Distinguishing Characteristics between Pandemic 2009–2010 Influenza A (H1N1) and Other Viruses in Patients Hospitalized with Respiratory Illness

BACKGROUND: Differences in clinical presentation and outcomes among patients infected with pandemic 2009 influenza A H1N1 (pH1N1) compared to other respiratory viruses have not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study was performed of all hospitalized patients at the peak of the pH1N1 season in whom a single respiratory virus was detected by a molecular assay targeting 18 viruses/subtypes (RVP, Luminex xTAG). Fifty-two percent (615/1192) of patients from October, 2009 to December, 2009 had a single respiratory virus (291 pH1N1; 207 rhinovirus; 45 RSV A/B; 37 parainfluenza; 27 adenovirus; 6 coronavirus; and 2 metapneumovirus). No seasonal influenza A or B was detected. Individuals with pH1N1, compared to other viruses, were more likely to present with fever (92% & 70%), cough (92% & 86%), sore throat (32% & 16%), nausea (31% & 8%), vomiting (39% & 30%), abdominal pain (14% & 7%), and a lower white blood count (8,500/L & 13,600/L, all p-values<0.05). In patients with cough and gastrointestinal complaints, the presence of subjective fever/chills independently raised the likelihood of pH1N1 (OR 10). Fifty-five percent (336/615) of our cohort received antibacterial agents, 63% (385/615) received oseltamivir, and 41% (252/615) received steroids. The mortality rate of our cohort was 1% (7/615) and was higher in individuals with pH1N1 compared to other viruses (2.1% & 0.3%, respectively; p = 0.04). CONCLUSIONS/SIGNIFICANCE: During the peak pandemic 2009-2010 influenza season in Rhode Island, nearly half of patients admitted with influenza-like symptoms had respiratory viruses other than influenza A. A high proportion of patients were treated with antibiotics and pH1N1 infection had higher mortality compared to other respiratory viruses

Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritised using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj]=4×10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj=3.2x10−3), had lower EF (27.3% vs. 29.8%; padj=5.8x10−3), and less likely to have ischaemic aetiology (37.3% vs 67.4%; padj=4×10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association to DCM were identified in ~5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower EF and were less likely to have had an ischaemic aetiology

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

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

Refractive development in albinism

Albinism is an uncommon genetic condition characterised by hypopigmentation of the hair, skin and eyes; and is associated with reduced vision, nystagmus and high refractive errors. Currently there is discrepancy in the literature in terms of the most prevalent form of refractive error in albinism. This thesis investigates refractive development in children with albinism. As nystagmus is a common feature of albinism, a group of children with Idiopathic Infantile Nystagmus (IIN) were also recruited in order to examine the effects of nystagmus on vision and refractive error. The Northern Ireland Nystagmus and Albinism (NINA) Study began in Autumn 2008 and concluded in Winter 2011. A series of retrospective, cross-sectional, prospective and imaging studies combined to explore refractive error and visual function in 105 participants (albinism n=73, IIN n=32) aged 4.5 months to 47 years. The findings were compared to published data on visually normal children and adults. The data demonstrated the following: • The most prevalent form of refractive error in albinism is hypermetropia. • High magnitudes of with- the-rule astigmatism are commonly found in albinism. • The emmetropisation process is impaired in albinism; infantile spherical and astigmatic refractive errors tend not to decrease with increasing age. • The degree of foveal hypoplasia demonstrated in albinism is related to visual acuity; poor acuity being associated with more severe hypoplasia. • The diagnoses of several individuals recruited with IIN were re-explored subsequent to their participation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Mating system variation and morph fluctuations in a polymorphic lizard

In polymorphic male painted dragon lizards (Ctenophorus pictus), red males win staged contests for females over yellow males, and yellow males have greater success in staged sperm competition trials than red males. This predicts different reproductive strategies in the wild with red males being more coercive or better mate guarders than yellow males. Yellow males would be expected to sire more offspring per copulation and have a greater proportion of offspring from clutches with mixed paternity. However, here we show using microsatellites that the frequency of mixed paternity in the wild is low (\u3c 20% on average across years), that all morphs on average have the same number of offspring sired per year, and that mating system variation (polyandry vs. monandry) is strongly correlated with perch density on male territories. Furthermore, a logistic regression on male successful vs. unsuccessful mate acquisition showed that red males were under negative selection when they dominated the population, which suggests ongoing frequency dependent selection on male colouration