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STUDY QUESTIONAre rare genetic variants in the conceptus associated with chromosomally normal pregnancy loss?SUMMARY ANSWERThe proportion of probands with at least one rare variant is increased in chromosomally normal loss conceptuses compared with controls.WHAT IS ALREADY KNOWNAmong non-consanguineous families, one study of seven chromosomally normal losses to four couples with recurrent pregnancy loss (RPL) and a case report of a family with RPL of which one was known to be chromosomally normal identify compound heterozygote variants in three different genes as possibly causal. Among consanguineous families, RPL of chromosomally normal pregnancies with non-immune hydrops fetalis (NIHF) has been attributed to recessive variants in genes previously implicated for NIHF and new candidate genes.STUDY DESIGN, SIZE, DURATIONThe starting sample was 52 chromosomally normal losses to 50 women, identified in 2003-2005 as part of a cohort study on trisomy and ovarian aging. The analytic sample comprises 19 conceptus-parent trios with DNA from 17 biologic parents (cases). The control group derives from the National Institutes of Mental Health’s National Database for Autism Research (NDAR). It comprises 547 trios of unaffected siblings of autism cases and their parents.PARTICIPANTS/MATERIALS, SETTING, METHODSWe use exome sequencing to identify rare variants in the coding region of the genome. We defined variant rarity in two ways: ultra-rare (absent in gnomAD) and rare (heterozygote −3in gnomAD). For autosomal recessives, we further required that the variant was absent as a homozygote in gnomAD. We compare the rates of rare predicted damaging variants (loss of function and missense – damaging) and the proportions of probands with at least one such variant in cases versus controls. Secondarily, 1) we repeat the analysis limiting it to variants in genes considered causal in fetal anomalies and 2) we compare the proportions of cases and controls with damaging variants in genes which we classified as possibly embryonic lethal based on a review which was blinded to case-control status.MAIN RESULTS AND THE ROLE OF CHANCEThe rates of ultra-rare damaging variants (allde novo) are 0.21 and 0.17 in case and control probands, respectively. The corresponding rates for rare potentially pathogenicde novovariants are 0.37 and 0.24, respectively; for autosomal recessive variants they 0.11 and 0.03. The proportions of probands with at least one rare potentially damaging variant were 36.8% among cases and 22.9% among controls (odds ratio (OR) = 2.0, 95% CI 0.9, 3.0). Secondary analyses show no damaging variants in fetal anomaly genes among case probands; the proportion with variants in possibly embryonic lethal genes was increased in case probands (OR=14.5, 95% CI 3.4, 61.1). Cases had variants in possibly embryonic lethal genesBAZ1A, FBN2andTIMP2. Post hocreview of these cases suggests thatCDH5may also be an embryonic lethal gene.LIMITATIONS, REASONS FOR CAUTIONThe number of case trios (n=19) limits the precision of our point estimates. We observe a moderate association between rare damaging variants and chromosomally normal loss with a confidence interval that includes unity. A larger sample is needed to estimate the magnitude of the association with precision and to identify the relevant biological pathways.WIDER IMPLICATIONS OF THE FINDINGSOur data add to a very small literature on this topic. They suggest rare genetic variants in the conceptus may be a cause of chromosomally normal loss.TRIAL REGISTRATION NUMBERN/A.STUDY FUNDING/COMPETING INTERESTS(S)Exome sequencing of case trios was performed by Baylor-Hopkins Center for Mendelian Genomics through National Human Genome Research Institute grant 5U54HG006542.Data used in the preparation of this manuscript were obtained from the National Institute of Mental Health (NIMH) Data Archive (NDA). NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s): src_subject_id. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDA.No author has a competing interest.

IMPORTANCE: Influenza is associated with an increased risk of cardiovascular events, but to our knowledge, few studies have explored the temporal association between influenza activity and hospitalizations, especially those caused by heart failure (HF). OBJECTIVE: To explore the temporal association between influenza activity and hospitalizations due to HF and myocardial infarction (MI). We hypothesized that increased influenza activity would be associated with an increase in hospitalizations for HF and MI among adults in the community. DESIGN, SETTING, AND PARTICIPANTS: As part of the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) study, a population-based study with hospitalizations sampled from 4 US communities, data were collected from 451 588 adults aged 35 to 84 years residing in the ARIC communities from annual cross-sectional stratified random samples of hospitalizations during October 2010 to September 2014. EXPOSURES: Monthly influenza activity, defined as the percentage of patient visits to sentinel clinicians for influenza-like illness by state, as reported by the Centers for Disease Control and Prevention Surveillance Network. MAIN OUTCOMES AND MEASURES: The monthly frequency of MI hospitalizations (n = 3541) and HF hospitalizations (n = 4321), collected through community surveillance and adjudicated as part of the ARIC Study. RESULTS: Between October 2010 and September 2014, 2042 (47.3%) and 1599 (45.1%) of the sampled patients who were hospitalized for HF and MI, respectively, were women and 2391 (53.3%) and 2013 (57.4%) were white, respectively. A 5% monthly absolute increase in influenza activity was associated with a 24% increase in HF hospitalization rates, standardized to the total population in each community, within the same month after adjusting for region, season, race/ethnicity, sex, age, and number of MI/HF hospitalizations from the month before (incidence rate ratio, 1.24; 95% CI, 1.11-1.38; P