Neural Networks, Logistic Regression, and Calibration: A Reply

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68566/2/10.1177_0272989X9801800414.pd

Telotristat ethyl reverses myxomatous changes in mice mitral valves

Rationale: Myxomatous mitral valve degeneration is a common pathological manifestation of mitral valve regurgitation, with or without valvular prolapse. In addition to similarities between naturally occurring and serotonergic valve degeneration, an increasing body of evidence has recently suggested that serotonin signaling is a regulator of degenerative valvulopathies. Studies have found that serotonin can be synthesized locally by valvular cells and serotonin receptors in turn may be activated to promote signaling. Recently, telotristat ethyl (TE) has been introduced as a treatment for carcinoid disease, by selectively inhibiting tryptophan hydroxylase 1, the rate-limiting enzyme in peripheral serotonin synthesis. TE provides a unique tool to test inhibition of serotonin synthesis in vivo, without impacting brain serotonin, to further confirm the role of local serotonin synthesis on heart valves. Objective: To confirm the link between serotonin and myxomatous valvular disease in vivo. Methods and results: A hypertension-induced myxomatous mitral valve disease mouse model was employed to test the effect of TE on valvular degeneration. Circulating serotonin and local serotonin in valve tissues were tested by enzyme immunoassay and immunohistochemistry, respectively. TE was administrated in two modes: (1) parallel with angiotensin II (A2); (2) post A2 treatment. Myxomatous changes were successfully recapitulated in hypertensive mice, as determined by ECM remodeling, myofibroblast transformation, and serotonin signaling activation. These changes were at least partially reversed upon TE administration. Conclusion: This study provides the first evidence of TE as a potential therapeutic for myxomatous mitral disease, either used to prevent or reverse myxomatous degeneration

An adapted heat transfer model for engines with tumble motion

In the last years, a growing interest about increasing the engine efficiency has led to the development of new engine technologies. The accurate determination of the heat transfer across the combustion chamber walls is highly relevant to perform a valid thermal balance while evaluating the potential of new engine concepts. Several works dealing with heat transfer correlations that consider the swirl motion are found in the literature; however, there is a lack of works dealing with heat transfer correlations which take into account the effect of the tumble movement. In this work, a new heat transfer model accounting for the tumble motion is presented. A two stroke HSDI Diesel engine with high tumble and no swirl is used to perform the theoretical study, the model development and its final calibration. Initially, a theoretical analysis of the gas movement phenomena is carried out based on CFD results and then, a model is developed and calibrated based on a skip-fire testing technique. Finally, a sensitivity study focused on evaluating the model robustness is performed. The results confirm an average RMSE reduction of 70% with respect to the Woschni model, being this consistent improvement qualitatively evidenced in the instantaneous heat transfer evolutionThe support of the Spanish Ministry of Economy and Competitiveness (TRA2013-41348-R) is greatly acknowledged.Olmeda González, PC.; Martín Díaz, J.; Novella Rosa, R.; Carreño, R. (2015). An adapted heat transfer model for engines with tumble motion. Applied Energy. 158:190-202. https://doi.org/10.1016/j.apenergy.2015.08.051S19020215

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-Controlled Study of Telotristat Ethyl

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥ 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl

Development and validation of a prediction model for 30-day mortality in hospitalised patients with COVID-19: the COVID-19 SEIMC score

Objective To develop and validate a prediction model of mortality in patients with COVID-19 attending hospital emergency rooms. Design Multivariable prognostic prediction model. Setting 127 Spanish hospitals. Participants Derivation (DC) and external validation (VC) cohorts were obtained from multicentre and single centre databases, including 4035 and 2126 patients with confirmed COVID-19, respectively. Interventions Prognostic variables were identified using multivariable logistic regression. Main outcome measures 30-day mortality. Results Patients? characteristics in the DC and VC were median age 70 and 61 years, male sex 61.0% and 47.9%, median time from onset of symptoms to admission 5 and 8 days, and 30-day mortality 26.6% and 15.5%, respectively. Age, low age-adjusted saturation of oxygen, neutrophil-to-lymphocyte ratio, estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation, dyspnoea and sex were the strongest predictors of mortality. Calibration and discrimination were satisfactory with an area under the receiver operating characteristic curve with a 95% CI for prediction of 30-day mortality of 0.822 (0.806?0.837) in the DC and 0.845 (0.819?0.870) in the VC. A simplified score system ranging from 0 to 30 to predict 30-day mortality was also developed. The risk was considered to be low with 0?2 points (0%?2.1%), moderate with 3?5 (4.7%?6.3%), high with 6?8 (10.6%?19.5%) and very high with 9?30 (27.7%?100%). Conclusions A simple prediction score, based on readily available clinical and laboratory data, provides a useful tool to predict 30-day mortality probability with a high degree of accuracy among hospitalised patients with COVID-19.Funding. This work was supported by Fundación SEIMC/GeSIDA. The funders had no role in study design, data collection, data interpretation or writing of the manuscript. JB, JRB, IJ, JC, JP and JRA received funding for research from Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, cofinanced by the European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014-2020. Spanish AIDS Research Network (RIS) (RD16/0025/0017 (JB), RD16/0025/0018 (JRA), RD16CIII/0002/0006 (IJ)). Spanish Network for Research in Infectious Diseases (REIPI) (RD16/0016/0001 (JRB), RD16/0016/0005 (JC) and RD16/0016/0009 (JP))

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of −54.0% (95% confidence limits, −85.0%, −25.1%, P < 0.001) and −89.7% (95% confidence limits, −113.1%, −63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659)

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes

Quality of care for hypertension in the United States

BACKGROUND: Despite heavy recent emphasis on blood pressure (BP) control, many patients fail to meet widely accepted goals. While access and adherence to therapy certainly play a role, another potential explanation is poor quality of essential care processes (QC). Yet little is known about the relationship between QC and BP control. METHODS: We assessed QC in 12 U.S. communities by reviewing the medical records of a randomly selected group of patients for the two years preceding our study. We included patients with either a diagnosis of hypertension or two visits with BPs of ≥140/90 in their medical records. We used 28 process indicators based on explicit evidence to assess QC. The indicators covered a broad spectrum of care and were developed through a modified Delphi method. We considered patients who received all indicated care to have optimal QC. We defined control of hypertension as BP < 140/90 in the most recent reading. RESULTS: Of 1,953 hypertensive patients, only 57% received optimal care and 42% had controlled hypertension. Patients who had received optimal care were more likely to have their BP under control at the end of the study (45% vs. 35%, p = .0006). Patients were more likely to receive optimal care if they were over age 50 (76% vs. 63%, p < .0001), had diabetes (77% vs. 71%, p = .0038), coronary artery disease (87% vs. 69%, p < .0001), or hyperlipidemia (80% vs. 68%, p < .0001), and did not smoke (73% vs. 66%, p = .0005). CONCLUSIONS: Higher QC for hypertensive patients is associated with better BP control. Younger patients without cardiac risk factors are at greatest risk for poor care. Quality measurement systems like the one presented in this study can guide future quality improvement efforts

Sotagliflozin in patients with diabetes and chronic kidney disease

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m 2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.)