Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment

Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents

Covid-19: Szenarien für Herbst/Winter 2022 – und darüber hinaus

Die vergangenen Monate haben dynamische Entwicklungen der Pandemie verdeutlicht. Als Folge dessen kam es quasi zeitgleich in Österreich im ersten Quartal des Jahres 2022 neben dem Beschluss äußerst restriktiver Vorgaben wie der Impfpflicht auch wieder zur Aufhebung fast aller Schutzmaßnahmen im Zusammenhang mit der COVID-19-Pandemie. Die letzten beiden Jahre haben gezeigt, wie dynamisch und rasch sich die Situation phasenweise in der Pandemie ändern kann. Jede Phase erfordert – und je länger die Pandemie andauert, umso mehr – verstärkt interdisziplinäre Zugänge und klare Zielsetzungen für Public Health Interventionen. Dies ist einerseits im Sinne einer verständlichen Kommunikation gegenüber der allgemeinen Bevölkerung wichtig, und andererseits im Sinne einer effektiven Bekämpfung der Ausbreitung der Pandemie unbedingt erforderlich

A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3’ of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Search for new physics in high-mass diphoton events from proton-proton collisions at √s = 13 TeV

Results are presented from a search for new physics in high-mass diphoton events from proton-proton collisions at sqrt(s) = 13 TeV. The data set was collected in 2016–2018 with the CMS detector at the LHC and corresponds to an integrated luminosity of 138 fb−1 . Events with a diphoton invariant mass greater than 500 GeV are considered. Two diferent techniques are used to predict the standard model backgrounds: parametric fts to the smoothly-falling background and a frst-principles calculation of the standard model diphoton spectrum at next-to-next-to-leading order in perturbative quantum chromodynamics calculations. The frst technique is sensitive to resonant excesses while the second technique can identify broad diferences in the invariant mass shape. The data are used to constrain the production of heavy Higgs bosons, Randall-Sundrum gravitons, the large extra dimensions model of Arkani-Hamed, Dimopoulos, and Dvali (ADD), and the continuum clockwork mechanism. No statistically signifcant excess is observed. The present results are the strongest limits to date on ADD extra dimensions and RS gravitons with a coupling parameter greater than 0.1

Region-wide environmental noise monitoring in Flanders through Citizen Science : protocol to integrate surveys and measurements

Within the Program for Innovation Procurement, the Flemish government is investing in innovative methods to answer numerous societal challenges. With support of this program the Department of Environment will develop a region-wide noise monitoring protocol in a two year project, started in April 2023. To achieve this, Ghent University partnered up with Scivil, the knowledge center for Citizen Science in Flanders. The noise monitoring question fits in an environmental noise indicator evaluation designed by the Ghent University in 2019-2020. This manuscript gives an overview of the project outline. We discuss the goals, the methodology, the technical implementation and the dataflow. We explain the strategy to include citizens to achieve both the societal and the scientific goals. Since this is a government funded project, the societal aspects have priority. The first component is the technology: hardware, quality, calibration, noise surveys, event classification, privacy and data storage. The second component is the citizen engagement: how to achieve the data collection at a reasonable cost? The third component is the sampling strategy: how to reach an unbiased dataset for multiple variables: spatial characteristics, sources and population? The last component deals with applications: trends in population exposure and perception. This protocol will provide matched exposure and perception data at an unprecedented scale

Emicizumab for acquired haemophilia A: A case series.

BACKGROUND: Emicizumab is approved to prevent bleeding in patients with congenital haemophilia A with or without inhibitors. However, no randomized trials addressed the efficacy of emicizumab in acquired haemophilia A (AHA). AIMS: To report the clinical and biochemical response of emicizumab in AHA. METHODS: This single-centre retrospective study included seven adults with AHA between November 2020 and May 2022. We collected patient characteristics, laboratory coagulation parameters, the use of haemostatic agents, bleeds and thrombotic events. Treatment was monitored using chromogenic FVIII assays. The assay with human reagents assesses both the emicizumab FVIII-like-activity and native patient FVIII-activity. The assay with bovine reagents only measures the patients' native FVIII-activity as emicizumab does not bind to bovine reagents. RESULTS: Patients presented with spontaneous hematoma (n = 7), intramuscular bleeding (n = 2), haematuria (n = 2) and/or gastro-intestinal bleeding (n = 2). Six patients had major bleedings. At diagnosis, APTT was prolonged (91 seconds, IQR 73-103), FVIII activity was 0% (IQR 0-1) and FVIII inhibitor 182 BU/mL (IQR 104-228). Emicizumab was administered weekly (3 mg/kg) for 4 weeks, and thereafter every 2 weeks until regression of the inhibitor. Three patients received activated FVIIa (cumulative dose of 1.7 mg/kg, IQR 1.2-2.2). All bleedings were controlled after treatment initiation, without further bleeds. After starting emicizumab, FVIII-like activity reached ≥5% at 12 days (IQR 7-14), whereas recovery of the intrinsic FVIII-activity ≥5% occurred at 128 days (IQR 88-173), coinciding with the disappearance of the FVIII inhibitor. There were no safety issues. CONCLUSION: In this AHA case series, no new clinically relevant bleeds were observed after initiation of emicizumab in conjunction with standard immunosuppressive therapy