Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in ...many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes.
Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.
In this event-driven, double-blind ...study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.
The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval CI, 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 95% CI, 1.05 to 2.32; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.
Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).
Saturn's largest moon, Titan, remains an enigma, explored only by remote sensing from Earth, and by the Voyager and Cassini spacecraft. The most puzzling aspects include the origin of the molecular ...nitrogen and methane in its atmosphere, and the mechanism(s) by which methane is maintained in the face of rapid destruction by photolysis. The Huygens probe, launched from the Cassini spacecraft, has made the first direct observations of the satellite's surface and lower atmosphere. Here we report direct atmospheric measurements from the Gas Chromatograph Mass Spectrometer (GCMS), including altitude profiles of the constituents, isotopic ratios and trace species (including organic compounds). The primary constituents were confirmed to be nitrogen and methane. Noble gases other than argon were not detected. The argon includes primordial 36Ar, and the radiogenic isotope 40Ar, providing an important constraint on the outgassing history of Titan. Trace organic species, including cyanogen and ethane, were found in surface measurements.
Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that ...depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells.
In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed.
The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced.
In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
Summary
We have developed clinical nomograms for predicting 5-year and 10-year fracture risks for any elderly man or woman. The nomograms used age and information concerning fracture history, fall ...history, and BMD T-score or body weight.
Introduction
Although many fracture risk factors have been identified, the translation of these risk factors into a prognostic model that can be used in primary care setting has not been well realized. The present study sought to develop a nomogram that incorporates non-invasive risk factors to predict 5-year and 10-year absolute fracture risks for an individual man and woman.
Methods
The Dubbo Osteoporosis Epidemiology Study was designed as a community-based prospective study, with 1358 women and 858 men aged 60+ years as at 1989. Baseline measurements included femoral neck bone mineral density (FNBMD), prior fracture, a history of falls and body weight. Between 1989 and 2004, 426 women and 149 men had sustained a low-trauma fracture (not including morphometric vertebral fractures). Two prognostic models based on the Cox’s proportional hazards analysis were considered: model I included age, BMD, prior fracture and falls; and model II included age, weight, prior fracture and fall.
Results
Analysis of the area under the receiver operating characteristic curve (AUC) suggested that model I (AUC = 0.75 for both sexes) performed better than model II (AUC = 0.72 for women and 0.74 for men). Using the models’ estimates, we constructred various nomograms for individualizing the risk of fracture for men and women. If the 5-year risk of 10% or greater is considered “high risk”, then virtually all 80-year-old men with BMD T-scores <-1.0 or 80-year-old women with T-scores <-2.0 were predicted to be in the high risk group. A 60-year-old woman’s risk was considered high risk only if her BMD T-scores ≤-2.5 and with a prior fracture; however, no 60-year-old men would be in the high risk regardless of their BMD and risk profile.
Conclusion
These data suggest that the assessment of fracture risk for an individual cannot be based on BMD alone, since there are clearly various combinations of factors that could substantially elevate an individual’s risk of fracture. The nomograms presented here can be useful for individualizing the short- and intermediate-term risk of fracture and identifying high-risk individuals for intervention to reduce the burden of fracture in the general population.
Essentials
Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors.
We conducted an open‐label, randomized, placebo‐controlled, three‐period crossover study in 15 ...subjects.
Both PCCs rapidly reversed apixaban‐mediated decreases in mean endogenous thrombin potential.
Four‐factor PCC administration had no effect on apixaban pharmacokinetics or anti‐FXa activity.
Summary
Background
Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs).
Objective
This open‐label, randomized, placebo‐controlled, three‐period crossover study assessed the effect of two four‐factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects.
Methods
Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30‐min infusion of 50 IU kg−1 Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential (ETP), measured with a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time, anti‐FXa activity, apixaban pharmacokinetics, and safety.
Results
Apixaban‐related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre‐PCC baseline to end of infusion were 425 nm min (95% confidence interval CI 219.8–630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI − 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre‐apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti‐FXa profiles were consistent across treatments.
Conclusions
Cofact and Beriplex reversed apixaban's steady‐state effects on several coagulation assessments.
In situ measurements of the mass, mixing state, and optical size of individual black‐carbon (BC) particles in the fine mode (90–600 nm) have been made in fresh emissions from urban and biomass ...burning sources with an airborne single‐particle soot photometer. Contrasts between the two sources are significant and consistent. Urban BC tends to smaller sizes, fewer coated particles, thinner coatings, and less absorption per unit mass than biomass‐burning BC. This suggests that urban BC may have a longer lifetime in the atmosphere and a different impact on BC radiative forcing in the first indirect effect than biomass‐burning BC. These measurements bound the likely variability in the microphysical state of BC emissions from typical continental processes, and provide direct measurements of the size distribution and coating state of fine‐mode BC for use in constraining climate and aerosol models. These results highlight the need for the integration of source‐specific information into such models.
Abstract Purpose These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties. Methods An open-label, randomized, ...crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal. Point estimates and 90% CIs for geometric mean ratios were generated for Cmax , AUC0–∞ , and AUC0–t. Findings Cmax and AUC met bioequivalence criteria for crushed tablets in water. Cmax and AUC decreased by 21.1% and 16.4%, respectively, with the lower bound of the CIs falling below the bioequivalence criteria for crushed tablets with applesauce. Similarly, administration of whole tablets with a high-fat, high-calorie meal reduced apixaban Cmax and AUC by 14.9% and 20.1%, respectively. The exposure reductions in both studies were considered not clinically significant. Implications Apixaban tablets can be administered crushed or whole, with or without food. The results of these alternative methods of administration support their use in patients who have difficulty swallowing tablets. ClinicalTrials.gov identifiers: NCT02101112 and NCT01437839.
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