Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI).
We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 ...preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI).
There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval CI, .14-1.05 in the 1-dose group and .39 95% CI, .14-1.07 in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 95% CI, .73-2.56 in the 1-dose group and 1.69 95% CI, .92-3.08 in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups.
Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts.
NCT02325791.
Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending ...aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.
Characterize complications following uvulopalatopharyngoplasty (UPPP) for obstructive sleep apnea.
Retrospective chart review.
Charts of patients undergoing UPPP at an academic teaching hospital from ...1999 to 2005 were reviewed.
345 consecutive patients (248 inpatients; 97 outpatients) were studied. The most common post-operative complication in the entire study was oxyhemoglobin desaturation (12.8%). Three patients suffered major complications (airway obstruction, pulmonary edema, arrhythmia). Regarding complications limited to the post-anaesthetic care unit alone, only 8.2% of patients had oxyhemoglobin desaturation after discontinuation of oxygen supplementation. Inpatients requiring supplemental oxygen on the ward had significantly higher mean AHI (37.4 vs. 31.4; p=0.05) and BMI (32.3 kg/m(2) vs. 28.9 kg/m(2); p=0.004) than those who did not. Those inpatients who were obese (BMI > 30 kg/m(2)) with an AHI≥22 were associated with an increased risk of requiring oxygen on the ward (odds ratio = 3.48, 95% CI = 1.56 - 7.78).
The incidence of post-UPPP complications is much lower than the literature has historically suggested. Selected patients should be able to safely undergo outpatient UPPP. Patients with higher AHI, higher BMI, or multiple comorbidities are at higher risk for postoperative complications and are most appropriate for overnight monitoring.
Prediction of disease risk is a key component of precision medicine. Common traits such as psychiatric disorders have a complex polygenic architecture, making the identification of a single risk ...predictor difficult. Polygenic risk scores (PRSs) denoting the sum of an individual’s genetic liability for a disorder are a promising biomarker for psychiatric disorders, but they require evaluation in a clinical setting.
We developed PRSs for 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, cross disorder, attention-deficit/hyperactivity disorder, and anorexia nervosa) and 17 nonpsychiatric traits in more than 10,000 individuals from the Penn Medicine Biobank with accompanying electronic health records. We performed phenome-wide association analyses to test their association across disease categories.
Four of the 6 psychiatric PRSs were associated with their primary phenotypes (odds ratios from 1.2 to 1.6). Cross-trait associations were identified both within the psychiatric domain and across trait domains. PRSs for coronary artery disease and years of education were significantly associated with psychiatric disorders, largely driven by an association with tobacco use disorder.
We demonstrated that the genetic architecture of electronic health record–derived psychiatric diagnoses is similar to ascertained research cohorts from large consortia. Psychiatric PRSs are moderately associated with psychiatric diagnoses but are not yet clinically predictive in naïve patients. Cross-trait associations for these PRSs suggest a broader effect of genetic liability beyond traditional diagnostic boundaries. As identification of genetic markers increases, including PRSs alongside other clinical risk factors may enhance prediction of psychiatric disorders and associated conditions in clinical registries.
Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke.
We tested if genetic ...susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6-23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium).
Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21-1.74) higher risk of strokes and 1.44× (95% CI, 1.18-1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 95% CI, 1.03-1.11) and ischemic strokes (odds ratio, 1.09 95% CI, 1.04-1.13).
Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.
Background
Severe alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study.
Objectives
This study aimed to determine the genetic ...variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population‐based cohort study.
Patients/Methods
The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018.
Results
Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss‐of‐function variant. Kaplan‐Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty‐one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non‐benign (PolyPhen‐2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0–10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE.
Conclusions
The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population‐based Swedish study.
Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary ...cancers, beyond known cancer syndromes, have been underexplored.
To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.
We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.
Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study investigates the frequency of a clinically reported variant in PMS2, NM_000535.7:c.2523G>A p.(W841∗), from next-generation sequencing studies in 2 racially diverse cohorts. We identified ...clinical reports of the PMS2 c.2523G>A p.(W841∗)variant in the National Precision Oncology Program’s somatic testing database (n = 25,168). We determined frequency of the variant in germline exome sequencing from the Penn Medicine Biobank (n = 44,256) and in gnomAD. The PMS2 c.2523G>A p.(W841∗) was identified as a homozygous variant on tumor testing in an adult patient of self-identified Black race/ethnicity with no evidence of constitutional mismatch repair deficiency. The variant was clinically reported on 35 total tumor and liquid biopsy tests (0.1%), and all individuals with the variant were of self-identified Black race/ethnicity (0.6% of n = 5787). In the Penn Medicine Biobank and gnomAD, the germline frequency of the variant was reported to be 0.2% and 1.3% in individuals of African genetic ancestry, respectively, and not found in any individuals of European genetic ancestry. The variant is found in a region of PMS2 with 100% homology to the PMS2CL pseudogene. PMS2 c.2523G>A p.(W841∗), when identified, is typically an African-ancestry-specific PMS2CL pseudogene variant, which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.
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