T. George, David Herion, and Monte J. Phillips
- Subjects
medicine.medical_specialty ,education.field_of_study ,medicine.diagnostic_test ,Cross-sectional study ,business.industry ,media_common.quotation_subject ,Alcohol dependence ,Population ,Medicine (miscellaneous) ,Poison control ,Alcohol ,Abstinence ,Toxicology ,Surgery ,Psychiatry and Mental health ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Young adult ,business ,Liver function tests ,education ,media_common - Abstract
Background: Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought. Methods: Platelet monoamine oxidase B (MAO-B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA-based measure of platelet MAO-B protein levels is described. Results: One subject population constituted a nontreatment-seeking, cross-sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO-B protein with the plasma levels of carbohydrate-deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ-glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross-sectional nontreatment-seeking population. In the treatment-seeking population, low MAO-B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol. Conclusions: The platelet MAO-B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO-B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO-B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program. Language: en
- Published
- 2011
33. Central excitability contributes to supramaximal volitional contractions in human incomplete spinal cord injury
- Author
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Arun Jayaraman, Michael D. Lewek, T. George Hornby, and Christopher K. Thompson
- Subjects
medicine.medical_specialty ,Contraction (grammar) ,Muscle fatigue ,Physiology ,Stimulation ,Long-term potentiation ,Stimulus (physiology) ,medicine.disease ,Muscular Contractions ,Physical medicine and rehabilitation ,Muscle action ,medicine ,Psychology ,Spinal cord injury - Abstract
Despite greater muscle fatigue in individuals with spinal cord injury (SCI) when compared to neurologically intact subjects using neuromuscular electrical stimulation (NMES)protocols, few studies have investigated the extent of volitional fatigue in motor incomplete SCI. Using an established protocol of 20 repeated, intermittent, maximal volitional effort (MVE) contractions, we previously demonstrated that subjects with incomplete SCI unexpectedly demonstrated a 15% increase in peak knee extensor torques within the first five MVEs with minimal evidence of fatigue after 20 contraction. In the present study, we investigated potential segmental mechanisms underlying this supramaximal torque generation. Changes in twitch properties and maximum compound muscle action potentials (M-waves) were assessed prior to and following one, three and five MVEs, revealing a significant 17% increase only in maximum twitch torques after a single MVE. Despite this post-activation potentiation of the muscle, use of conventional NMES protocols to elicit repeated muscular contractions resulted in a significant decrease in evoked torque generation, suggesting limited the muscular contributions to the observed phenomenon. To evaluate potential central mechanisms underlying the augmented torques, non-linear responses to wide-pulse width (1 ms), low-intensity, variable-frequency (25–100 Hz) NMES were also tested prior to and following repeated MVEs.When variable-frequency NMES was applied following the repeated MVEs, augmented and prolonged torques were observed and accompanied by sustained quadriceps electromyographic activity often lasting > 2s after stimulus termination. Such data suggest a potential contribution of elevated spinal excitability to the reserve in volitional force generation in incomplete SCI.
- Published
- 2011
34. Manually-Assisted Versus Robotic-Assisted Body Weight−Supported Treadmill Training in Spinal Cord Injury: What Is the Role of Each?
- Author
-
David Chen, T. George Hornby, and David J. Reinkensmeyer
- Subjects
Adult ,medicine.medical_specialty ,Robotic assisted ,business.industry ,Rehabilitation ,MEDLINE ,Physical Therapy, Sports Therapy and Rehabilitation ,Robotics ,Walking ,Quadriplegia ,medicine.disease ,Treadmill training ,Body weight ,Exercise Therapy ,Physical medicine and rehabilitation ,Neurology ,Therapy, Computer-Assisted ,medicine ,Humans ,Female ,Neurology (clinical) ,business ,Spinal cord injury ,Spinal Cord Injuries - Published
- 2010
35. Characteristics of intensive care units in Michigan: Not an open and closed case
- Author
-
Robert C. Hyzy, Judith H. Maselli, Sean M. Berenholtz, Chris T. George, Peter J. Pronovost, Scott A. Flanders, Christine A. Goeschel, Sam R. Watson, and Andrew D. Auerbach
- Subjects
Michigan ,medicine.medical_specialty ,Leadership and Management ,MEDLINE ,Intensivist ,Assessment and Diagnosis ,Article ,law.invention ,law ,Surveys and Questionnaires ,Intensive care ,Critical care nursing ,medicine ,Care Planning ,business.industry ,Health Policy ,General Medicine ,Odds ratio ,Intensive care unit ,Confidence interval ,Hospital medicine ,Intensive Care Units ,Leadership ,Models, Organizational ,Emergency medicine ,Fundamentals and skills ,business - Abstract
OBJECTIVE: Delivery of critical care by intensivists has been recommended by several groups. Our objective was to understand the delivery of critical care physician services in Michigan and the role of intensivists and nonintensivist providers in providing care. DESIGN: Descriptive questionnaire. PARTICIPANTS AND SETTING: Intensive care unit (ICU) directors and nurse managers at 96 sites, representing 115 ICUs from 72 hospitals in Michigan. MEASUREMENTS AND RESULTS: The primary outcome measure was the percentage of sites utilizing a closed vs. an open model of ICU care. Secondary outcome measures included the percentage of ICUs utilizing a high-intensity service model, hospital size, ICU size, type of clinician providing care, and clinical activities performed. Twenty-four (25%) sites used a closed model of intensive care, while 72 (75%) had an open model of care. Hospitals with closed ICUs were larger and had larger ICUs than sites with open ICUs (P < 0.05). Hospitalists serving as attending physicians were strongly associated with an open ICU (odds ratio [OR] ¼ 12.2; 95% confidence interval [CI] ¼ 2.5-60.2), as was the absence of intensivists in the group (OR ¼ 12.2; 95%CI ¼ 1.4-105.8), while ICU and hospital size were not associated. At 18 sites (20%) all attendings were board certified in Critical Care. Sixty sites had less than 50% board-certified attending physicians. CONCLUSIONS: The closed intensivist-led model of intensive care delivery is not in widespread use in Michigan. In the absence of intensivists, alternate models of care, including the hospitalist model, are frequently used. Journal of Hospital Medicine 2010;5:4–9. V C 2010 Society of Hospital Medicine.
- Published
- 2010
36. What Peter Drucker's four great lessons taught us to do
- Author
-
T. George Harris and Craig Burton Wynett
- Subjects
Sociology ,Management ,Law and economics - Published
- 2009
37. Ethical Considerations for Administering Alcohol or Alcohol Cues to Treatment-Seeking Alcoholics in a Research Setting: Can the Benefits to Society Outweigh the Risks to the Individual?
- Author
-
Gunter Schumann, David T. George, Henry R. Kranzler, Kenneth E Johnson, Mary-Anne Enoch, David Goldman, and Howard B. Moss
- Subjects
Harm reduction ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Alcohol dependence ,Medicine (miscellaneous) ,Alcohol abuse ,Context (language use) ,Craving ,Abstinence ,Toxicology ,medicine.disease ,Help-seeking ,Substance abuse ,Psychiatry and Mental health ,medicine ,medicine.symptom ,Psychiatry ,business ,media_common - Abstract
There has recently been a welcome surge of interest in the development of medications to augment psychosocial behavioral therapies to treat alcoholics. Preclinical studies are identifying candidate medications that may block reinstatement of alcohol-seeking behavior, a model of relapse in humans. The development of effective therapeutic agents can be speeded up by the establishment of research paradigms such as craving reduction, by which novel drugs can be initially evaluated with higher throughput and lower cost than a full clinical trial. If medications that facilitate abstinence are to be developed they may need to be tested in the target population—treatment-seeking alcoholics—rather than in heavy drinkers or non-treatment-seeking alcoholics. Thus to test whether a new medication is able to reduce or abolish craving for alcohol it may be necessary to administer alcohol or alcohol cues to treatment seeking, abstinent alcoholics in a research setting. The alcohol exposure could take the form of inhalation of alcohol fumes (George et al., 2008), tasting alcoholic beverages, drinking alcoholic beverages, or receiving alcohol intravenously either passively (alcohol-clamp method; Ramchandani and O’Connor, 2006) or actively (CASE method; Zimmermann et al., 2008). Some of the research designed to identify treatments may also involve the administration of drugs that may mimic the actions of alcohol, for example as shown in drug discrimination studies. Administration of these alcohol-like drugs may entail some of the same risks as administration of alcohol. The purpose of this commentary, distilled from ideas put forth at a roundtable at the 2008 RSA Annual Meeting, is to discuss whether the administration of alcohol to treatment-seeking alcoholics is ever justified. Can it ever be ethical to induce craving or give alcohol to treatment seeking, abstinent alcoholics? Can the benefits to society outweigh the risks to the individual? Can these risks be reduced to acceptable levels? What safeguards are currently in place and what research is currently being done in this domain? Can this whole issue be avoided by conducting research on alcoholics who choose harm reduction (reduced alcohol consumption) rather than abstinence as a treatment goal? The issue of administering alcohol to treatment-seeking alcoholics has been raised periodically (Dolinsky and Babor, 1997; Modell et al., 1993) and indeed there are national guidelines. This commentary will examine the issues described above in the context of the National Advisory Guidelines. In this commentary “alcoholics” refers to all individuals with alcohol dependence (American Psychiatric Association, 1994).
- Published
- 2009
38. Clinical effectiveness of a brief educational intervention in Type 1 diabetes: results from the BITES (Brief Intervention in Type 1 diabetes, Education for Self-efficacy) trial
- Author
-
J. T. George, J. C. Thow, P. Dromgoole, Ian Russell, David J. Torgerson, T. Wells, Abel Peña Valdovinos, and S. Lomax
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,diabetes treatment satisfaction ,law.invention ,Endocrinology ,Patient Education as Topic ,Randomized controlled trial ,law ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Glycated Hemoglobin ,Type 1 diabetes ,business.industry ,Incidence (epidemiology) ,Original Articles ,Middle Aged ,medicine.disease ,Obesity ,Hypoglycemia ,Confidence interval ,Surgery ,Clinical trial ,glycaemic control ,Diabetes Mellitus, Type 1 ,Treatment Outcome ,educational intervention ,Physical therapy ,Female ,Brief intervention ,business ,self-efficacy ,Risk Reduction Behavior ,Education and Psychological Care - Abstract
Aims Intensive 5-day educational interventions for people with Type 1 diabetes have shown improved outcomes in a number of European studies. The aim was to assess the effectiveness of a brief (2.5 days) psycho-educational intervention.Methods Our randomized trial in a secondary-care setting had 54 and 60 participants allocated to intervention and control groups, respectively. Primary outcomes were HbA1c and severe hypoglycaemia. Secondary outcomes were blood pressure, weight, height, lipids and psychometric profile.Results HbA1c showed no statistically significant change at 3 months [difference = 0.01, 95% confidence interval (CI) –0.23, 0.26, P = 0.92], 6 months (difference = –0.06, 95% CI –0.32, 0.20, P = 0.67) and 12 months (difference = 0.01, 95% CI –0.30, 0.32, P = 0.94). Incidence of severe hypoglycaemia (per patient per year) in the intervention group (0.41) and control group (0.48) was not statistically different. Treatment satisfaction improved at 3 months (difference = 9.4, 95% CI 5.2, 13.6, P = 0.0005), 6 months (difference = 10.4, 95% CI 6.0, 14.8, P = 0.0005) and 12 months (difference = 7.1, 95% CI 2.1, 12.1, P = 0.006). The ‘Managing psychological aspects’ and ‘Setting and achieving goals’ dimensions of the Diabetes Empowerment Scale also showed significant improvement at 3, 6 and 12 months. Diabetes Knowledge Test, Illness Perception Questionnaire, Hypoglycaemia Fear Scale and Short Form 36 showed no significant change.Conclusions This brief intervention had no significant impact on HbA1c or severe hypoglycaemia, but improved diabetes treatment satisfaction and patient empowerment. Current Controlled Trials ISRCTN75807800.
- Published
- 2008
39. 3D EIT for breast cancer imaging: System, measurements, and reconstruction
- Author
-
Kim Hwa Lim, Gary A. Ybarra, Gang Ye, William T. Joines, Qing Huo Liu, and Rhett T. George
- Subjects
Physics ,business.industry ,Focused Impedance Measurement ,Early detection ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,Imaging phantom ,Electronic, Optical and Magnetic Materials ,Optics ,Electrode ,Electrical and Electronic Engineering ,business ,Electrical impedance tomography ,Electrical impedance ,Microwave ,Biomedical engineering ,Voltage - Abstract
Electrical impedance tomography (EIT) is a developing imaging modality for early detection of breast cancer. In an EIT system, a low-frequency current is applied sequentially between different electrode pairs while voltage measurements are made at other electrodes to arrive at the electrical impedance values. The set of impedance measurement data is then computed to produce a 3D electrical conductivity map of the volume to be imaged. In this work, the design, measurements, and inversion of a full 3D EIT system are discussed. Experimentally determined EIT images of phantom objects are presented. © 2008 Wiley Periodicals, Inc. Microwave Opt Technol Lett 50: 3261–3271, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.23932
- Published
- 2008
40. 2D EIT for biomedical imaging: Design, measurement, simulation, and image reconstruction
- Author
-
Guining Shi, Kim Hwa Lim, Qing Huo Liu, Rhett T. George, William T. Joines, Kyle McCarter, Gary A. Ybarra, and S.A. Wartenberg
- Subjects
Computer science ,Iterative method ,business.industry ,Electrical engineering ,Inverse ,Iterative reconstruction ,Solver ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,Finite element method ,Electronic, Optical and Magnetic Materials ,Experimental system ,Medical imaging ,Electrical and Electronic Engineering ,business ,Algorithm ,Electrical impedance tomography - Abstract
A 2D electrical impedance tomography (EIT) system has been developed at Duke University as an experimental system to test the forward and inverse algorithms for EIT application. The forward model is based on the 2nd-order finite element method (FEM), while the image reconstruction is based on the distorted Born iterative method (DBIM). The major contributions of this work are the application of the higher-order FEM as a forward solver, and the DBIM as an inverse solver to the integrated EIT system. The forward model has been validated with the measured data to within 0.5% accuracy. Excellent images have been reconstructed with these collected EIT data sets. © 2007 Wiley Periodicals, Inc. Microwave Opt Technol Lett 49: 2989–2998, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.22938
- Published
- 2007
41. Sex‐ and Drinking History Dysregulate ω‐3 and ω‐6 Pathways during the Onset of Liver injury in Very Heavy Drinking Alcohol Dependents
- Author
-
Melanie L. Schwandt, Matthew C. Cave, Shirish Barve, David T. George, Ming Song, Vatsalya Vatsalya, and Craig J. McClain
- Subjects
Liver injury ,Heavy drinking ,business.industry ,Physiology ,Alcohol ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Genetics ,Medicine ,business ,Molecular Biology ,Biotechnology - Published
- 2015
42. Temporal facilitation of spastic stretch reflexes following human spinal cord injury
- Author
-
T. George Hornby, Jennifer H. Kahn, Ming Wu, and Brian D. Schmit
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,Physiology ,Electromyography ,medicine.disease ,Tonic (physiology) ,medicine.anatomical_structure ,Physical medicine and rehabilitation ,medicine ,Spastic ,Reflex ,Stretch reflex ,Ankle ,medicine.symptom ,Psychology ,Spinal cord injury ,Muscle contraction - Abstract
Recent evidence suggests that alterations in ionic conductances in spinal motoneurones, specifically the manifestation of persistent inward currents, may be partly responsible for the appearance of hyperexcitable reflexes following spinal cord injury (SCI). We hypothesized that such alterations would manifest as temporal facilitation of stretch reflexes in human SCI. Controlled, triangular wave, ankle joint rotations applied at variable velocities (30–120 deg s−1) and intervals between stretches (0.25–5.0 s) were performed on 14 SCI subjects with velocity-dependent, hyperexcitable plantarflexors. Repeated stretch elicited significant increases in plantarflexion torques and electromyographic (EMG) activity from the soleus (SOL) and medial gastrocnemius (MG). At higher velocities (≥ 90 deg s−1), reflex torques declined initially, but subsequently increased to levels exceeding the initial response, while mean EMG responses increased throughout the joint perturbations. At lower velocities (≤ 60 deg s−1), both joint torques and EMGs increased gradually. Throughout a range of angular velocities, reflex responses increased significantly only at intervals ≤ 1 s between stretches and following at least four rotations. Ramp-and-hold perturbations used to elicit tonic stretch reflexes revealed significantly prolonged EMG responses following one or two triangular stretches, as compared to single ramp-and-hold excursions. Post hoc analyses revealed reduced reflex facilitation in subjects using baclofen to control spastic behaviours. Evidence of stretch reflex facilitation post-SCI may reflect changes in underlying neuronal properties and provide insight into the mechanisms underlying spastic reflexes.
- Published
- 2006
43. Stimulation-induced changes in lower limb corticomotor excitability during treadmill walking in humans
- Author
-
T. George Hornby and James W. Stinear
- Subjects
Physiology ,medicine.medical_treatment ,Motor nerve ,Stimulation ,Neurological disorder ,Stimulus (physiology) ,medicine.disease ,Peripheral ,Transcranial magnetic stimulation ,medicine ,Primary motor cortex ,Psychology ,Neuroscience ,Common peroneal nerve - Abstract
Magnetic stimulation of human primary motor cortex (M1) paired with electrical stimulation of a peripheral motor nerve has been used to produce a lasting modulation of corticomotor (CM) excitability. This ‘paired associative stimulation’ (PAS) protocol has been used to induce bidirectional changes in excitability in upper limb CM pathways. The present study tested the hypothesis that temporally dependent PAS applied to the common peroneal nerve during the swing phase of walking would induce bidirectional changes in CM excitability consistent with the Hebbian principle of activity-dependent plasticity. Fourteen subjects with no known neurological disorder participated in two data collection sessions each. PAS was delivered as a single block of 120 pairs of stimuli delivered in a 10 min period during treadmill walking at 4.0 km h−1. Changes in CM excitability were assessed by examining the size of motor potentials evoked by transcranial magnetic stimulation prior to and following PAS. Tibialis anterior motor-evoked potentials amplitude increased to 121% over baseline when the magnetic stimulus was delivered over M1 after the estimated arrival time of the afferent volley in sensorimotor cortex and decreased to 83% of baseline when the magnetic stimulus was delivered prior to the estimated afferent volley arrival. This extent of modulation was undiminished following a further 10 min period of walking without stimulation. The temporal nature of the bidirectional effects following PAS, their rapid evolution and subsequent persistence supported the study's hypothesis and were similar to the effects described by others in quiescent muscles of the upper limb.
- Published
- 2005
44. Motoneurons: A preferred firing range across vertebrate species?
- Author
-
T. George Hornby, Robert M. Reinking, Jennifer C. McDonagh, and Douglas G. Stuart
- Subjects
Physiology ,Cellular and Molecular Neuroscience ,Plateau potentials ,Physiology (medical) ,medicine ,Animals ,Humans ,Motor Neurons ,biology ,Chemistry ,Lamprey ,Depolarization ,Motor neuron ,biology.organism_classification ,Turtles ,Compound muscle action potential ,Electrophysiology ,Motor unit ,medicine.anatomical_structure ,Vertebrates ,Cats ,Neurology (clinical) ,medicine.symptom ,Neuroscience ,Muscle contraction - Abstract
The term “preferred firing range” describes a pattern of human motor unit (MU) unitary discharge during a voluntary contraction in which the profile of the spike-frequency of the MU's compound action potential is dissociated from the profile of the presumed depolarizing pressure exerted on the unit's spinal motoneuron (MN). Such a dissociation has recently been attributed by inference to the presence of a plateau potential (PP) in the active MN. This inference is supported by the qualitative similarities between the firing pattern of human MUs during selected types of relatively brief muscle contraction and that of intracellularly stimulated, PP-generating cat MNs in a decerebrate preparation, and turtle MNs in an in vitro slice of spinal cord. There are also similarities between the stimulus-response behavior of intracellularly stimulated turtle MNs and human MUs during the elaboration of a slowly rising voluntary contraction. This review emphasizes that there are a variety of open issues concerning the PP. Nonetheless, a rapidly growing body of comparative vertebrate evidence supports the idea that the PP and other forms of non-linear MN behavior play a major role in the regulation of muscle force, from the lamprey to the human. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
- Published
- 2002
45. Atypical autonomic regulation in perpetrators of violent domestic abuse
- Author
-
Stephen W. Porges, Shawn F. Reed, Sarah G. Petrulis, David T. George, John C. Umhau, and Robert R. Rawlings
- Subjects
medicine.medical_specialty ,Endocrine and Autonomic Systems ,Cognitive Neuroscience ,General Neuroscience ,Poison control ,Human factors and ergonomics ,Experimental and Cognitive Psychology ,Arousal ,Autonomic nervous system ,Neuropsychology and Physiological Psychology ,Developmental Neuroscience ,Neurology ,Internal medicine ,Heart rate ,Injury prevention ,medicine ,Cardiology ,Domestic violence ,Vagal tone ,Psychology ,Biological Psychiatry - Abstract
Perpetrators of domestic violence describe symptoms that are compatible with exaggerated autonomic arousal at the time of the domestic violence. This inappropriate arousal may be reflected in altered heart rate regulation. If heart rate is systematically regulated by vagal mechanisms, then increases in heart rate should correlate with decreases in cardiac vagal activity, as indexed by respiratory sinus arrhythmia (RSA). We hypothesized that perpetrators of domestic violence have an alteration in heart rate regulation. To test this hypothesis we compared the results of a postural shift performed on perpetrators, healthy volunteers, and nonviolent alcoholics. Results showed there were no significant differences in heart rate, RSA, or catecholamines. However, the significant inverse relationship between posture-elicited changes in RSA and heart rate present in the healthy volunteers was not found in perpetrators. These differences in the covariation between heart rate and RSA may represent differences in the neural regulation of heart rate and may be related to difficulties in controlling autonomic state.
- Published
- 2002
46. Hypothalamic Function in Response to 2-Deoxy-d-Glucose in Long-Term Abstinent Alcoholics
- Author
-
Sarah G. Petrulis, John C. Umhau, David T. George, Rosalyn Diaz, and James R. Biddison
- Subjects
endocrine system ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,Medicine (miscellaneous) ,Glucose analog ,Adrenocorticotropic hormone ,Abstinence ,Toxicology ,Psychiatry and Mental health ,Endocrinology ,Hypothalamus ,Internal medicine ,medicine ,Corticosteroid ,Analysis of variance ,Psychology ,human activities ,Glucocorticoid ,Hydrocortisone ,medicine.drug ,media_common - Abstract
Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. Methods: To characterize HPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-D-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. Results: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. Conclusions: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved.
- Published
- 2001
47. Laser Flash Photolysis Studies of the UVA Sunscreen Mexoryl SX
- Author
-
Ann Cantrell, T. George Truscott, David J. McGarvey, and Louise Mulroy
- Subjects
Chemistry ,Singlet oxygen ,Analytical chemistry ,Quantum yield ,chemistry.chemical_element ,General Medicine ,Nanosecond ,Photochemistry ,Biochemistry ,Oxygen ,chemistry.chemical_compound ,Ultrafast laser spectroscopy ,Flash photolysis ,Physics::Chemical Physics ,Physical and Theoretical Chemistry ,Triplet state ,Luminescence - Abstract
The results of a nanosecond laser flash photolysis investigation of the UVA sunscreen Mexoryl* SX in various solvent environments and within a commercial sunscreen formulation are reported. To the best of our knowledge this is the first laser flash photolysis study of a commercial suncare formulation. In each of these environments kinetic UV-visible absorption measurements following nanosecond 355 nm laser excitation reveals a short-lived species with a solvent-dependent absorption maximum around 470–500 nm and a solvent-dependent lifetime of ?50–120 ns. This transient absorption is attributed to the triplet state of Mexoryl* SX on the basis that it is quenched by molecular oxygen leading to the formation of singlet oxygen in acetonitrile. The singlet oxygen quantum yield (φΔ), determined by comparative time-resolved near-infrared luminescence measurements and extrapolated to the limit of complete triplet state quenching, is estimated as 0.09 ± 0.03 in acetonitrile. In aqueous solution the shorter triplet state lifetime combined with lower ambient oxygen concentrations precludes significant triplet state quenching. For the commercial sunscreen formulation there was no observable difference in the measured triplet lifetime between samples exposed to oxygen or argon, suggesting that the singlet oxygen quantum yield in such environments is likely to be orders of magnitude lower than that measured in acetonitrile.
- Published
- 1999
48. Properties of spinal motoneurons and interneurons in the adult turtle: Provisional classification by cluster analysis
- Author
-
Douglas G. Stuart, Jennifer C. McDonagh, Robert M. Reinking, T. George Hornby, Edwin E. Gilliam, and Robert B. Gorman
- Subjects
biology ,General Neuroscience ,Lamprey ,Anatomy ,Hindlimb ,biology.organism_classification ,Spinal cord ,Tonic (physiology) ,Electrophysiology ,chemistry.chemical_compound ,Slice preparation ,medicine.anatomical_structure ,chemistry ,Biocytin ,medicine ,Spontaneous discharge ,Neuroscience - Abstract
The purpose of the present study was to compare, in motoneurons (MNs) vs. interneurons (INs), selected passive, transitional, and active (firing) properties, as recorded in slices of lumbosacral spinal cord (SC) taken from the adult turtle. The cells were provisionally classified on the basis of (1) the presence (in selected INs) or absence (MNs and other INs) of spontaneous discharge, (2) a cluster analysis of selected properties of the nonspontaneously firing cells, (3) a comparison to previous data on turtle MNs and INs, and (4) a qualitative comparison of the results with those reported for other vertebrate species (lamprey, cat). The provisional nomenclature accommodated properties appropriate for solely MNs (Main MN group) vs. nonspontaneously firing INs (Main IN-N) vs. spontaneously firing INs (IN-S) and for neurons with two degrees of intermediacy between the Main MN and the Main IN-N groups (Overlap MN, Overlap MN/IN). Morphological reconstructions of additional cells, which had been injected with biocytin during the electrophysiological tests, were shown to provide clear-cut support for the provisional classification procedure. The values for the measured parameters in the 96 tested cells covered the spectrum reported previously across adult vertebrate species and were robust in measurements made on different SC slices up to 5 days after their removal from the host animal. The interspecies comparisons permitted the predictions that (1) our Main MN and Overlap MN cells would be analogous to two MN types that innervate fast-twitch and slow-twitch skeletomotor muscle fibers, respectively, in the cat, and (2) the MNs in our Overlap MN/IN group probably innervate slow (nontwitch, tonic) muscle fibers whose presence has recently been established in the turtle hindlimb. In summary, the results bring out the utility of the SC slice preparation of the turtle for study of spinal motor mechanisms in adult tetrapod vertebrates, particularly as an adjunct to the in vivo cat, because of the ease with which robust measurements can be made of the active properties of both MNs and INs.
- Published
- 1998
49. Hormonal induction of sex reversal and progeny testing in the zebra cichlidCichlasoma nigrofasciatum
- Author
-
T. George and T. J. Pandian
- Subjects
Progeny testing ,medicine.medical_specialty ,Autosome ,biology ,Feminization (biology) ,Physiology ,General Medicine ,Sex reversal ,biology.organism_classification ,Fecundity ,Endocrinology ,Cichlasoma ,Cichlid ,Internal medicine ,medicine ,Animal Science and Zoology ,Hormone - Abstract
Hormonal sex reversal was induced in the ornamental cichlid C. nigrofasciatum by dietary administration of estradiol-beta or 17 alpha-methyltestosterone. The treatments involving 200 mg estradiol-beta and 200 mg 17 alpha-methyltestosterone/kg diet for 20 days in the 4-day posthatchling C. nigrofasciatum resulted in 100% feminization and 82% masculinization, respectively Superoptimal doses led to higher mortality and stunted growth, especially among the surviving males, which resisted feminization. Progeny testing of the feminized and masculinized individuals indicated that sex was determined by XX and XY (male heterogamety) sex chromosomes; however, the role played by autosomes in these individuals was also apparent. Live homogamous males (YY) could not be produced. Progeny testing further showed that hormonal treatment impaired growth and reproductive performance of the sex-re versed females and males. F-1 progenies sired by the sex-reversed females as well as males also suffered higher mortality, extended interspawning period and lower fecundity. (C) 1996 Wiley-Liss, Inc.
- Published
- 1996
50. Remoxipride versus thioridazine in the treatment of first episodes of schizophrenia in drug-naive patients: A case for specific, low potency D2 antagonists
- Author
-
K. Vaddadi, Tim Lambert, Nicholas A Keks, A. Zorbas, Paul C. Burnett, F. Varghese, G. Johnson, T. George, H. Hustig, J. McGrath, David L. Copolov, K. Kerr, Christine Hill, Stanley V. Catts, and Graham D. Burrows
- Subjects
First episode ,medicine.medical_treatment ,Antagonist ,Thioridazine ,Pharmacology ,medicine.disease ,Psychiatry and Mental health ,Drug-naïve ,Neurology ,Schizophrenia ,medicine ,Haloperidol ,Remoxipride ,Pharmacology (medical) ,Neurology (clinical) ,Antipsychotic ,Psychology ,medicine.drug - Abstract
Remoxipride, a substituted benzamide, is a selective D-2 antagonist with an atypical neuroleptic profile. Previous studies have demonstrated its antipsychotic efficacy against haloperidol and, more recently, thioridazine. Of the 144 patients enrolled in the Australian remoxipride-thioridazine comparative trial, 28 presented for their first episode of schizophrenia and/or had no previous neuroleptic treatment. These patients form the subject of this paper.
- Published
- 1995
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