The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Racial and ethnic differences in contraceptive use among women who desire no future children, 2006–2010 National Survey of Family Growth

ObjectiveTo evaluate racial/ethnic differences in contraceptive use among women who do not desire future pregnancy.Study designWe used the 2006-2010 National Survey of Family Growth to examine the associations between race/ethnicity and 1) use of any contraceptive method at last heterosexual intercourse and 2) effectiveness of contraceptive method used among women who stated that they did not desire any (more) children. We conducted multivariable logistic regression to assess the independent effect of race/ethnicity on these outcomes, adjusting for socio-demographic factors, reproductive characteristics, and indicators of healthcare access and utilization.ResultsThe study sample consisted of 2900 women, aged 15-44 years. The vast majority of women (91.2%) used contraception at last sex, although this varied significantly by race/ethnicity (p<.01). In the fully adjusted model controlling for demographic and reproductive characteristics as well as healthcare access, compared to whites, black women were significantly less likely to use any contraception at last sex (OR: 0.43; 95% CI: 0.27-0.73), while there was no significant difference for Hispanic women (OR: 0.95; 95% CI: 0.52-1.72). Among women who used a method at last sex, the type of contraceptive method varied significantly by race/ethnicity in bivariate analysis (p<.01), although most women (59%) used a highly effective method. In the fully adjusted model, racial/ethnic differences were no longer significant.ConclusionsIn this nationally representative cohort of women who report that they do not desire (more) children, black women were significantly less likely than white women to use any contraception at last intercourse; this difference did not appear to be due to differential access to health care.ImplicationsSignificant racial/ethnic differences exist in contraceptive use among women who have completed childbearing, which do not appear to be explained by differential socioeconomic status, reproductive characteristics or utilization of healthcare. Other factors, including social mobility and locus of reproductive control, that may contribute to these variations should be further explored

Does a History of Unintended Pregnancy Lessen the Likelihood of Desire for Sterilization Reversal?

BackgroundUnintended pregnancy has been significantly associated with subsequent female sterilization. Whether women who are sterilized after experiencing an unintended pregnancy are less likely to express desire for sterilization reversal is unknown.MethodsThis study used national, cross-sectional data collected by the 2006-2010 National Survey of Family Growth. The study sample included women ages 15-44 who were surgically sterile from a tubal sterilization at the time of interview. Multivariable logistic regression was used to examine the relationship between a history of unintended pregnancy and desire for sterilization reversal while controlling for potential confounders.ResultsIn this nationally representative sample of 1,418 women who were sterile from a tubal sterilization, 78% had a history of at least one unintended pregnancy and 28% expressed a desire to have their sterilization reversed. In unadjusted analysis, having a prior unintended pregnancy was associated with higher odds of expressing desire for sterilization reversal (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.15-2.79). In adjusted analysis controlling for sociodemographic factors, unintended pregnancy was no longer significantly associated with desire for reversal (OR: 1.46; 95% CI: 0.91-2.34).ConclusionAmong women who had undergone tubal sterilization, a prior history of unintended pregnancy did not decrease desire for sterilization reversal

Medicinal and Recreational Marijuana Use Among HIV-Infected Women in the Women's Interagency HIV Study (WIHS) Cohort, 1994–2010

BackgroundDespite the major benefits of effective antiretroviral therapy on HIV-related survival, there is an ongoing need to help alleviate medication side effects related to antiretroviral therapy use. Initial studies suggest that marijuana use may reduce HIV-related symptoms, but medical marijuana use among HIV-infected individuals has not been well described.MethodsThe authors evaluated trends in marijuana use and reported motivations for use among 2776 HIV-infected women in the Women's Interagency HIV Study between October 1994 and March 2010. Predictors of any and daily marijuana use were explored in multivariate logistic regression models clustered by person using generalized estimating equation. In 2009, participants were asked if their marijuana use was medical, "meaning prescribed by a doctor," or recreational, or both.ResultsOver the 16 years of this study, the prevalence of current marijuana use decreased significantly from 21% to 14%. In contrast, daily marijuana use almost doubled from 3.3% to 6.1% of all women and from 18% to 51% of current marijuana users. Relaxation, appetite improvement, reduction of HIV-related symptoms, and social use were reported as common reasons for marijuana use. In 2009, most marijuana users reported either purely medicinal use (26%) or both medicinal and recreational usage (29%). Daily marijuana use was associated with higher CD4 cell count, quality of life, and older age. Demographic characteristics and risk behaviors were associated with current marijuana use overall but were not predictors of daily use.ConclusionsThis study suggests that both recreational and medicinal marijuana use are relatively common among HIV-infected women in the United States

Does a History of Unintended Pregnancy Lessen the Likelihood of Desire for Sterilization Reversal?

BACKGROUND: Unintended pregnancy has been significantly associated with subsequent female sterilization. Whether women who are sterilized after experiencing an unintended pregnancy are less likely to express desire for sterilization reversal is unknown. METHODS: This study used national, cross-sectional data collected by the 2006–2010 National Survey of Family Growth. The study sample included women ages 15–44 who were surgically sterile from a tubal sterilization at the time of interview. Multivariable logistic regression was used to examine the relationship between a history of unintended pregnancy and desire for sterilization reversal while controlling for potential confounders. RESULTS: In this nationally representative sample of 1,418 women who were sterile from a tubal sterilization, 78% had a history of at least one unintended pregnancy and 28% expressed a desire to have their sterilization reversed. In unadjusted analysis, having a prior unintended pregnancy was associated with higher odds of expressing desire for sterilization reversal (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.15–2.79). In adjusted analysis controlling for sociodemographic factors, unintended pregnancy was no longer significantly associated with desire for reversal (OR: 1.46; 95% CI: 0.91–2.34). CONCLUSION: Among women who had undergone tubal sterilization, a prior history of unintended pregnancy did not decrease desire for sterilization reversal

Racial and ethnic differences in contraceptive use among women who desire no future children, 2006–2010 National Survey of Family Growth

OBJECTIVE: To evaluate racial/ethnic differences in contraceptive use among women who do not desire future pregnancy. STUDY DESIGN: We used the 2006–2010 National Survey of Family Growth to examine the associations between race/ethnicity and 1) use of any contraceptive method at last heterosexual intercourse and 2) effectiveness of contraceptive method used among women who stated that they did not desire any (more) children. We conducted multivariable logistic regression to assess the independent effect of race/ethnicity on these outcomes, adjusting for socio-demographic factors, reproductive characteristics, and indicators of healthcare access and utilization. RESULTS: The study sample consisted of 2,900 women, aged 15–44 years. The vast majority of women (91.2%) used contraception at last sex, although this varied significantly by race/ethnicity (p<0.01). In the fully adjusted model controlling for demographic and reproductive characteristics as well as healthcare access, compared to whites, black women were significantly less likely to use any contraception at last sex (OR: 0.43; 95% CI:0.27–0.73), while there was no significant difference for Hispanic women (OR:0.95; 95% CI:0.52–1.72). Among women who used a method at last sex, the type of contraceptive method varied significantly by race/ethnicity in bivariate analysis (p<0.01), although most women (59%) used a highly effective method. In the fully adjusted model, racial/ethnic differences were no longer significant. CONCLUSIONS: In this nationally-representative cohort of women who report that they do not desire (more) children, black women were significantly less likely than white women to use any contraception at last intercourse; this difference did not appear to be due to differential access to healthcare. IMPLICATIONS: Significant racial/ethnic differences exist in contraceptive use among women who have completed childbearing, which do not appear to be explained by differential socioeconomic status, reproductive characteristics, or utilization of healthcare. Other factors, including social mobility and locus of reproductive control, that may contribute to these variations should be further explored