The influence of trinucleotide repeats in the androgen receptor gene on androgen-related traits and diseases.

CONTEXT: Trinucleotide repeats in the androgen receptor have been proposed to influence testosterone signaling in men, but the clinical relevance of these trinucleotide repeats remains controversial. OBJECTIVE: To examine how androgen receptor trinucleotide repeat lengths affect androgen-related traits and disease risks and whether they influence the clinical importance of circulating testosterone levels. METHODS: We quantified CAG and GGC repeat lengths in the androgen receptor (AR) gene of European-ancestry male participants in UK Biobank from whole-genome and whole-exome sequence data using ExpansionHunter, and tested associations with androgen-related traits and diseases. We also examined whether the associations between testosterone levels and these outcomes were affected by adjustment for the repeat lengths. RESULTS: We successfully quantified the repeat lengths from whole-genome and/or whole-exome sequence data in 181,217 males. Both repeat lengths were shown to be positively associated with circulating total testosterone level and bone mineral density, whereas CAG repeat length was negatively associated with male-pattern baldness, but their effects were relatively small and were not associated with most of the other outcomes. Circulating total testosterone level was associated with various outcomes, but this relationship was not affected by adjustment for the repeat lengths. CONCLUSION: In this large-scale study, we found that longer CAG and GGC repeats in the AR gene influence androgen resistance, elevate circulating testosterone level via a feedback loop and play a role in some androgen-targeted tissues. Generally, however, circulating testosterone level is a more important determinant of androgen action in males than repeat lengths.

Laser Versus Cold Steel for Endoscopic Management of Subglottic Stenosis.

OBJECTIVE: Endoscopic management of subglottic stenosis (SGS) includes a wide range of techniques. This 17-year review compares treatment outcomes between carbon dioxide (CO2) laser and cold steel. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary care center. METHODS: A chart review was performed for all patients undergoing endoscopic treatment of SGS at Cleveland Clinic between July 12, 2000 and September 1, 2017. Data collected included demographics, stenosis etiology, stenosis severity, comorbidities, treatment modality, and airway procedure history. The primary endpoint was repeated treatment-free survival (RTFS) within 2 years using a Kaplan-Meier analysis and Cox proportional hazard model. RESULTS: A total of 139 patients (median [interquartile range] aged 48.7 [37.8, 57.0] years; 83.4% female) were included in the analysis, with etiologies including idiopathic (56.8%), granulomatosis with polyangiitis (25.2%), and intubation (16.5%). All patients underwent either cold steel (107 patients) or CO2 laser (32 patients) lysis of stenosis with concurrent dilation. RTFS within 2 years was 50.2% for CO2 laser and 31.9% for cold steel (hazard ratio [HR] and 95% confidence interval [CI]: 1.69, 0.96-2.97, P = .07). In patients with no prior airway procedures, there was no difference in RTFS between laser and cold knife (P = .41). However, in patients with prior airway procedures, RTFS was significantly greater in the laser group, even after adjusting for age, smoking history, and stenosis etiology (50.0% vs 16.8%, adjusted HR and CI: 2.82, 1.14-6.98, P = .025). CONCLUSION: Endoscopic lysis of SGS with CO2 laser should be considered in revision cases.

Experimental demonstration of quantum-inspired optical symmetric hypothesis testing.

We use a phase-sensitive measurement to perform a binary hypothesis testing, i.e., distinguish between one on-axis and two symmetrically displaced Gaussian point spread functions. In the sub-Rayleigh regime, we measure a total error rate lower than allowed by direct imaging. Our results experimentally demonstrate that linear-optical spatial mode transformations can provide useful advantages for object detection compared with conventional measurements, even in the presence of realistic experimental cross talk, paving the way for meaningful improvements in identifying, detecting, and monitoring real-world, diffraction-limited scenes.

Greater Saphenous Vein Graft Harvest from Anterolateral Thigh Free Flap Incision: A Novel Technique.

The greater saphenous vein can be harvested from the standard incision for an anterolateral free flap and used as a vein graft in complex head and neck reconstruction. Laryngoscope, 134:648-650, 2024.

Surgical Management of Airway Stenosis During Pregnancy: A Scoping Review.

OBJECTIVE: There are several options for surgical management of subglottic stenosis, including endoscopic and open procedures. However, treatment algorithms, outcomes, and anesthetic management of subglottic stenosis during pregnancy are not well described. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane databases. REVIEW METHODS: A scoping review of management of subglottic stenosis during pregnancy was performed, and then reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria consisted of those with subglottic or tracheal stenosis aged greater than 18 years, those in whom management was performed during pregnancy, and those who reported delivery related outcomes. RESULTS: After systematic review and detailed search of 330 identified articles, 15 articles met inclusion criteria and were included in the final analysis. All studies were case reports or case series (level 4 evidence). This study identified 27 patients. The median age was 29 and the median gestational age at intervention was 28 weeks. Left lateral positioning and fetal heart rate monitoring were used in nearly every case. The most common intervention performed was endoscopic balloon dilation. In many cases, jet ventilation or transnasal humidified rapid insufflation ventilatory exchange was satisfactory for maintenance of the airway. Three women ultimately required tracheostomy prior to labor and delivery. There was no fetal death or complications reported in these studies, and all but one woman proceeded to deliver at term. CONCLUSION: Endoscopic balloon dilation during pregnancy is safe and effective, resulting in optimized respiratory outcomes for the mother and safe delivery of the fetus. The third trimester appears to be safe for airway intervention. Laryngoscope, 134:1014-1022, 2024.

The mitigated carbon emissions of transitioning to virtual medical school and residency interviews: A survey-based study.

PURPOSE: Prior to COVID, thousands of medical school and residency applicants traversed their countries for in-person interviews each year. However, data on the greenhouse gas emissions from in-person interviews is limited. This study estimated greenhouse gas emissions associated with in-person medical school and residency interviews and explored applicant interview structure preferences. METHODS: From March to June 2022, we developed and distributed a nine-question, website-based survey to collect information on applicant virtual interview schedule, demographics and preference for future interview format. We calculated theoretical emissions for all interviews requiring air travel and performed a content analysis of interview preference explanations. RESULTS: We received responses from 258 first-year and 253 fourth-year medical students at 26 allopathic US medical schools who interviewed virtually in 2020-2021 and 2021-2022, respectively. Residency applicants participating in the study were interviewed at a mean of 15.3 programs (SD 5.4) and had mean theoretical emissions of 4.31 tons CO2 eq. Medical school applicants participating in the study were interviewed at a mean of 6.9 programs and had mean theoretical emissions of 2.19 tons CO2 eq. Ninety percent of medical school applicants and 91% of residency applicants participating in the study expressed a preference for hybrid or virtual interviews going forward. CONCLUSION: In-person medical training interviews have significant greenhouse gas emissions. Virtual and hybrid alternatives have a high degree of acceptability among applicants.

Negative Nonlinear CD-ee Dependence in Polycrystalline BINOL Thin Films.

Generally, the relationship between the observed circular dichroism and the enantiomeric excess in chiral systems (CD-ee dependence) is linear. While positive nonlinear behavior has often been reported in the past, examples of negative nonlinear (NN) behavior in CD-ee dependence are rare and not well understood. Here, we present a strong NN CD-ee dependence within polycrystalline thin films of BINOL by using second-harmonic-generation circular dichroism (SHG-CD) and commercial CD spectroscopy studies. Theoretical calculations, microscopy, and FTIR studies are employed to further clarify the underlying cause of this observation. This behavior is attributed to the changing supramolecular chirality of the system. Systems exhibiting NN CD-ee dependence hold promise for highly accurate enantiomeric excess characterization, which is essential for the refinement of enantio-separating and -purifying processes in pharmaceuticals, asymmetric catalysis, and chiral sensing. Our findings suggest that a whole class of single-species systems, i.e., racemate crystals, might possess NN CD-ee dependence and thus provide us a vast playground to better understand and exploit this phenomenon.

HLA allele-calling using multi-ancestry whole-exome sequencing from the UK Biobank identifies 129 novel associations in 11 autoimmune diseases.

The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms do not perform well in this region. Instead, the field has adopted the assessment of the association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often based on genotyping arrays, these association studies impute HLA alleles, decreasing accuracy and thus statistical power for rare alleles and in non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 UK Biobank (UKB) participants to directly call HLA alleles using the HLA-HD algorithm. We show this method is more accurate than imputing HLA alleles and harness the improved statistical power to identify 360 associations for 11 auto-immune phenotypes (at least 129 likely novel), leading to better insights into the specific coding polymorphisms that underlie these diseases. We show that HLA alleles with synonymous variants, often overlooked in HLA studies, can significantly influence these phenotypes. Lastly, we show that HLA sequencing may improve polygenic risk scores accuracy across ancestries. These findings allow better characterization of the role of the HLA region in human disease.

Off-axis aberrations improve the resolution limits of incoherent imaging.

The presence of off-axis tilt and Petzval curvature, two of the lowest-order off-axis Seidel aberrations, are shown to improve the Fisher information of two-point separation estimation in an incoherent imaging system compared to an aberration-free system. Our results show that the practical localization advantages of modal imaging techniques within the field of quantum-inspired superresolution can be achieved with direct imaging measurement schemes alone.

Predicting ExWAS findings from GWAS data: a shorter path to causal genes.

GWAS has identified thousands of loci associated with disease, yet the causal genes within these loci remain largely unknown. Identifying these causal genes would enable deeper understanding of the disease and assist in genetics-based drug development. Exome-wide association studies (ExWAS) are more expensive but can pinpoint causal genes offering high-yield drug targets, yet suffer from a high false-negative rate. Several algorithms have been developed to prioritize genes at GWAS loci, such as the Effector Index (Ei), Locus-2-Gene (L2G), Polygenic Prioritization score (PoPs), and Activity-by-Contact score (ABC) and it is not known if these algorithms can predict ExWAS findings from GWAS data. However, if this were the case, thousands of associated GWAS loci could potentially be resolved to causal genes. Here, we quantified the performance of these algorithms by evaluating their ability to identify ExWAS significant genes for nine traits. We found that Ei, L2G, and PoPs can identify ExWAS significant genes with high areas under the precision recall curve (Ei: 0.52, L2G: 0.37, PoPs: 0.18, ABC: 0.14). Furthermore, we found that for every unit increase in the normalized scores, there was an associated 1.3-4.6-fold increase in the odds of a gene reaching exome-wide significance (Ei: 4.6, L2G: 2.5, PoPs: 2.1, ABC: 1.3). Overall, we found that Ei, L2G, and PoPs can anticipate ExWAS findings from widely available GWAS results. These techniques are therefore promising when well-powered ExWAS data are not readily available and can be used to anticipate ExWAS findings, allowing for prioritization of genes at GWAS loci.

High Tracheal Resection With Intralaryngeal Extension as an Alternative to Cricotracheal Resection for Treatment of Subglottic Stenosis.

OBJECTIVE: Some patients with subglottic stenosis (SGS) require open airway reconstruction, which traditionally involves resection of the anterior cricoid cartilage. As an alternative, we present a novel technique: cricoid-sparing high tracheal resection with excision of subglottic stenotic tissue from below. A novel set of posterior circumferential cricoid sutures is used to reline the exposed cricoid plate. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary care center. METHODS: The surgical technique is described and illustrated. A chart review was performed for all patients who underwent surgery between January 1, 2016, and June 30, 2021. RESULTS: Fourteen patients (100% female) underwent this airway resection and reconstruction surgery during the study time period. After a mean follow-up of 12 months, no patients required tracheostomy. Twelve of 14 patients (86%) had durable airways. Two patients (14%) have required repeated endoscopic procedures for recurrent stenosis and are considered treatment failures. None exhibited postoperative dysfunction to suggest posterior cricoarytenoid muscle injury. Thirteen patients (93%) had a postoperative normal voice or only transient dysphonia. One patient had permanent unilateral vocal fold paralysis. CONCLUSION: Cricoid-sparing high tracheal resection is a safe and effective alternative to cricotracheal resection, especially for predominantly posterior SGS. The cricoid cartilage and cricothyroid muscles are left undisturbed, potentially decreasing the risk of postoperative dysphonia, namely lowered fundamental frequency. This is especially meaningful in the setting of a predominantly female patient population.

Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.

OBJECTIVES: Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. METHODS: As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). RESULTS: Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). CONCLUSION: Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.

Quantum Fisher information for estimating N partially coherent point sources.

A partially coherent object's localization parameters are shown to be theoretically estimable with higher precision than those of an incoherent object, and the maximum number of independent parameters that have non-vanishing precision in the sub-Rayleigh regime is 3 (compared to 2 for an incoherent object). Normalization schemes, which are crucial in the proper interpretation of quantum Fisher information results in the presence of partial coherence, are introduced and detailed.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases.

Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.

Coherent mode decomposition of multiple quantum well light emission.

Developing a richer understanding of the various properties of light is central to the field of photonics. One often neglected degree of freedom (DOF) is the second-order correlation of the light field, known as coherence. To make proper use of this DOF, one needs to first obtain information about the field's coherence, which may be characterized through the cross spectral density (CSD) function. We present a measurement of the CSD of a ubiquitous, partially coherent source: a multiple quantum well device in its near-field region, where a photonic structure would commonly encounter the emitted field. We show a departure from the coherence area that is expected from an incoherent source and demonstrate the application of coherent mode decomposition as a way to further analyze the measured results.

Genomes of Vibrio metoecus co-isolated with Vibrio cholerae extend our understanding of differences between these closely related species.

BACKGROUND: Vibrio cholerae, the causative agent of cholera, is a well-studied species, whereas Vibrio metoecus is a recently described close relative that is also associated with human infections. The availability of V. metoecus genomes provides further insight into its genetic differences from V. cholerae. Additionally, both species have been co-isolated from a cholera-free brackish coastal pond and have been suggested to interact with each other by horizontal gene transfer (HGT). RESULTS: The genomes of 17 strains from each species were sequenced. All strains share a large core genome (2675 gene families) and very few genes are unique to each species (< 3% of the pan-genome of both species). This led to the identification of potential molecular markers-for nitrite reduction, as well as peptidase and rhodanese activities-to further distinguish V. metoecus from V. cholerae. Interspecies HGT events were inferred in 21% of the core genes and 45% of the accessory genes. A directional bias in gene transfer events was found in the core genome, where V. metoecus was a recipient of three times (75%) more genes from V. cholerae than it was a donor (25%). CONCLUSION: V. metoecus was misclassified as an atypical variant of V. cholerae due to their resemblance in a majority of biochemical characteristics. More distinguishing phenotypic assays can be developed based on the discovery of potential gene markers to avoid any future misclassifications. Furthermore, differences in relative abundance or seasonality were observed between the species and could contribute to the bias in directionality of HGT.