Minimum-norm estimation for a bi-exponential survival model

We present a novel semi-parametric model for two-sample survival data, and an estimation method with a simple, closed-form solution. We study analytically the asymptotics of the estimators, and conduct a small simulation study.

Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability

The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF) mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT) transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI)-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4) that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin sensitivity. Collectively, we demonstrate that by promoting adipose inflammation and limiting fat tissue expandability, IL-1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity

Long-term Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Rosacea: Results From an Extension of Two Phase III, Vehicle-controlled Trials

OBJECTIVE: We sought to assess the long-term safety and tolerability of microencapsulated benzoyl peroxide cream, 5% (E-BPO cream, 5%), in subjects with rosacea. Efficacy and tolerability have been previously demonstrated in two 12-week, randomized, double-blind, vehicle-controlled Phase III trials. METHODS: In this open-label extension study (NCT03564145; clinicaltrials.gov), all subjects from the initial placebo-controlled Phase III trials could receive E-BPO cream, 5%, for up to an additional 40 weeks, up to a total of 52 weeks of E-BPO cream, 5%, exposure. If a subject was assessed at study visits as clear or almost clear using the 5-point Investigator Global Assessment (IGA) scale (IGA 0 or 1), E-BPO cream, 5%, was not dispensed. If a subject was assessed as mild to severe (IGA 2+), E-BPO cream, 5%, was applied daily until they reached clear or almost clear. RESULTS: The safety and tolerability profile for E-BPO cream, 5%, was similar to that reported in the Phase III studies. Five subjects (0.9%) discontinued study drug due to treatment-related adverse events, and 17 subjects (3.2%) experienced an adverse event considered related to study drug. IGA success after 40 weeks of active treatment was 66.5 percent for subjects continuing from the Phase III vehicle group (n=172) and 67.6 percent for subjects who continued Phase III E-BPO cream, 5% (n=363). The study ended early in accordance with the protocol. LIMITATIONS: Safety and tolerability of E-BPO were not compared with those of unencapsulated BPO. CONCLUSION: E-BPO cream, 5%, showed a favorable safety and tolerability profile during this 40-week, open-label extension study

Long-term Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Rosacea: Results From an Extension of Two Phase III, Vehicle-controlled Trials

OBJECTIVE: We sought to assess the long-term safety and tolerability of microencapsulated benzoyl peroxide cream, 5% (E-BPO cream, 5%), in subjects with rosacea. Efficacy and tolerability have been previously demonstrated in two 12-week, randomized, double-blind, vehicle-controlled Phase III trials. METHODS: In this open-label extension study (NCT03564145; clinicaltrials.gov), all subjects from the initial placebo-controlled Phase III trials could receive E-BPO cream, 5%, for up to an additional 40 weeks, up to a total of 52 weeks of E-BPO cream, 5%, exposure. If a subject was assessed at study visits as clear or almost clear using the 5-point Investigator Global Assessment (IGA) scale (IGA 0 or 1), E-BPO cream, 5%, was not dispensed. If a subject was assessed as mild to severe (IGA 2+), E-BPO cream, 5%, was applied daily until they reached clear or almost clear. RESULTS: The safety and tolerability profile for E-BPO cream, 5%, was similar to that reported in the Phase III studies. Five subjects (0.9%) discontinued study drug due to treatment-related adverse events, and 17 subjects (3.2%) experienced an adverse event considered related to study drug. IGA success after 40 weeks of active treatment was 66.5 percent for subjects continuing from the Phase III vehicle group (n=172) and 67.6 percent for subjects who continued Phase III E-BPO cream, 5% (n=363). The study ended early in accordance with the protocol. LIMITATIONS: Safety and tolerability of E-BPO were not compared with those of unencapsulated BPO. CONCLUSION: E-BPO cream, 5%, showed a favorable safety and tolerability profile during this 40-week, open-label extension study

Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Rosacea: Results From Two Phase III, Randomized, Vehicle-Controlled Trials

OBJECTIVE: A new formulation of benzoyl peroxide (E-BPO cream, 5%) entraps benzoyl peroxide (BPO) in silica microcapsules. This study assesses the efficacy, safety, and tolerability of E-BPO cream, 5%, in rosacea in two Phase III clinical trials. METHODS: In two 12-week, randomized, double-blind, vehicle cream-controlled Phase III trials, 733 subjects at least 18 years old with moderate to severe rosacea were randomized (2:1) to once-daily E-BPO cream, 5%, or vehicle. RESULTS: In Study 1, the proportion of subjects achieving IGA clear/almost clear at Week 12 was 43.5 percent for E-BPO cream, 5%, and 16.1 percent for vehicle. In Study 2, the respective values were 50.1 percent and 25.9 percent. In Study 1, the decrease in lesion count from baseline to Week 12 was -17.4 for E-BPO cream, 5%, versus -9.5 for vehicle. In Study 2, the respective values were -20.3 and -13.3 (all \u3c0.001). The difference was also significant at Week 2. There were no treatment-related serious adverse events; 1.4 percent of subjects (1.8% E-BPO cream, 5%, 0.4% vehicle) discontinued due to adverse events. Assessed local tolerability was found to be similar among subjects in both E-BPO and vehicle. UNLABELLED: E-BPO was not compared with unencapsulated BPO. CONCLUSION: E-BPO is an effective and well tolerated treatment for rosacea. Clinicaltrials.gov Identifiers: NCT03564119, NCT03448939

Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Rosacea: Results From Two Phase III, Randomized, Vehicle-Controlled Trials

OBJECTIVE: A new formulation of benzoyl peroxide (E-BPO cream, 5%) entraps benzoyl peroxide (BPO) in silica microcapsules. This study assesses the efficacy, safety, and tolerability of E-BPO cream, 5%, in rosacea in two Phase III clinical trials. METHODS: In two 12-week, randomized, double-blind, vehicle cream-controlled Phase III trials, 733 subjects at least 18 years old with moderate to severe rosacea were randomized (2:1) to once-daily E-BPO cream, 5%, or vehicle. RESULTS: In Study 1, the proportion of subjects achieving IGA clear/almost clear at Week 12 was 43.5 percent for E-BPO cream, 5%, and 16.1 percent for vehicle. In Study 2, the respective values were 50.1 percent and 25.9 percent. In Study 1, the decrease in lesion count from baseline to Week 12 was -17.4 for E-BPO cream, 5%, versus -9.5 for vehicle. In Study 2, the respective values were -20.3 and -13.3 (all P\u3c0.001). The difference was also significant at Week 2. There were no treatment-related serious adverse events; 1.4 percent of subjects (1.8% E-BPO cream, 5%, 0.4% vehicle) discontinued due to adverse events. Assessed local tolerability was found to be similar among subjects in both E-BPO and vehicle. E-BPO was not compared with unencapsulated BPO. UNLABELLED: E-BPO was not compared with unencapsulated BPO. CONCLUSION: E-BPO is an effective and well tolerated treatment for rosacea. Clinicaltrials.gov Identifiers: NCT03564119, NCT03448939

Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes

High fat feeding induces only a minor adipose tissue macrophage infiltration in IL-1βKO mice.

<p>(<b>A</b>) Quantitative real-time PCR analysis of adipose tissue (epididymal fat pad) of <i>IL-1b, il6</i> and <i>tnf</i> (normalized to <i>tbp</i>, <i>18S</i> and <i>36b4</i>). n≥3 per group. (<b>B–D</b>) Representative X20 light microscopy images of adipose tissue stained with H&E or with anti-Mac2 antibody. The mean±SEM number of crown like structures (CLS) per X10 microscopic field was counted as described in Materials and Methods. mRNA levels of <i>f4/80</i>, a macrophage marker, was assessed by quantitative real-time PCR. (<b>E–G</b>) Similar analysis as described above (B–D), but for IL-1βKO-NC and IL-1βKO-HFF mice. n = 3–6 animals per group were included in the analysis. *p<0.05 compared to IL-1βKO-NC; ***p<0.001 compared to WT-NC.</p

Role of adipose IL-1β in hepatocyte insulin resistance as revealed by co-culture approach.

<p>(<b>A</b>) Schematic representation of the fat explants – primary hepatocyte co-culture experimental design. (<b>B</b>) Insulin-stimulated Akt and GSK3 phosphorylation in primary hepatocytes from IL-1RIKO liver co-cultured or not with fat explants from WT-NC or WT-HFF and densitometry analysis of 2–5 mice per group. *p = 0.05 compared to incubation with fat explants from WT-HFF mice. (<b>C</b>) Insulin-stimulated Akt phosphorylation in primary hepatocytes from WT mice co-cultured with fat explants from WT-HFF, IL-1βKO-HFF, or WT-HFF in the presence of IL-1 receptor antagonist (WT-HFF+RA). The right graph depicts densitometry analysis of 7–9 mice per group. *p<0.05 compared to the signal obtained from primary hepatocytes incubated with fat explants from WT-HFF mice.</p

Role of IL-1β in adipose tissue macrophage recruitment, ATM lipid content, and adipose inflammatory profile in dietary obesity.

<p>(<b>A</b>) FACS plots and gating of the stromal-vascular cells (SVCs) to detect adipose tissue macrophages (ATMs). Leucocytes (<b>B</b>), ATMs (<b>C</b>) in adipose tissue of WT-NC (n = 4), WT-HFF (n = 11), IL-1βKO-NC (n = 3) and IL-1βKO-HFF (n = 7). (<b>D</b>) Histogram of lipid content (determined with Bodipy) in representative mice of the 4 mouse groups (<b>E</b>)<b>.</b> Quantitative real-time PCR analysis of M1 or M2- genes in epididymal adipose tissue of (<b>F</b>) WT-NC, WT-HFF (n = 4, 11, respectively), and (<b>G</b>) IL-1βKO-NC and IL-1βKO-HFF (n = 3 and 7, respectively). The expression of each transcript was normalized to <i>tbp</i>, <i>18S</i> and <i>36b4</i> mRNA/rRNA, and a value of 1 was assigned to the normal chow group (NC) of each strain. *p<0.05, compared to NC; **p<0.01 compared to NC ***p<0.001.</p