Objective:
White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ...ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
Methods:
We performed a meta‐analysis of genome‐wide association studies (GWASs) for WMH burden in 9,361 stroke‐free individuals of European descent from 7 community‐based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
Results:
We identified 6 novel risk‐associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (pdiscovery = 4.0 × 10−9; preplication = 1.3 × 10−7; pcombined = 4.0 × 10−15). Other SNPs in this region also reaching genome‐wide significance were rs9894383 (p = 5.3 × 10−9), rs11869977 (p = 5.7 × 10−9), rs936393 (p = 6.8 × 10−9), rs3744017 (p = 7.3 × 10−9), and rs1055129 (p = 4.1 × 10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample).
Interpretation:
This large GWAS of WMH burden in community‐based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH. Ann Neurol 2011;69:928–939
Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and ...transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of
loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering proinflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring
loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300, with potential clinical implications on alteration of the immune landscape. SIGNIFICANCE: This study provides insights into the dynamic role of CBP/p300 in the differentiation of Tregs, with potential clinical implications in the alteration of the immune landscape in follicular lymphoma.
Background
Despite efforts to increase participation of adolescents and young adults (AYAs; 15–39 years) in cancer clinical trials (CTs), enrollment remains very low. Even when provided access to ...CTs, AYAs are less likely to participate than children and older adults. A better understanding of oncologist‐ and AYA survivor‐reported barriers, facilitators, and potential areas for CT enrollment improvement is needed.
Procedures
From December 2019 to August 2020, we conducted 43 semi‐structured interviews with oncologists (n = 17) and AYA cancer survivors (n = 26) who were offered and/or participated in CTs at cancer centers in California and Utah. Thematic analyses were used to interpret the findings.
Results
Oncologists identified a lack of available CTs, strict eligibility criteria, lack of awareness of open CTs, and poor communication between pediatric and adult oncologists as major barriers to enrollment. AYA cancer survivors identified financial and psychosocial barriers, and a poor understanding of what a CT means and its potential benefits as barriers to enrollment. Areas for improvement identified by oncologists and AYAs include educational, financial, and psychosocial support to AYAs. Oncologists also emphasized the need to increase CT availability, improve awareness of open CTs, and better communication between both pediatric and adult oncologists and oncologists and AYAs.
Conclusions
For AYAs with cancer, a lack of CT eligibility and physician awareness of open CTs likely factor into their lower CT enrollment. Potential strategies to improve AYA enrollment in CTs require comprehensive collaboration between pediatric and adult institutions, as well as educational, psychosocial, and financial support to AYAs.
Abstract
Background
Households have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the magnitude and ...determinants of household transmission in increasingly vaccinated populations.
Methods
From September 2020 to January 2022, symptomatic nonhospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least 1 other SARS-CoV-2–uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts.
Results
We evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case’s symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45% 95% confidence interval {CI}, 29%–62%), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41% 95% CI, 25%–59%) among all contacts and 12/29 (41% 95% CI, 24%–61%) among vaccinated contacts. At least 1 comorbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts.
Conclusions
Among households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.
Although vaccination prevents infection and severe illness, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 was common among households with symptomatic SARS-CoV-2 infection, particularly during the Delta and Omicron periods. Household contacts will need to employ additional interventions to avoid infection.
Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by ...common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
In the absence of entomological information, tools for predicting
spp. presence can help evaluate the entomological risk of malaria transmission. Here, we illustrate how species distribution models ...(SDM) could quantify potential dominant vector species presence in malaria elimination settings. We fitted a 250 m resolution ensemble SDM for
Wiedemann. The ensemble SDM included predictions based on seven different algorithms, 110 occurrence records and 70 model projections. SDM covariates included nine environmental variables that were selected based on their importance from an original set of 28 layers that included remotely and spatially interpolated locally measured variables for the land surface of Costa Rica. Goodness of fit for the ensemble SDM was very high, with a minimum AUC of 0.79. We used the resulting ensemble SDM to evaluate differences in habitat suitability (HS) between commercial plantations and surrounding landscapes, finding a higher HS in pineapple and oil palm plantations, suggestive of
presence, than in surrounding landscapes. The ensemble SDM suggested a low HS for
at the presumed epicenter of malaria transmission during 2018-2019 in Costa Rica, yet this vector was likely present at the two main towns also affected by the epidemic. Our results illustrate how ensemble SDMs in malaria elimination settings can provide information that could help to improve vector surveillance and control.
Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a ...guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO.
This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO.
There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis.
Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.
Determine the factors associated with mortality in venovenous extracorporeal membrane oxygenation (V-V ECMO) patients with COVID-19 infection and provide an updated report of clinical outcomes for ...patients treated with V-V ECMO for COVID-19 in Minnesota.
Multicenter prospective observational study.
The four adult Extracorporeal Life Support Organization-certified Centers of Excellence in Minnesota.
A total of 100 patients treated with V-V ECMO for COVID-19-associated acute respiratory distress syndrome (ARDS) from March 2020 to May 2021.
Not applicable.
The primary outcome was 60-day survival for patients treated with V-V ECMO for COVID-19. Outcomes of patients treated from November 2020 to May 2021(cohort 2) were compared with data from a previous cohort of patients, collected from March 2020 to October 2020 (cohort 1). The data from both cohorts were merged into a single dataset (Combined Cohort). Survival on V-V ECMO due to COVID-19-associated ARDS significantly decreased after October 2020 (63% vs 41%;
= 0.026). The median interval from hospital admission to V-V ECMO cannulation was significantly associated with 60-day mortality (10 d 6-14 d in nonsurvivors vs 7 d 4-9 d in survivors;
= 0.001) in the Combined Cohort and was also significantly longer in cohort 2 than cohort 1 (10 d 7-14 d vs 6 d 4-10 d;
< 0.001). In the Combined Cohort, the 60-day survival for patients who did not receive steroids was 86% (
= 12) versus 45% (
= 39) for patients who received at least one dose of steroids (
= 0.005).
There was a significant increase in mortality for patients treated with V-V ECMO for COVID-19-associated ARDS in cohort 2 compared with cohort 1. Further research is required to determine the cause of the worsening trend in mortality.
Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric ...patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery).
Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n = 36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n = 53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n = 67) or within 24 hours of negative RT-PCR (n = 43).
Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28-3844 pg/mL (N) and 1.65-1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw.
Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.
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