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El Objetivo del trabajo fue exponer la noción de estado y ciudadanía en los mitos quechuas en el sur de Ayacucho, en un contexto de movimientos campesinos, de emigración, de aspiraciones de modernidad y desarrollo. Metodológicamente, la información primaria se registró a través de entrevistas semiestructuradas, la fuente secundaria se obtuvo de los escritos de los pobladores, interpretando la evidencia etnográfica desde la perspectiva de la antropología sociocultural. El resultado del trabajo evidencia la noción del estado desde la epopeya de un héroe cultural, tayta Antapillo, quien emergió en la tercera y séptima década del siglo XX; míticamente dice ser el representante comunal que vinculó a los campesinos con el estado, portando los sentidos de “liberación social” de los atropellados de los grupos de poder y de las autoridades oficiales. Se concluye que el viaje de tayta Antapillo de los Andes a la ciudad de Lima a negociar con el gobierno, representa el sentir de los comuneros en la búsqueda de ser escuchados por el estado y acceder a la ciudadanía para revertir y restituir las condiciones sociales, económicas, políticas y culturales atropellados por el poder local.

INTRODUCTION: In the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881), patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) were randomized (1:1:1) to placebo, ertugliflozin 5 mg or 15 mg (doses pooled for analyses as prospectively planned). In this post hoc analysis, the effects of ertugliflozin on kidney outcomes were assessed in analyses stratified by baseline heart failure (HF). METHODS: Baseline HF was defined as a history of HF or prerandomization left ventricular ejection fraction ≤45%. Outcomes included estimated glomerular filtration rate (eGFR) over time, total 5-year eGFR slopes and time to first event of a prespecified exploratory kidney composite outcome of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death. All analyses were stratified by baseline HF status. RESULTS: Compared with no-HF at baseline (n = 5807; 70.4%), patients with HF (n = 2439; 29.6%) had a notably faster rate of eGFR decline, which is unlikely to be explained by the slightly lower baseline eGFR in that group. Ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slopes (ml/min per 1.73 m(2) per year [95% confidence intervals; CI]) were 0.96 (0.67–1.24) and 0.95 (0.76–1.14) for HF and no-HF subgroups, respectively. The placebo HF (vs. placebo no-HF) subgroup had a higher incidence of the composite kidney outcome (35/834 [4.20%] vs. 50/1913 [2.61%]). Hazard ratios (95% CI) for the effect of ertugliflozin on the composite kidney outcome did not differ significantly between HF and no-HF subgroups: 0.53 (0.33–0.84) and 0.76 (0.53–1.08), respectively (P(interaction) = 0.22). CONCLUSION: Although patients with HF at baseline had a faster rate of eGFR decline in VERTIS CV, the beneficial effects of ertugliflozin on kidney outcomes did not differ when stratified by baseline HF.

Background A recent meta‐analysis of sodium–glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials. Hypothesis The apparent heterogeneity of the meta‐analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials. Methods We performed a meta‐analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE‐TIMI 58 (NCT01730534), and EMPA‐REG OUTCOME (NCT01131676). Results Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51–0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I 2 = 0.0%). Conclusions Our meta‐analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors.

The effect of ertugliflozin (ERTU) on serum uric acid (SUA) and gout-related outcomes in VERTIS CV (NCT01986881) was investigated. Patients with T2D and ASCVD were randomized to ERTU 5 mg (n=2752) , 15 mg (n=2747) (doses pooled for analyses) , placebo (PBO; n=2747) . Changes in SUA and composite of gout onset or initiation of anti-gout medication were assessed. LSM changes from baseline in SUA (mg/dL [95% CI]) at week 260 were −0. (−0.25, −0.13) and 0. (−0.02, 0.15) in the ERTU and PBO groups, respectively, nominal P Disclosure V.S.Sridhar: None. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. M.N.Essex: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. M.Maldonado: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding The VERTIS CV study and this analysis were sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown.Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes.For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome.In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods.NCT01986881.

Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) "dip" with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated.Patients were categorized into tertiles based on change in eGFR at week 6:+1.00 mL/min/1.73 m2 (tertile 1),-5.99 and ≤+1.00 (tertile 2), and ≤-6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline-week 6) and chronic periods (week 6-30 days after last dose of trial medication).In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m2/year; weeks 6-156) were -0.76 (-1.03, -0.50), -0.29 (-0.51, -0.07), and -0.05 (-0.26, 0.17) in tertiles 1, 2, and 3, respectively (p value0.001), and approximately -1.5 mL/min/1.73 m2/year across tertiles in the placebo group (p value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were -0.77, -0.71, and -0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All pinteraction values were0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups.With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.

This prespecified exploratory analyses from VERTIS CV (NCT01986881) aimed to assess the effects of the sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on glucosuria-related (glycated haemoglobin [HbA1c], uric acid, body weight) and natriuresis-related (blood pressure, haemoglobin, haematocrit, serum albumin) biomarkers according to kidney function risk category.Patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (1:1:1). Analyses compared placebo (n = 2747) versus ertugliflozin (pooled; n = 5499) on glucosuria- and natriuresis-related biomarkers according to baseline estimated glomerular filtration rate (eGFR) subgroup and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) risk category.Patients were classified according to KDIGO CKD low- (49%), moderate- (32%) and high-/very-high-risk categories (19%), and eGFR groups 1 (25%), 2 (53%) and 3 (19%). At Week 18, the high-/very-high-risk category had a smaller placebo-subtracted least squares mean (LSM) change from baseline (95% confidence interval) in HbA1c (-0.34 [-0.43, -0.25]) compared with the low- and moderate-risk categories (-0.54 [-0.60, -0.49] and - 0.47 [-0.54, -0.40], respectively). This pattern was maintained throughout the study (PIn VERTIS CV, ertugliflozin was associated with physiologically favourable changes in glucosuria- and natriuresis-related biomarkers. Glycaemic efficacy of ertugliflozin was attenuated in patients with higher chronic kidney disease (CKD) risk. Effects on other biomarkers were consistent, regardless of CKD risk stage.

El trabajo explica las representaciones y funciones culturales del wamani Antapillo a partir de los mitos quechuas acopiados en sur de Ayacucho. Los mitos reproducen y reacomodan simbólicamente la representación humana, geográfica y zoológica del wamani. Este ser espiritual, como parte de sus funciones culturales, articula sentidos comunitarios de la generosidades, complementariedades y correspondencias recíprocas en la vida cotidiana de los habitantes que constituyen una comunidad que comparten estas tradiciones

Aims/hypothesisThis study aimed to evaluate the effect of ertugliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.govNCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population.MethodsPost hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks.ResultsOverall, mean (SD) baseline eGFR was 88.2 (18.8) ml min−1(1.73 m)−2and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were −2.3, −2.7 and −0.7 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were −0.2, 0.1 and −2.0 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was −29.5% (−44.8, −9.8;p p 1c(mmol/mol [95% CI]) at week 104 were similar between treatment groups: −6.84 (−7.64, −6.03), −7.74 (−8.54, −6.94) and −6.84 (−7.65, −6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c(% [95% CI]) at week 104 were: −0.63 (−0.70, −0.55), −0.71 (−0.78, −0.64) and −0.63 (−0.70, −0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively.Conclusions/interpretationErtugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1cdid not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria.Trial registrationclinicaltrials.govNCT01999218 and NCT02033889.

Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow the decline of kidney function in outcome trials, but the biological mediator(s) underlying the therapeutic benefit are not well established. Purpose We performed a post-hoc analysis exploring potential mediators of the effects of the SGLT2 inhibitor ertugliflozin on the VERTIS CV exploratory kidney composite outcome (sustained 40% decrease from baseline in estimated glomerular filtration rate [eGFR], chronic kidney replacement therapy or kidney death). Methods In VERTIS CV, 8246 participants with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomised to placebo, ertugliflozin 5 mg or 15 mg (pooled for analyses, as prospectively planned), and were followed for a mean of 3.5 years. The hazard ratio (HR; 95% confidence interval) for the pre-specified exploratory kidney composite outcome was 0.66 (0.50, 0.88). Cox regression models were used to evaluate covariates that were significantly differentially changed from baseline with ertugliflozin treatment as candidate mediators, with a mediator identified as a covariate when added to an unadjusted model of randomised treatment assignment a) yielded a larger hazard ratio; and b) the mediator retained P100%. Results Of 22 covariates significantly changed by ertugliflozin, nine were identified as potential mediators (Table). The covariates with a high percentage of mediation were those related to changes in blood erythrocytes (haemoglobin, haematocrit and red blood cell mass), with average changes in haemoglobin having the highest percentage of mediation (61.8%). Serum uric acid was associated with a mediation of 29.4% and 50.0% for the early and average post-randomisation effect periods, respectively. Early changes in glycated haemoglobin had a large mediation (50%), but the average change during the trial was not significant. Average change in serum albumin had a large mediation (29.4%). Average changes in body weight and systolic blood pressure had percentages of mediation of 41.2% and 14.7%, respectively. Conclusion Multiple factors may be involved in the reduction of the kidney composite outcome observed with ertugliflozin. In the short-term, changes in glycaemia had a high mediation effect. Over the long-term, changes suggestive of haemoconcentration and/or haematopoiesis (natriuresis-related effects), showed the highest percentage of mediation, followed by changes in serum uric acid and body weight (glucosuria-related effects). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA in collaboration with Pfizer Inc., New York, NY, USA

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA. Disclosure D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.

El trabajo explora la disociación, asociación y la emergencia del conflicto social en la comunidad quechua de Hualla, a raíz de la exploración minera en el territorio comunal. Este episodio generó sentidos contradictorios en la lógica de los pobladores, unos interesados en la empresa extractiva e ilusionados con el discurso de progreso y desarrollo que aglutinó sentidos de oportunidad para mejorar sus condiciones de vida. Mientras que los anti–mineros son contarios a la inversión extractiva. Ambas posturas debilitaron la organización comunal y familiar.

Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract

El trabajo constata la práctica cotidiana de la reciprocidad en el contexto de la fiesta, donde los pobladores reproducen y reconfiguran sus formas y sentidos comunitarios junto a aspectos culturales modernos. Ambos modelos coexisten activa, creativa y recreativamente en la vida comunal. En las fiestas, los actores interactúan regidos por un ideal de generosidad, se ayudan e intercambian bienes y servicios entre parientes, asentados, migrantes y retornantes. En un contexto donde el capitalismo apabulla a las sociedades tradicionales, en la comunidad quechua de Hualla persiste la reciprocidad, la fiesta y memoria colectiva, la tradición oral, el trabajo colectivo, interfamiliar y familiar festivo y competitivo, con otra forma de ver a la vida entre los hombres, la naturaleza y lo sagrado.

OBJECTIVE To evaluate the efficacy and safety of empagliflozin versus placebo as add-on therapy in patients with type 2 diabetes and inadequate glycemic control with linagliptin and metformin. RESEARCH DESIGN AND METHODS Patients with HbA1c ≥8.0% and ≤10.5% (≥64 and ≤91 mmol/mol) while receiving stable-dose metformin received open-label linagliptin 5 mg (n = 606) for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (≥53 and ≤91 mmol/mol) were randomized to receive double-blind, double-dummy treatment with empagliflozin 10 mg (n = 112), empagliflozin 25 mg (n = 111), or placebo (n = 110) for 24 weeks; all patients continued treatment with metformin and linagliptin 5 mg. The primary end point was the change from baseline in HbA1c after 24 weeks of double-blind treatment. RESULTS At week 24, empagliflozin significantly reduced HbA1c (mean baseline 7.96–7.97% [63–64 mmol/mol]) versus placebo; the adjusted mean differences in the change from baseline with empagliflozin 10 and 25 mg versus placebo were −0.79% (95% CI ‒1.02, ‒0.55) (−8.63 mmol/mol [‒11.20, ‒6.07 mmol/mol]) and −0.70% (95% CI ‒0.93, ‒0.46) (−7.61 mmol/mol [‒10.18, ‒5.05 mmol/mol]), respectively (both P < 0.001). Fasting plasma glucose and weight were significantly reduced in both empagliflozin groups versus placebo (P < 0.001 for all comparisons). More patients receiving placebo than empagliflozin 10 and 25 mg reported adverse events during double-blind treatment (68.2%, 55.4%, and 51.8%, respectively). CONCLUSIONS Empagliflozin treatment for 24 weeks improved glycemic control and weight versus placebo as an add-on to linagliptin 5 mg and metformin and was well tolerated.

El trabajo explora la emergencia del conflicto social en la comunidad quechua de Hualla, a raíz de la exploración minera en el territorio comunal. Este episodio generó sentidos contradictorios en la lógica de los pobladores, unos interesados en la empresa extractiva e ilusionados con el discurso de progreso y desarrollo que aglutinó sentidos de oportunidad para mejorar sus condiciones de vida. Mientras, los contarios a la inversión extractiva se movilizan en defensa y el cuidado del medio ambiente. Ambas posturas debilitaron la organización comunal y familiar de la comunidad. Concluyendo el conflicto en el retiro de la empresa extractiva.

2 RCT evaluating ertugliflozin 5 mg (E5, n=652), 15 mg (E15, n=640) vs. non-ertugliflozin (NE, glimepiride or placebo, n=644) in T2D patients were pooled to evaluate effects on eGFR (MDRD) and albuminuria (UACR, geometric mean of % change from baseline). eGFR and UACR were analyzed by mixed model repeated measures with treatment, time, trial, baseline measures [A1C, SBP, eGFR/UACR] as covariates in overall population and by presence of UACR >30 mg/g. Baseline characteristics in the treatment groups were balanced. Overall, mean baseline eGFR was 88.2 ml/min/1.73m2 and geometric mean baseline UACR was 11.6 mg/g. At week 6, changes in eGFR were: -2.3, -2.7 and -0.7 ml/min/1.73m2, for the E5, E15 and NE groups, respectively. Mean eGFR with ertugliflozin increased over time, while it decreased in the NE group. The week 104 ΔeGFR [95% CI] compared to NE was 1.81 ([0.13, 3.49]; p=0.04) and 2.10 ml/min/1.73m2 ([0.42, 3.78]; p=0.01) for E5 and E15, respectively. In patients with baseline UACR > 30 mg/g (n=415) the ertugliflozin groups had greater UACR reductions. The week 104 ΔUACR [95% CI] compared to NE was -29.0% ([-47.0, -4.5]; p=0.02) for E5 and -32.7% ([-50.4, -8.6]; p=0.01) for E15. Ertugliflozin acutely reduced eGFR in an expected fashion, possibly based of known hemodynamic effects. Over 104 weeks, eGFR values were higher with ertugliflozin than control, suggestive of renal function preservation. Ertugliflozin reduced UACR in subjects with baseline albuminuria. Disclosure D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. R. Frederich: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Z. Xu: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck & Co., Inc.

El objetivo principal del ensayo es relacionar la importancia de la participación ciudadana y la valoración objetiva del patrimonio cultural por parte de la comunidad, para lo cual se realizó la revisión literaria de las teorías relacionadas al tema de participación ciudadanía y patrimonio cultural; de la misma manera a nivel general, latinoamericano, nacional y local. También fue llevada a cabo la revisión de artículos científicos afines al tema de investigación, se acudió a la verificación de artículos legales: Constitución de la República del Ecuador 2008, Código Orgánico de Organización Territorial, Autonomía y Descentralización y otras normativas existentes en el Ecuador, en referencia a la participación y patrimonio cultural. El método utilizado para la investigación, fue el descriptivo con enfoque cualitativo y cuantitativo, con abordaje deductivo; mediante la técnica de encuesta y entrevista a los ciudadanos residentes del barrio Twintza, parroquia rural Anconcito, para tener suficiente información con respecto al conocimiento relacionado al tema objeto de estudio; pero se evidenció un contraste entre la valoración teórica del patrimonio y la participación ciudadana. Además no se implementan los mecanismos apropiados que permitan al habitante su participación ciudadana, incrementando la comprensión y apropiación de su entorno patrimonial local, debido a que las instituciones encargadas no cumplen con los roles establecidos en las normativas y por lo tanto no ha sido reconocido en su justo valor por la ciudadanía, para su goce y utilización. En consecuencia no ha provocado mejoras en las condiciones de vida que propone el Buen Vivir.

INTRODUCCION: Las hernias diafragmaticas traumaticas son consecuencia de trauma contuso grave o trauma penetrante. El diagnostico de las lesiones del diafragma y las consiguientes hernias a traves del mismo, siguen siendo un reto para el cirujano ya que no logran ser facilmente determinadas en su etapa aguda y son subdiagnosticadas en un 10% de los casos. Se expone a continuacion un caso de hernia diafragmatica traumatica con presentacion tardia. CASO CLINICO: Paciente de sexo masculino de 73 anos, quien acudio por presentar dolor toracico atipico cronico. Los sintomas acompanantes fueron saciedad precoz, perdida de peso no intencional, hiporexia y dolor abdominal colico recurrente. En una tomografia toracica se evidencio un defecto diafragmatico izquierdo de 14 x10 x 8cm con contenido abdominal intratoracico. Entre los antecedentes personales se refirio hipertension arterial desde hace 10 anos y un antecedente de herida penetrante con arma blanca hace veinte anos en region dorsal izquierda. RESULTADOS: El diagnostico pre-operatorio fue hernia diafragmatica. El paciente fue sometido a reduccion laparoscopica del contenido abdominal (estomago, colon transverso e intestino delgado) y frenorrafia. El paciente no presento complicaciones, tolero tempranamente la dieta y presento buena mecanica respiratoria. El control radiologico posoperatorio demostro un contorno normal del diafragma con el campo pulmonar izquierdo expandido completamente con ligero derrame pleural ipsilateral. Fue dado de alta en buenas condiciones a las 72 horas de su ingreso. El seguimiento del paciente por consulta externa ha sido hasta el momento por 6 meses sin complicaciones. CONCLUSION: La cirugia minimamente invasiva por via abdominal puede corregir de manera adecuada una patologia poco frecuente pero muy importante como es la hernia diafragmatica traumatica cronica. En este caso la relevancia es su forma de presentacion tardia.

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing’s disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing’s disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing’s disease. Electronic supplementary material The online version of this article (doi:10.1007/s11102-013-0503-3) contains supplementary material, which is available to authorized users.

Cushing’s disease (CD) is a rare disorder of chronic hypercortisolism due to an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma. Because hypercortisolism symptoms are wide ranging, it is important to assess a variety of outcomes including both clinical factors, such as cortisol levels, and health-related quality of life (HR-QOL), to better understand the severity and impact of CD on patients and the potential efficacy of CD treatment. Pasireotide, a somatostatin analog that targets somatostatin receptors on the pituitary adenoma, is under development as a treatment for CD. A phase III clinical trial was conducted to investigate its safety and efficacy in patients with CD. In this trial, HR-QOL was assessed with the Cushing’s Quality-of-Life (CushingQOL) questionnaire, specifically developed and validated in patients with Cushing’s syndrome. Reliability, validity, the ability to detect change, and a minimal important difference (MID) were evaluated for the CushingQOL questionnaire using data from patients diagnosed with CD who participated in the phase III clinical trial designed to assess the safety and efficacy of different doses of pasireotide. Adult patients (n = 162) with CD participated in a randomized, double-blind, multinational, phase III clinical trial. Patients received subcutaneous pasireotide (600 μg or 900 μg) twice daily for 3 months (double blind). After 3 months, some patients were unblinded based on their mean urinary free cortisol (mUFC) levels and were given the chance to increase their dosage, while the other patients remained blinded. At month 6, an open-label 6-month period began. The CushingQOL questionnaire was self-administered four times (baseline [n = 160], and at months 3 [n = 134], 6 [n = 113], and 12 [n = 76]). A confirmatory factor analysis (CFA) was conducted. Reliability estimates were calculated for internal consistency (coefficient alpha) and test retest (intraclass correlation coefficients [ICCs]) for patients with stable hypercortisolism at month 3 and month 6. Construct validity hypotheses (correlations), mean differences in known groups (ANOVAs), and responsiveness effect sizes (Guyatt’s) were estimated based on measures of cortisol, body mass index (BMI), waist circumference, weight, facial rubor (redness), striae (stretch marks), bruising, supraclavicular fat pad, dorsal fat pad, and results of the Beck Depression Inventory II (BDI-II). The half-standard deviation distribution method was used to estimate MID. CFA loadings supported a one-factor solution for the CushingQOL questionnaire items. Internal consistency reliability (0.87–0.88) and ICCs (0.87) were high. Construct validity hypotheses were in the anticipated direction. Changes in CushingQOL scores were moderately correlated with changes in mUFC levels, in BMI, and in weight. Mean scores for minimally depressed patients were significantly higher (indicating better HR-QOL) than for severely depressed patients. Moderate Guyatt’s responsiveness effect sizes were observed for patients who achieved reductions in weight, BMI, and waist circumference. Using the half-standard deviation method, an estimate of the MID was computed as 10.1. This study provided evidence within the context of a longitudinal design that the CushingQOL questionnaire is a reliable, valid, and responsive instrument for the assessment of HR-QOL in adults with CD in accordance with recommendations set forth by regulatory agencies in the USA and Europe.

Aim To evaluate the efficacy and safety of linagliptin versus placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes. Materials and methods Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (>53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks’ double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary end point was change from baseline (defined as the last value before first intake of randomized, double-blind treatment) in HbA1c at week 24. Results At week 24, HbA1c (mean baseline 7.82–8.04 [62–64 mmol/mol]) was significantly reduced with linagliptin versus placebo; adjusted mean (SE) differences in change from baseline in HbA1c with linagliptin versus placebo were −0.32% (0.10) (−3.59 [1.08] mmol/mol) (P = 0.001) for patients on empagliflozin 10 mg and metformin, and −0.47% (0.10) (−5.15 [1.04] mmol/mol) (P

Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with "A-β+" KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A-β+ KPD patients presenting with "provoked" compared with "unprovoked" DKA. Clinical, biochemical, and β-cell functional characteristics were compared between provoked and unprovoked A-β+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A-β+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A-β+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. β-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. "Unprovoked" A-β+ KPD is a distinct syndrome characterized by reversible β-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas "provoked" A-β+ KPD is characterized by progressive loss of β-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term β-cell functional reserve, insulin independence, and glycemic control in KPD.

OBJECTIVE Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes. RESEARCH DESIGN AND METHODS Over 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects. RESULTS The majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported. CONCLUSIONS Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

OBJECTIVE—Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of β-cell autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes. RESEARCH DESIGN AND METHODS—A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, β-cell functional reserve, insulin sensitivity, and insulin requirement. Frequencies of susceptibility and resistance alleles at HLA DQA1, DQB1, and DRB1 loci were correlated with clinical and phenotypic features of KPD subgroups and compared with those of ethnic-specific population control subjects. RESULTS—Susceptibility alleles were more frequent (P < 0.0001) in the two A+ than the two A− KPD subgroups; in the latter, the frequency was no greater than in population control subjects (except for DQB1*0302). Susceptibility alleles differentiated the two clinically similar β− subgroups (more frequent in A+β− than A−β− KPD; P < 0.01). Resistance alleles were more frequent in the two β+ than the two β− KPD subgroups (P < 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American A−β+ KPD patients than in African-American control subjects. DQB1*0302 was more frequent in all KPD subgroups compared with control subjects. CONCLUSIONS—HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPD. Inheritance of these alleles may influence long-term β-cell functional reserve.

Ketosis-prone diabetes (KPD) is a widespread, emerging, heterogeneous syndrome characterized by patients who present with diabetic ketoacidosis or unprovoked ketosis but do not necessarily have the typical phenotype of autoimmune type 1 diabetes. Multiple, severe forms of beta-cell dysfunction appear to underlie the pathophysiology of KPD. Until recently, the syndrome has lacked an accurate, clinically relevant and etiologically useful classification scheme. We have utilized a large, longitudinally followed, heterogeneous, multiethnic cohort of KPD patients to identify four clinically and pathophysiologically distinct subgroups that are separable by the presence or absence of beta-cell autoimmunity and the presence or absence of beta-cell functional reserve. The resulting "Abeta" classification system of KPD has proven to be highly accurate and predictive of such clinically important outcomes as glycemic control and insulin dependence, as well as an aid to biochemical and molecular investigations into novel causes of beta-cell dysfunction. In this review, we describe the current state of knowledge in regard to the natural history, pathophysiology, and treatment of the subgroups of KPD, with an emphasis on recent advances in understanding their immunological and genetic bases.

Autoantibodies directed against specific epitopes in the insulin receptor are rarely the cause of either recurrent hypoglycemia or a severe form of insulin resistance (type B insulin resistance). Type B insulin resistance occurs more commonly in women of African heritage and is frequently associated with a history of other autoimmune diseases. We present the unusual case of a 61-year-old African American woman with a background of autoimmune hypothyroidism and autoimmune hepatitis who developed type 2 diabetes mellitus and marked facial acanthosis nigricans (AN) over a period of weeks. Despite treatment with multiple oral antidiabetic agents, she rapidly developed severe, recalcitrant hyperglycemia and ketoacidosis, requiring hospitalization and intravenous insulin administration for 4 weeks at rates of up to 180 U/h. Immunologic testing revealed a high titer of anti-insulin receptor autoantibodies of both immunoglobulin G and immunoglobulin A classes. After a recurrence of diabetic ketoacidosis despite aggressive management, the patient was treated with a short course of cyclophosphamide; within 10 weeks, she experienced striking improvement of her hyperglycemia as well as marked regression of the AN lesions. Subsequently, the patient also experienced episodes of fasting hypoglycemia, which resolved with a brief course of glucocorticoids. She has since remained euglycemic with no therapy for 5 years. We have documented, for the first time, regression of AN in temporal association with disappearance of circulating anti-insulin receptor autoantibodies and achievement of euglycemia in a patient with type B insulin resistance.

El presente texto es una breve reflexión sobre el evento de arte moderno y contemporáneo: Whitney Biennial 2014 en donde se incluyen algunos datos históricos sobre su organización y el museo que le sirve de sede.

We previously characterized patients presenting with diabetic ketoacidosis prospectively into four subgroups of ketosis-prone diabetes mellitus (KPDM), based on the presence or absence of beta-cell autoimmunity (A+ or A-) and beta-cell functional reserve (B+ or B-). The A+B- KPDM subgroup comprises patients with classic, autoimmune type 1 diabetes, whereas the A+B+ KPDM subgroup has only partial beta-cell loss and a distinct clinical phenotype.We hypothesized that epitope specificity of autoantibodies directed against the 65-kDa isoform of glutamate decarboxylase (GAD65) reflects differences in beta-cell destruction.Sera of sequential GAD65Ab-positive KPDM patients admitted for diabetic ketoacidosis (n = 36) were analyzed for their epitope recognition using five GAD65-specific recombinant Fab and their ability to inhibit GAD65 enzymatic activity. All patients were followed longitudinally to assess beta-cell functional reserve and insulin dependence.Binding to an amino-terminal epitope defined by monoclonal antibody DPD correlated positively with fasting serum C-peptide levels at baseline (P = 0.0008) and after 1 yr (P = 0.007). Binding to the DPD-defined epitope also correlated positively with area under the curve for C-peptide after glucagon stimulation (P = 0.007) and with homeostasis model assessment percent B at 1 yr (P = 0.03). Binding to the DPD-defined epitope was significantly stronger in A+B+ than in A+B- patients (P = 0.001). Sera of 16 patients (44%) significantly inhibited GAD65 enzymatic activity, but this did not correlate with beta-cell function.DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

Aim To evaluate factors predictive of insulin discontinuation in subjects with ketosis-prone Type 2 diabetes. Methods One hundred and six subjects with ketosis-prone Type 2 diabetes were recruited during the index episode of diabetic ketoacidosis (DKA). All subjects were followed in a special clinic for at least 6 months. If the subject's glycaemic control reached specified glycaemic goals, exogenous insulin was gradually decreased until discontinuation. Baseline and follow-up characteristics were compared between the off-insulin and the on-insulin groups. Results At the end of the follow-up period (915 ± 375 days) insulin was discontinued in 47% subjects. Subjects in the off-insulin group were significantly older at the time of diagnosis of diabetes. In the off-insulin group the majority of subjects were newly diagnosed with diabetes. After 6 months of follow-up, subjects in the off-insulin group had significantly lower mean HbA1c, higher mean C-peptide-to-glucose ratio and had more clinic visits per year. In the proportional hazard analysis, new-onset diabetes [hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.02–2.45], and a higher C-peptide-to-glucose ratio at 6 months of follow-up (HR 1.77; 95% CI 1.22–2.63) were significant predictors of insulin discontinuation. Conclusions In subjects with ketosis-prone Type 2 diabetes, the best predictors of insulin discontinuation are having new-onset diabetes, and higher β-cell functional reserve (as measured by the C-peptide-to-glucose ratio).

This study was designed to determine if patients with ketosis-prone diabetes could be distinguished clinically on the basis of features of the metabolic syndrome (MetS).Participants with ketosis-prone diabetes admitted to our institution during a 3-year period were studied. One hundred seventy-two patients from four ethnic backgrounds were divided into two groups: with or without MetS, as defined by the World Health Organization. Pearson's chi-square test or one-way ANOVA was used as appropriate to evaluate group differences.Of the 172 patients, 74 (43%) had at least three characteristics of MetS (+MetS group), while 98 (57%) had less than three characteristics of MetS (-MetS group). The +MetS group had significantly higher beta-cell functional reserve as measured by the glucagon stimulation test [area under the curve (AUC) for C-peptide levels 19.50+/-2.26 compared with 8.66+/-1.66 ng/ml over 10 min; P=.0001]. A significantly higher proportion of patients in the +MetS group had preserved beta-cell functional reserve than in the -MetS group (70% compared with 30%; P.00001). After 12 months of follow-up, +MetS patients had significantly lower HbA1c levels (8.3+/-0.4% compared with 9.8+/-0.4%; P=.01) and higher C-peptide/glucose ratios (2.01+/-0.28 compared with 1.14+/-0.21; P=.02) than the -MetS patients did.Patients with ketosis-prone diabetes with the MetS are more likely to have features associated with Type 2 diabetes, despite having developed diabetic ketoacidosis (DKA), with better beta-cell functional reserve and glycemic control after the index DKA episode.

Aim: To derive predictors of good glycaemic control in patients presenting with diabetic ketoacidosis (DKA) followed prospectively in a specialized clinic. Methods: One hundred and sixty-one adult patients were admitted during a 31-month period and followed for at least 12 months. After 1 year, the patients were classified into three groups: good control (GC) (HbA1c ≤ 7%), intermediate control (IC) (HbA1c 7–9%) and poor control (PC) (HbA1c > 9%). Characteristics of patients in the three groups were compared both at baseline and during follow-up. Results: At 12 months, 36% of the patients were classified as GC, 27% as IC and 37% as PC. GC patients had higher fasting serum C-peptide levels 0.7 ± 0.54 compared to 0.38 ± 0.29 and 0.16 ± 0.21 nmol/l, respectively, for the IC and PC patients (p

Objectives. Dyslipidemia associated with antiretroviral therapy is a common clinical problem among HIV-infected patients. Considering that the challenge of adherence to drugs (both antiretroviral and lipid lowering) may be substantial in routine HIV care, our objective was to evaluate the lipid-lowering effects of statins and fibrates in the management of HIV dyslipidemias in clinical practice setting. Methods. Retrospective review of 103 ethnically diverse dyslipidemic HIV patients on antiretroviral therapy treated with lipid-lowering drugs (using National Cholesterol Education and Prevention II [NCEP II] guidelines) who were followed for a median of 70 weeks. Results. An overall mean reduction of 16% in total cholesterol, 20% non-HDL cholesterol, and 18% in triglycerides was noted. There were no significant changes in HDL levels. On evaluation of the different drug classes, the mean (median) change in total cholesterol, were −9 (−7)% with fibrates, −11 (−14)% with statins and −23 (−22)% for dual therapy with fibrates and statins. The triglycerides decreased by −11 (−40)% in those treated with fibrates; −1 (−21)% in those with statins alone, and −32 (−42)% in those with dual therapy. Overall less than a fifth of patients reached the defined NCEP target goal reduction. On logistic regression analysis, only stopping protease inhibitors/ritonavir was independently associated with significant cholesterol reduction (OR: 10.14; 95% CI: 2.1–48.9; p Conclusion. In a primary care setting, the use of statins and/or fibrates may add to the complexity of HIV care, with only modest lipid lowering effects.

Objective To determine the effectiveness of fenofibrate in treating hypertriglyceridemia associated with highly active antiretroviral therapy–associated HIV lipodystrophy syndrome (HLS). Methods The authors recruited from their HIV metabolic clinic 55 adult patients with anthropomorphic changes consistent with HLS together with hypertriglyceridemia. The patients had no prior history of taking lipid-lowering medications and were free of liver and renal disease. They were on various highly active antiretroviral therapy regimens, and these regimens were not altered during the course of the study. Fenofibrate was started at 54 mg a day and the dose increased every 2 weeks to a maximum of 162 mg/day. Fasting lipid concentrations were measured at baseline and 6 months after the intervention. Results At baseline, the fasting plasma concentrations of total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were 259 ± 11, 886 ± 172, and 35.7 ± 2.3 (mean ± SEM) mg/dL, respectively. After 6 months of fenofibrate treatment, the fasting plasma concentrations were as follows: total cholesterol, 243 ± 13; triglycerides, 552 ± 104, and HDL cholesterol, 35.7 ± 1.8 mg/dL. The decrease in fasting plasma triglyceride concentration was statistically significant (P 0.05). Fenofibrate was well tolerated, and no subjects dropped out of the study. Conclusion Fenofibrate is an effective, well-tolerated treatment for hypertriglyceridemia associated with HLS.

OBJECTIVE—Diabetic ketoacidosis (DKA) is a common complication of diabetes. We analyzed the inpatient costs of treating DKA in a multiethnic, indigent population in Houston, Texas. RESEARCH DESIGN AND METHODS—We measured the cost of resources utilized for all patients admitted to our hospital with DKA from 1 January to 31 December 1998. We also analyzed their medical records to determine the factors that precipitated the episode of DKA and then grouped them into three categories: acute illnesses, noncompliance with diabetes treatment, and new-onset diabetes. The data were analyzed by one-way ANOVA. The Tukey-Kramer procedure was used for post hoc multiple comparisons. RESULTS—There were 167 admissions for DKA. The mean age was 40 ± 13 years. The ethnic distribution was 49% African American, 32% Hispanic American, and 18% white. The total inhospital cost of treating DKA was $1,816,255. The mean cost per hospitalization was $10, 876 ± 11,024. The frequency distribution by category of DKA-precipitating factor was 18% acute illness, 59% noncompliance, and 23% new onset. There were differences in mean cost of DKA associated with the three categories: $20,864 ± 17,910 for acute illness, $11,863 ± 8,701 for new onset, and $7,470 ± 6,300 for noncompliance (P < 0.0001). The total cost for each category was $671,375 for acute illness, $694,082 for noncompliance, and $450,798 for new onset. CONCLUSIONS—DKA is an expensive complication among indigent, multiethnic diabetic patients. Although the mean cost per admission was lowest for DKA precipitated by noncompliance, this causal category was responsible in sum for the greatest portion of the economic burden.

ObjectiveCushing's disease (CD) can significantly impair patients' health-related quality of life (HRQOL). This study investigated the treatment effectiveness of pasireotide on HRQOL of CD patients, and assessed the relationships between HRQOL and urinary free cortisol (UFC) and CD-related signs and symptoms.DesignIn this phase III, randomized, double-blind study, patients with UFC ≥1.5×upper limit of normal (ULN) received s.c. pasireotide 600 or 900 μg twice daily. The trial primary endpoint was UFC at or below ULN at month 6 without dose titration. Open-label treatment continued through month 12. HRQOL was measured using the Cushing's Quality of Life Questionnaire (CushingQoL) instrument at baseline and follow-up visits until month 12 during which clinical signs and features of CD, and the Beck Depression Inventory II (BDI-II), were also collected.MethodsPearson's/Spearman's correlations between changes in CushingQoL and changes in clinical signs and symptoms were assessed. Changes in CushingQoL and the proportion of patients achieving a clinically meaningful improvement in CushingQoL were also compared among patients stratified by mean UFC (mUFC) control status (controlled, partially controlled, and uncontrolled) at month 6. Analyses were also conducted at month 12, with multivariable adjustment for baseline characteristics and CushingQoL.ResultsChange in CushingQoL was significantly correlated with changes in mUFC (r=−0.40), BMI (r=−0.39), weight (r=−0.41), and BDI-II (r=−0.54) at month 12 but not at month 6. The percentage of CushingQoL responders at month 12 based on month 6 mUFC control status were as follows: 63, 58.8, and 37.9% in the controlled, partially controlled, and uncontrolled groups respectively. Adjusted CushingQoL scores at month 12 were 58.3 for controlled patients (Δ=11.5 vs uncontrolled,P=0.012) and 54.5 for partially controlled patients (Δ=7.7 vs uncontrolled,P=0.170).ConclusionsPasireotide treatment can result in a meaningful HRQOL improvement among those who complete a 12-month treatment period, most often among patients achieving biochemical control.