De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females

Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.     

Impact of Race and Socioeconomic Status on Outcomes in Patients Hospitalized with COVID-19

BackgroundThe impact of race and socioeconomic status on clinical outcomes has not been quantified in patients hospitalized with coronavirus disease 2019 (COVID-19).ObjectiveTo evaluate the association between patient sociodemographics and neighborhood disadvantage with frequencies of death, invasive mechanical ventilation (IMV), and intensive care unit (ICU) admission in patients hospitalized with COVID-19.DesignRetrospective cohort study.SettingFour hospitals in an integrated health system serving southeast Michigan.ParticipantsAdult patients admitted to the hospital with a COVID-19 diagnosis confirmed by polymerase chain reaction.Main MeasuresPatient sociodemographics, comorbidities, and clinical outcomes were collected. Neighborhood socioeconomic variables were obtained at the census tract level from the 2018 American Community Survey. Relationships between neighborhood median income and clinical outcomes were evaluated using multivariate logistic regression models, controlling for patient age, sex, race, Charlson Comorbidity Index, obesity, smoking status, and living environment.Key ResultsBlack patients lived in significantly poorer neighborhoods than White patients (median income: $34,758 (24,531–56,095) vs. $63,317 (49,850–85,776), p < 0.001) and were more likely to have Medicaid insurance (19.4% vs. 11.2%, p < 0.001). Patients from neighborhoods with lower median income were significantly more likely to require IMV (lowest quartile: 25.4%, highest quartile: 16.0%, p < 0.001) and ICU admission (35.2%, 19.9%, p < 0.001). After adjusting for age, sex, race, and comorbidities, higher neighborhood income ($10,000 increase) remained a significant negative predictor for IMV (OR: 0.95 (95% CI 0.91, 0.99), p = 0.02) and ICU admission (OR: 0.92 (95% CI 0.89, 0.96), p < 0.001).ConclusionsNeighborhood disadvantage, which is closely associated with race, is a predictor of poor clinical outcomes in COVID-19. Measures of neighborhood disadvantage should be used to inform policies that aim to reduce COVID-19 disparities in the Black community.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06527-1.KEY WORDS: COVID-19, disparities, disadvantage, socioeconomic status, race     

High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study

Background

As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.

Methods

Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.

Results

Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.

Conclusions

Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.

     

Improving the Gastrointestinal Tolerability of Aspirin in Older People

Interventions to reduce mortality and disability in older people are vital. Aspirin is cheap and effective and known to prevent cardiovascular and cerebrovascular disease, many cancers, and Alzheimer dementia. The widespread use of aspirin in older people is limited by its gastrointestinal side effects. Understanding age-related changes in gastrointestinal physiology that could put older people at risk of the side effects of aspirin may direct strategies to improve tolerance and hence lead to greater numbers of older people being able to take this effective intervention.     

Relationship of systolic BP to obstructive sleep apnea in patients with heart failure

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is an independent risk factor for hypertension in the general population. Hypertension is, in turn, an important risk factor for the development and progression of congestive heart failure (CHF). Our objective was to determine whether OSA would be associated with elevated daytime BP in medically treated patients with CHF. DESIGN: Cross-sectional study. SETTING: Tertiary care, university-affiliated sleep disorders and heart failure clinics. PATIENTS: Three hundred one consecutive patients with CHF. MEASUREMENTS AND RESULTS: We measured daytime BP and performed overnight sleep studies to assess for the presence of OSA. Among these patients, OSA was present in 121 patients (40%) and their systolic BP was significantly higher than in patients without OSA. Patients with OSA were 2.89 times (95% confidence interval, 1.25 to 6.73) more likely to have systolic hypertension (ie, BP > or = 140 mm Hg) than those without OSA after controlling for other risk factors, including obesity. The degree of systolic BP elevation was directly related to the frequency of obstructive apneas and hypopneas. CONCLUSIONS: In medically treated patients with CHF, daytime systolic BP and the prevalence of systolic hypertension are significantly increased in patients with OSA, compared to those without OSA, independent of other potentially confounding factors. OSA may therefore have contributed to the presence of systolic hypertension in some of these patients.