With the goal to generate and characterize the phenotypes of null alleles in all genes within an organism and the recent advances in custom nucleases, genome editing limitations have moved from ...mutation generation to mutation detection. We previously demonstrated that High Resolution Melting (HRM) analysis is a rapid and efficient means of genotyping known zebrafish mutants. Here we establish optimized conditions for HRM based detection of novel mutant alleles. Using these conditions, we demonstrate that HRM is highly efficient at mutation detection across multiple genome editing platforms (ZFNs, TALENs, and CRISPRs); we observed nuclease generated HRM positive targeting in 1 of 6 (16%) open pool derived ZFNs, 14 of 23 (60%) TALENs, and 58 of 77 (75%) CRISPR nucleases. Successful targeting, based on HRM of G0 embryos correlates well with successful germline transmission (46 of 47 nucleases); yet, surprisingly mutations in the somatic tail DNA weakly correlate with mutations in the germline F1 progeny DNA. This suggests that analysis of G0 tail DNA is a good indicator of the efficiency of the nuclease, but not necessarily a good indicator of germline alleles that will be present in the F1s. However, we demonstrate that small amplicon HRM curve profiles of F1 progeny DNA can be used to differentiate between specific mutant alleles, facilitating rare allele identification and isolation; and that HRM is a powerful technique for screening possible off-target mutations that may be generated by the nucleases. Our data suggest that micro-homology based alternative NHEJ repair is primarily utilized in the generation of CRISPR mutant alleles and allows us to predict likelihood of generating a null allele. Lastly, we demonstrate that HRM can be used to quickly distinguish genotype-phenotype correlations within F1 embryos derived from G0 intercrosses. Together these data indicate that custom nucleases, in conjunction with the ease and speed of HRM, will facilitate future high-throughput mutation generation and analysis needed to establish mutants in all genes of an organism.
•Menopausal symptoms are experienced at different rates among religious groups.•High prevalence of hot flashes among Baptists women is linked to higher rates of smoking and a high body mass ...index.•Lifestyle factors in certain religious groups should be considered when treating menopausal symptoms.
This study's aim is to examine patterns of menopause symptoms and attitudes among United States women from different religious affiliations.
We used data from a national sample of midlife and older adults. For this analysis, we included only women who were postmenopausal or had undergone hysterectomy. We constructed univariate and multivariate logistic regression models to examine the relationship between religious affiliation and menopause symptoms and attitudes while adjusting for potential confounders.
Menopause symptoms (hot flashes, pain in sexual interactions, pleasure in sexual interactions, trouble falling asleep) and attitudes (relief on periods stopping, regret on periods stopping, worry about becoming less attractive) measured by self-report on Likert scales.
Across denominations, 47 % of women experienced hot flashes, 48 % experienced pain in sexual interactions, 95 % experienced pleasure, and 88 % had trouble falling asleep. Regarding attitudes towards menopause and aging, 62 % felt relief in their periods stopping, while 56 % expressed worry about becoming less attractive with aging. Baptist women were more likely to experience hot flashes and trouble falling asleep compared to Catholic women. However, when adjusted for smoking status, this relationship did not persist. Unaffiliated and Spiritual women were less likely to experience trouble falling asleep and more likely to report pleasure in sexual interactions compared to Catholic women. Spiritual women were significantly more likely to feel regret on periods stopping compared to Catholics.
There is a relationship between religious affiliation and the menopause experience. These findings demonstrate the importance of considering social influences on women's health.
Highlights • Sex is an important component of overall well-being, but sexual dysfunction is common in midlife women. • A holistic, biopsychosocial approach is necessary to guide research and clinical ...care regarding women’s sexual function. • Longitudinal studies reveal an association between advancing menopause status and worsening sexual function. • Future research should focus on how sexual function changes with aging and treatments for sexual dysfunction in older women.
Table of Contents Preamblee79 Introductione81 Methodology and Evidence Reviewe81 Organization of the GWCe82 Document Review and Approvale82 Scope of the CPGe82 Definitions of Urgency and Riske83 ...Clinical Risk Factorse83 Coronary Artery Diseasee83 Heart Failuree85 Role of HF in Perioperative Cardiac Risk Indicese85 Risk of HF Based on Left Ventricular Ejection Fraction: Preserved Versus Reducede85 Risk of Asymptomatic Left Ventricular Dysfunctione85 Role of Natriuretic Peptides in Perioperative Risk of HFe86 Cardiomyopathye86 Valvular Heart Disease: Recommendationse87 Aortic Stenosis: Recommendatione87 Mitral Stenosis: Recommendatione88 Aortic and Mitral Regurgitation: Recommendationse88 Arrhythmias and Conduction Disorderse88 Cardiovascular Implantable Electronic Devices: Recommendatione89 Pulmonary Vascular Disease: Recommendationse90 Adult Congenital Heart Diseasee90 Calculation of Risk to Predict Perioperative Cardiac Morbiditye90 Multivariate Risk Indices: Recommendationse90 Inclusion of Biomarkers in Multivariable Risk Modelse91 Approach to Perioperative Cardiac Testinge91 Exercise Capacity and Functional Capacitye91 Stepwise Approach to Perioperative Cardiac Assessment: Treatment Algorithme93 Supplemental Preoperative Evaluatione95 The 12-Lead Electrocardiogram: Recommendationse95 Assessment of LV Function: Recommendationse96 Exercise Stress Testing for Myocardial Ischemia and Functional Capacity: Recommendationse97 Cardiopulmonary Exercise Testing: Recommendatione97 Pharmacological Stress Testinge97 Noninvasive Pharmacological Stress Testing Before Noncardiac Surgery: Recommendationse97 Radionuclide MPIe98 Dobutamine Stress Echocardiographye98 Stress Testing--Special Situationse99 Preoperative Coronary Angiography: Recommendatione99 Perioperative Therapye99 Coronary Revascularization Before Noncardiac Surgery: Recommendationse100 Timing of Elective Noncardiac Surgery in Patients With Previous PCI: Recommendationse115 Future Research Directionse116 Referencese117 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)e129 Appendix 2 Reviewer Relationships With Industry and Other Entities (Relevant)e131 Appendix 3 Related Recommendations From Other CPGse136 Appendix 4 Abbreviationse137 Preamble The American College of Cardiology (ACC) and the American Heart Association (AHA) are committed to the prevention and management of cardiovascular diseases through professional education and research for clinicians, providers, and patients. Since 1980, the ACC and AHA have shared a responsibility to translate scientific evidence into clinical practice guidelines (CPGs) with recommendations to standardize and improve cardiovascular health.
The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although ...improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear.
Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years.
CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death.
The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).
The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a ...survival benefit. However, the efficacy of this approach is uncertain.
In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds.
Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval CI, 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).
The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).
Sister chromatid cohesion (SCC) is an important process in chromosome segregation. ESCO2 is essential for establishment of SCC and is often deleted/altered in human cancers. We demonstrate that esco2 ...haploinsufficiency results in reduced SCC and accelerates the timing of tumor onset in both zebrafish and mouse p53 heterozygous null models, but not in p53 homozygous mutant or wild-type animals. These data indicate that esco2 haploinsufficiency accelerates tumor onset in a loss of heterozygosity (LOH) sensitive background. Analysis of The Cancer Genome Atlas (TCGA) confirmed ESCO2 deficient tumors have elevated number of LOH events throughout the genome. Further, we demonstrated heterozygous loss of sgo1, important in maintaining SCC, also results in reduced SCC and accelerated tumor formation in a p53 heterozygous background. Surprisingly, while we did observe elevated levels of chromosome missegregation and micronuclei formation in esco2 heterozygous mutant animals, this chromosomal instability did not contribute to the accelerated tumor onset in a p53 heterozygous background. Interestingly, SCC also plays a role in homologous recombination, and we did observe elevated levels of mitotic recombination derived p53 LOH in tumors from esco2 haploinsufficient animals; as well as elevated levels of mitotic recombination throughout the genome of human ESCO2 deficient tumors. Together these data suggest that reduced SCC contributes to accelerated tumor penetrance through elevated mitotic recombination.
Women often undergo physical changes during the menopause transition, but the relationship between body image and sexual function in midlife is unclear. We used a qualitative approach to explore how ...body image relates to sexual function and satisfaction in midlife women.
We conducted 19 individual interviews and 3 focus groups (total N = 39) among sexually active women 45-60 years of age using a semistructured guide. Sessions were audiorecorded and transcribed. Two investigators developed a codebook using an iterative process; the primary investigator then coded all data. Codes relating to body image were examined to identify key themes.
The mean age was 58 (range 46-59); 54% were White, 36% Black, and 10% were of another race. Most (72%) were peri- or postmenopausal. All but two women identified as heterosexual. Feeling attractive was an important reason for sexual activity. Changes in appearance, especially weight gain and breast changes, were common among these women. Women's body image impacted their sexual satisfaction; women who felt self-conscious about their bodies reported that these concerns had a negative impact on their sexual satisfaction, whereas women who felt confident discussed better sexual satisfaction, even in the face of bodily changes. Black women were more likely to discuss feeling confident than White women.
Feeling attractive is important to sexual satisfaction in midlife women. Bodily changes, especially weight gain, are common during midlife. While many women are self-conscious about their appearance, some women develop increased self-acceptance. Supporting positive body image may help midlife women maintain sexual satisfaction with aging.
Recommendations2389 Future Research Directions2389 References2390 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)2397 Appendix 2 Reviewer Relationships With Industry and ...Other Entities (Relevant)2399 Appendix 3 Related Recommendations From Other CPGs2404 Preamble The American College of Cardiology (ACC) and the American Heart Association (AHA) are committed to the prevention and management of cardiovascular diseases through professional education and research for clinicians, providers, and patients. Since 1980, the ACC and AHA have shared a responsibility to translate scientific evidence into clinical practice guidelines (CPGs) with recommendations to standardize and improve cardiovascular health. Harm B (187,211,218,219,224-227,238) Table A Left Main CAD Revascularization Recommendations From the 2011 CABG and PCI CPGs CABG indicates coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; COR, Class of Recommendation; CPG, clinical practice guideline; EF, ejection fraction; LAD, left anterior descending; LIMA, left internal mammary artery; LOE, Level of Evidence; LV, left ventricular; N/A, not applicable; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; STEMI, ST-elevation myocardial infarction; STS, Society of Thoracic Surgeons; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; TIMI, Thrombolysis In Myocardial Infarction; UA/NSTEMI, unstable angina/non-ST-elevation myocardial infarction; UPLM, unprotected left main disease; and VT, ventricular tachycardia.
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