Infertility and mortality Stentz, Natalie C.; Koelper, Nathanael; Barnhart, Kurt T. ...
American journal of obstetrics and gynecology,
March 2020, 2020-03-00, 20200301, Letnik:
222, Številka:
3
Journal Article
Recenzirano
Infertility affects 1 in 10 American reproductive-age women. The impact of this disease beyond the reproductive years is largely unknown.
The objective of the study was to determine the association ...of infertility history with all-cause and cause-specific mortality.
This secondary analysis of a multicenter randomized clinical trial included 75,784 women (aged 55–74 years) prospectively enrolled in the Prostate, Lung, Colorectal, and Ovarian cancer-screening trial from 1992 through 2001 and followed up a minimum of 10 years for health-related outcomes and death (856,935 person-years). We examined the association of infertility history (inability to conceive for 1 year or greater) of all-cause and cause-specific mortality using disease risk score–adjusted Cox-proportional hazard regression models.
Infertile women had a 10% increased risk of death (from any cause) during the study period compared with the unexposed (adjusted hazard risk, 1.10, 95% confidence interval, 1.02–1.18, P = .010). This effect was predominantly noted in women at an otherwise low risk of mortality who had a 26% increased risk of death (adjusted hazard risk, 1.26, 95% confidence interval, 1.12–1.42, P < .001). No differences in cardiovascular or diabetic mortality were noted. The risk of cancer death at any time over the study period was increased by 23% in infertile women compared with the unexposed (adjusted hazard risk, 1.23, 95% confidence interval, 1.10–1.37, P < .001). This effect was predominantly noted in women at an otherwise low risk of cancer mortality who had a 47% increased risk of cancer death (adjusted hazard risk, 1.47, 95% confidence interval, 1.25–1.73, P < .001). While no differences are seen in the risk of death from endometrial or ovarian cancer, the risk of death from breast cancer was more than doubled in infertile women at an otherwise low risk of breast cancer death compared with the unexposed (adjusted hazard risk, 2.64, 95% confidence interval, 1.71–4.08, P < .001).
Infertility is a harbinger of future morbidity and mortality. Infertile women are at an increased risk of all-cause and cancer-related mortality. Consideration of infertility history in health care maintenance presents an opportunity for screening and early intervention for long-term health outcomes.
Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of ...great clinical importance.
We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.
Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter 0.7 mmol per liter vs. 0.5 mmol per liter, P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter 1.6 mmol per liter vs. 0.9 mmol per liter, P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter 0.4 mmol per liter vs. 0.3 mmol per liter, P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).
As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).
Site-specific proteolysis by the enzymatic cleavage of small linear sequence motifs is a key posttranslational modification involved in physiology and disease. The ability to robustly and rapidly ...predict protease-substrate specificity would also enable targeted proteolytic cleavage by designed proteases. Current methods for predicting protease specificity are limited to sequence pattern recognition in experimentally derived cleavage data obtained for libraries of potential substrates and generated separately for each protease variant. We reasoned that a more semantically rich and robust model of protease specificity could be developed by incorporating the energetics of molecular interactions between protease and substrates into machine learning workflows. We present Protein Graph Convolutional Network (PGCN), which develops a physically grounded, structure-based molecular interaction graph representation that describes molecular topology and interaction energetics to predict enzyme specificity. We show that PGCN accurately predicts the specificity landscapes of several variants of two model proteases. Node and edge ablation tests identified key graph elements for specificity prediction, some of which are consistent with known biochemical constraints for protease:substrate recognition. We used a pretrained PGCN model to guide the design of protease libraries for cleaving two noncanonical substrates, and found good agreement with experimental cleavage results. Importantly, the model can accurately assess designs featuring diversity at positions not present in the training data. The described methodology should enable the structure-based prediction of specificity landscapes of a wide variety of proteases and the construction of tailor-made protease editors for site-selectively and irreversibly modifying chosen target proteins.
Agents operating in the real world often have limited time available for planning their next actions. Producing optimal plans is infeasible in these scenarios. Instead, agents must be satisfied with ...the best plans they can generate within the time available. One class of planners well-suited to this task are anytime planners, which quickly find an initial, highly suboptimal plan, and then improve this plan until time runs out.
A second challenge associated with planning in the real world is that models are usually imperfect and environments are often dynamic. Thus, agents need to update their models and consequently plans over time. Incremental planners, which make use of the results of previous planning efforts to generate a new plan, can substantially speed up each planning episode in such cases.
In this paper, we present an A
∗-based anytime search algorithm that produces significantly better solutions than current approaches, while also providing suboptimality bounds on the quality of the solution at any point in time. We also present an extension of this algorithm that is both anytime and incremental. This extension improves its current solution while deliberation time allows and is able to incrementally repair its solution when changes to the world model occur. We provide a number of theoretical and experimental results and demonstrate the effectiveness of the approaches in a robot navigation domain involving two physical systems. We believe that the simplicity, theoretical properties, and generality of the presented methods make them well suited to a range of search problems involving dynamic graphs.
To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression ...with pioglitazone treatment in persons with prediabetes.
CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10(-3) mm/year; 95% CI: 2.39×10(-3)-7.14×10(-3) mm/year) compared with placebo (9.69×10(-3) mm/year; 95% CI: 7.24×10(-3)-12.15×10(-3) mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA(1c), fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM ...versus maintenance of IGT or conversion to normal glucose tolerance.
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln I0-120/G0-120) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln I0-120/G0-120 × Matsuda index of insulin sensitivity; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
The aim of basin modeling is to characterise fluids and rocks in a basin considering its history and data partly describing its present state. In usual basin simulators, only a simplified description ...of geomechanics based on the hypothesis of oedometric strain is used. To both enhance the modeling of basin history and to characterise actual in situ stresses, the effect of stress redistribution, horizontal stresses, and strain variations during basin history should be considered. To address this point, a coupled basin-geomechanics framework based on a new constitutive law is proposed in this paper using the prototype simulator
A
2
. This framework has been built to provide relevant results for various kinds of basin cases including tectonic loading. A finite strain poromechanical approach is considered along with an modified Drucker–Prager Cap model to describe rock compaction under natural sedimentation, erosion, and tectonics. The constitutive model can be seen as a tensorial extension of the compaction models of Athy or Schneider as it allows to recover the same behaviour in oedometric context. Simple test cases are modeled considering typical sand or shale properties, emphasizing the effect of tectonic loading on the present-day pore pressures and in situ stresses. It appears that even relatively moderate tectonic loading (
5
%
of horizontal strain) can lead to overpressures of several hundreds of bars and to a complete change in in situ stress regime for deeply buried layers (above a depth of 2000 m).
We stabilized the carrier-envelope phase of the pulses emitted by a femtosecond mode-locked laser by using the powerful tools of frequency-domain laser stabilization. We confirmed control of the ...pulse-to-pulse carrier-envelope phase using temporal cross correlation. This phase stabilization locks the absolute frequencies emitted by the laser, which we used to perform absolute optical frequency measurements that were directly referenced to a stable microwave clock.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete ...end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index MI), insulin secretion (IS)/insulin resistance (IR; ΔI0-120/ΔG0-120, ΔIS rate ISR0-120/ΔG0-120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio OR 0.28 95% CI 0.15-0.49; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 95% CI 0.54-0.80), IS (OR 0.61 95% CI 0.50-0.75), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 95% CI 0.19-0.37; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
Objective:
The objective was to test the clinical utility of Quantose MQ to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose MQ is derived from ...fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal.
Research Design and Methods:
Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained.
Results:
Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13–0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose MQ increased in pioglitazone-treated subjects (by 1.45 3.45 mg·min−1·kgwbm−1) (median interquartile range) (P < .001 vs placebo), as did the Matsuda index (by 3.05 4.77 units; P < .0001). Quantose MQ correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose MQ outperformed both Matsuda and fasting insulin in predicting incident diabetes.
Conclusions:
In IGT subjects, Quantose MQ parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose MQ may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.
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