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Damasus I (305-384) ascended to the office of the Bishop of Rome after a bitter and bloody battle with Ursinus in 366 CE. The violence was a culmination of doctrinal squabbles and power contests which erupted in the Roman church over the course of the fourth century. Damasus engaged in a substantial program of physical renovation and enlargement of martyr sites and personally penned numerous epigrams both extolling the virtue of the honored dead and the patronage of the bishopric. Scholarship related to Damasus and his works is typically narrowly focused, considering motive(s) for his actions, his use of specific architecture and/or materials, the content of his epigrams, etc. This dissertation expands the analysis to synthesize elements of space and architectural theory, sensory theory, and anthropological issues to fully explore the impact of his works related to martyr sites on the minds and bodies of pilgrims visiting such sites during martyr festival. Damasus I (305-384) ascended to the office of the Bishop of Rome after a bitter and bloody battle with Ursinus in 366 CE. The violence was a culmination of doctrinal squabbles and power contests which erupted in the Roman church over the course of the fourth century. Damasus engaged in a substantial program of physical renovation and enlargement of martyr sites and personally penned numerous epigrams both extolling the virtue of the honored dead and the patronage of the bishopric. Scholarship related to Damasus and his works is typically narrowly focused, considering motive(s) for his actions, his use of specific architecture and/or materials, the content of his epigrams, etc. This dissertation expands the analysis to synthesize elements of space and architectural theory, sensory theory, and anthropological issues to fully explore the impact of his works related to martyr sites on the minds and bodies of pilgrims visiting such sites during martyr festival. The bishop’s interventions at the catacomb of Callistus serve as a prime example of his use of architectural features, materials, decoration, and rhetoric to forge a distinct collective memory for visitors to the space – memory that was both manifestly Christian and manifestly Roman. Damasus’ use of materials and architectural features redefined the catacomb as monumental space. His proscription of physical movement and the stunning impact of the performance of his epigrams, combined with the sights, sounds, and smells within the space engaged the visitors’ senses to incite synesthesia and visceral seeing toward an encounter with the divine. These elements--catacomb-as-monument and synesthesia--provided visitors a shared visceral experience, which cemented a message of unity and a distinct collective identity for the fracturing Roman Christian community. The bishop’s interventions at the catacomb of Callistus serve as a prime example of his use of architectural features, materials, decoration, and rhetoric to forge a distinct collective memory for visitors to the space – memory that was both manifestly Christian and manifestly Roman. Damasus’ use of materials and architectural features redefined the catacomb as monumental space. His proscription of physical movement and the stunning impact of the performance of his epigrams, combined with the sights, sounds, and smells within the space engaged the visitors’ senses to incite synesthesia and visceral seeing toward an encounter with the divine. These elements--catacomb-as-monument and synesthesia--provided visitors a shared visceral experience, which cemented a message of unity and a distinct collective identity for the fracturing Roman Christian community.

Searching for genes in which loss-of-function mutations confer protection against disease is a strategy to identity drug targets. This study reports an association between loss-of-function mutations in ANGPTL4 and protection against coronary artery disease. Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease, 1 – 3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example . . .

Whole-exome sequencing revealed an association between four rare loss-of-function mutations in the apoliprotein C3 gene ( APOC3 ) and low plasma triglyceride levels. Carriers of these mutations had a reduction in the risk of coronary heart disease of nearly 40%. In observational studies, plasma triglyceride levels are associated with the risk of coronary heart disease. 1 , 2 Heritability accounts for more than 50% of the individual variation in triglyceride levels. 3 Genomewide association studies have identified common DNA sequence variants at more than 150 genetic loci that are related to plasma lipids 4 , 5 and have suggested that plasma triglyceride-rich lipoproteins directly influence the risk of coronary heart disease. 6 These findings lead to two unanswered questions: first, to what extent do rare DNA sequence variants, particularly those in protein-coding sequences, contribute to individual variation in plasma triglyceride levels and the risk of coronary . . .

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS. The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0·75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885. Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0·87 (95% credible interval 0·665–1·102, posterior probability of superiority 0·877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS. Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS. AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.

Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Martin Farrall and colleagues report the results of a large genome-wide association meta-analysis of coronary artery disease based on 1000 Genomes imputation. They identify ten new risk loci and show that susceptibility to this disease is largely determined by common SNPs with small effect sizes. Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV 1 ), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126 , distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV 1 . This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease Original Article, N Engl J Med 2016;374:1134-1144. The author footnote (page 1134) should have read, “The authors, who are members of the Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, are listed in the Appendix.” The article is correct at NEJM.org.

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.