· As in Eq., the coefficient γ 1 in Eq. was significant and positive, γ , t(35) = , p, and the coefficient γ 2 was significant and negative, γ 2 = −, t(Coefficient γ 3 was marginally significant and positive, γ , t(35) = , p, indicating that participants were (marginally) more likely to experience distress after breakup to the extent that they had · One of the most unique affordances of online dating is the ability to determine compatibility levels with potential partners through online interaction before deciding whether to meet them FtF (Finkel et al., ). One must consider, then, how this type of meeting might alter the outcomes of online dating blogger.com by: 93 · Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this
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For more information about PLOS Subject Areas, click here. An association between testosterone therapy TT and cardiovascular disease has been reported and TT use is increasing rapidly. In men aged 65 years and older, the RR was 2. The RR for Finkel et al online dating prescription increased with age from 0.
In men under age 65 years, excess risk was confined to those with a prior history of heart disease, finkel et al online dating, with RRs of 2.
In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased. Citation: Finkle WD, Greenland S, Finkel et al online dating GK, Adams JL, Frasco MA, Cook MB, et al.
PLoS ONE 9 1 : e Editor: Yan Gong, College of Pharmacy, University of Florida, United States of America. Received: August 9, ; Accepted: December 2, ; Published: January 29, This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This study was supported by the Intramural Research Program of the National Cancer Institute.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors would like to clarify the Competing Interests Section to state that 1 William Finkle is owner of Consolidated Research Inc. CRI 2 John Adams, Sander Greenland, Gregory Ridgeway and Melissa Frasco are consultants to CRI.
These affiliations do not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Testosterone therapy TT has been used in healthy older men to treat diminished extremity strength and physical function associated an age-related decline in serum testosterone.
In a small randomized trial of testosterone gel on muscle function in men 65 years of age or older was discontinued due to an excess of a variety of cardiovascular events in the testosterone arm. In all 3 studies, combined cardiovascular disease endpoints were used since individual outcomes, particularly severe events, were too few to evaluate. Perhaps because of this, or for other factors, the point estimates of risks were also divergent among the studies, with hazard ratios ranging from less than 1.
All of these studies also recognized the importance of evaluating risk among those men with and without preexisting heart disease, but did not have sufficient numbers of subjects to adequately assess this issue.
All three studies were also predominantly of older men, and unable to address risks in younger men where the increases in prescriptions have been the most dramatic. Therefore, using a large healthcare database, we evaluated the hypotheses that TT might increase the risk of acute non-fatal myocardial infarction MIand that this effect might also be particularly strong finkel et al online dating those with pre-existing cardiac disease.
We also explored whether these same effects finkel et al online dating apply to younger men as well. The Truven Health MarketScan® Commercial Claims and Encounters Database includes employees, dependents and retirees with commercial or Medicare insurance whose employers license healthcare data to Truven Health Analytics Truven.
The MarketScan data contributors include Fortune employers 60 percent and health plans covering numerous other finkel et al online dating and unions 40 percent. The data include diagnoses, procedures, finkel et al online dating, and prescriptions finkel et al online dating all enrollees.
Enrollees in are distributed regionally within the U. as Northeast 24 percentNorth Central 37 percentSouth 20 percentand West 19 percent. We used the data from toincluding patient-specific enrollment history, year of birth, gender, inpatient and outpatient diagnoses ICD-9 codes and treatments, and outpatient prescriptions. The data for the study were hosted in secure facilities of Consolidated Research, Inc.
CRIas required by the Agreement between CRI Los Angeles, California and Truven Health Analytics Ann Arbor, Michigan. We received IRB exemption for this study from the NIH Office of Human Subjects Research Protections OHSRP since the study was conducted in claims data that were anonymized or de-identified by Truven prior to release. The database is available from Truven under licensing agreements similar to ours.
We formed cohorts from the database from men with a minimum of 22 months of continuous enrollment for analyses with post-prescription follow-up intervals of 90 days, and 25 months for analyses with post prescription follow-up intervals of 91 to days. We did not have data on how much of the prescribed medication was consumed. The most common TT prescriptions were testosterone gel, testosterone micronized, testosterone cypionate, and testosterone transdermal system.
We selected men receiving PDE5I prescriptions as a comparison group because some indications for prescription are similar to those for TT prescription. In addition, PDE5I is commonly prescribed to older men, does not have androgenic effects, and is not metabolized to other sex steroid hormones, such as dihydrotestosterone or estrogens.
Also, while PDE5I is recommended for men healthy enough to engage in sexual activity, the drugs themselves, after extensive scrutiny, finkel et al online dating, have not been associated with adverse cardiovascular events [9]. The covariates were those recorded in the 18 to 12 month interval prior to the initial prescription for TT prescription or PDE5I. The pre-prescription interval was the one year prior to the initial prescription, the post-prescription interval was 90 days following the initial prescription, thus the prescription cohorts were restricted to those men with a minimum of 18 months enrollment prior to and three months after their initial prescription.
In the post-prescription interval, patients were followed until a diagnosis of acute non-fatal myocardial infarction, refilled first prescription, or 90 days following initial prescription, whichever occurred first. For those who did not refill their initial prescription, we analyzed an additional day interval 91— days post-prescriptiona time when this group likely had minimal use of these drugs.
A refill and a subsequent prescription were treated equally in the analysis. Patients with first prescriptions for both TT prescription and PDE5I during follow-up were excluded from this analysis. The study outcome was a diagnosis of acute MI ICD Men with a history of MI prior to the first prescription for TT or PDE5I were excluded from the post-prescription analyses. Age at the time of initial prescription was included as a covariate. Diagnostic covariates were identified by the ICD 9 codes recorded for inpatient or outpatient diagnoses, reported to be associated with MI, [10] including angina, arrhythmia, heart disease, prior MI, heart failure, hypertension, hyperlipidemia, stroke, peripheral vascular disease, cerebrovascular disease, transient ischemic attack, renal disease, obesity, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, alcohol-induced liver disease, alcohol dependence, and rheumatoid arthritis, osteoarthritis and arthritis NOS.
Full descriptive tabulations are provided as supplementary material. We examined risk of MI with TT prescription in all subjects. Since previous studies indicated that cardiovascular events appeared early in treatment, finkel et al online dating, we focused on the 90 day interval following the filling of a first prescription.
For those who did not refill their prescription, we also assessed the interval of 91— days, finkel et al online dating. To examine potential effect modification by pre-existing disease, we estimated the effect of TT prescription by prior history of a heart disease diagnosis ICD— We also examined the RR for PDE5I and compared the RRs in the TT prescription and PDE5I cohorts.
To estimate the effect of TT prescription relative to PDE5I, we weighted the PDE5I patients with weights derived from propensity scores, specifically their estimated odds of being prescribed TT prescription rather than PDE5I.
These weights were then used in a Poisson regression model for the MI rate to obtain doubly robust estimates of effect. We also estimated the ratio of rate ratios RRR. This measure adjusts the post-prescription rate ratio for the corresponding rate ratio in the pre-prescription interval, and also controls finkel et al online dating any differences in ascertainment between the pre- and post-prescription periods.
It is intended to account for otherwise uncontrolled differences in the baseline rates of the cohorts. We estimated RRR from a Poisson regression model with MI as the outcome, log-exposure time as an offset, a drug indicator, and the patient features listed above.
Since pre-prescription rates were weighted to be identical, finkel et al online dating, the finkel et al online dating of the product of the indicator variables for the prescription type is the natural logarithm of RRR, finkel et al online dating. All statistical analyses were conducted using the STARx and SAS software packages STARx, CRI, Los Angeles, California, SAS 9.
In men aged 65 years and older the RR was 2. The difference in RR between men 65 and older and those under 65 reflects a broader trend of increasing RR with increasing age. The RRs were 0. Men aged 65 years and older, whose follow-up was not right-censored because they did not refill their prescription, were followed for an additional 90 day period 91— days post-prescription during which the RR was 0.
In men under age 65 the corresponding RR was 1. For the comparison group of PDE5I users, the baseline distributions of prior cardiovascular diagnoses, risk factors, and medication use were less common than in the TT prescription cohort, but after weighting, the distributions of covariates in each prescription cohort were nearly identical Table 2.
This procedure also resulted in the same adjusted pre-prescription rates of MI in both prescription groups: 3. When the data were stratified into ages 65 years and older and less than age 65 years, weighting also achieved nearly identical distributions of the covariates between the TT and PDE5I cohorts for each age group Tables S1 and S2.
In men aged 65 years and older, the adjusted RR for PDE5I was 1. The adjusted ratio of the rate ratios RRRs comparing those for TT prescription to those for PDE5I were 1.
The data for both prescription groups were also divided into men with a previously recorded diagnosis of any heart disease, finkel et al online dating, and those without Table 4. For TT prescription, in men under age 65 years, the RR was 2. In men aged 65 year and older, the RR was 2. The comparable RRs for PDE5I for those under age 65 years were 1. For PDE5I among those aged 65 years and older, the RR was 1.
The corresponding RRRs for TT prescription compared to PDE5I were 2. As odds-of-treatment weighting is less familiar than unweighted regression methods, we also examined the effect of controlling for the covariates using an unweighted Poisson regression.
In subjects aged 65 years and older, the RRR was 2. The lower estimates suggest that weighting in the primary analysis helped reduce possible upward confounding. Among men aged 65 years and older, we observed a two-fold increase in the risk of MI in the 90 days after filling an initial TT finkel et al online dating, the risk declined to baseline in the 91 to days after initial TT prescription, among those who did not refill their prescription. Since we censored follow-up at the first refill, and the supply for most prescriptions was 30 to 90 days, it is likely that there was little use of the medication in the 91 to day post-prescription interval when the risk declined.
Thus, the pattern of change in risk by supply of testosterone is consistent with an effect of the drug, and underscores the concerns raised by three recent studies in predominantly older men [4] — [6].
Among younger men with a history of heart disease, we observed a two to three-fold increased risk of MI in the 90 days following an initial TT prescription and no excess risk in younger men without such a history.
Among older men, the two-fold increased risk was associated with TT prescription finkel et al online dating of cardiovascular disease history, although this analysis was based on relatively small numbers of MI cases in each subgroup, finkel et al online dating. More relevant perhaps is the rapid increase with age in the prevalence of diagnosed and undiagnosed coronary artery disease reported from autopsy studies, both overall and among accident victims, [14][15] so that advanced age may be a more sensitive indicator of coronary disease prevalence than prior diagnoses.
However, since that study had less than men with normal coronary arteries, they likely had insufficient statistical precision to address this question. Overall, finkel et al online dating, our own findings appear consistent with a higher frequency of thrombotic events following TT prescription among men with more extensive coronary vascular disease. A majority of the included studies were of men whose serum androgen levels were deemed to be below normal physiological levels hypogonadism.
Taken together, finkel et al online dating, the evidence supports an association between testosterone therapy and risk of serious, finkel et al online dating, adverse cardiovascular-related events—including non-fatal myocardial infarction—in men. However, there is some evidence that low endogenous testosterone levels may also be positively associated with cardiovascular events [16]finkel et al online dating, [17].
But, as extensively reviewed by Xu et al. Exogenous testosterone TT is associated with physiologic changes that predispose to clotting and thrombotic disorders finkel et al online dating increased blood pressure [18]polycythemia [19]reductions in HDL cholesterol [18][20]and hyperviscosity of the blood and platelet aggregation.
Despite plausible biologic mechanisms linking TT prescription to an elevated risk of MI, our study has limitations related to use of a health-care database that did not include information on the serologic or diagnostic indications for treatment. However, the accuracy of an MI diagnosis is considered to be reliable in such databases, [31] and the established risk factors for MI apply to both fatal and non-fatal events.
· Furthermore, as the “evidentiary value movement” (Finkel et al., ) makes inroads in the empirical sciences, color scientists would do well to be at the leading edge of implementing such rigorous practices as publically archiving research materials and data, designating exploratory from confirmatory analyses, supplementing or even replacing significant testing with “new statistics · Finkel, Y. et al. Comprehensive annotations of human herpesvirus 6A and 6B genomes reveal novel and conserved genomic features. eLife 9, e (). CAS Article Google Scholar · Why Physical Attraction Matters, and When It Might Not Research into why our actions don't match our words when it's time to pair up. Posted Jan 05,
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