Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.

How podcasts teach: A comprehensive analysis of the didactic methods of the top hundred medical podcasts.

PURPOSE: Medical podcasts have grown in popularity, but little is known about their didactic methods. This study sought to systemically describe the pedagogical approach employed by the 100 most popular medical podcasts in the United States. This study also aimed to assess factors related to quality control and conflicts of interest in podcasting. METHODS: The authors averaged the rank positions for Apple podcasts in the Medicine category in the United States from 06/01/18 to 09/30/20 to generate a list of the 100 highest-ranked medical podcasts. They developed and validated a categorization system of didactic methods based on Bloom's taxonomy and collected data on didactic methods, as well as podcast affiliation, target audience, format, advertising, continuing medical education (CME) offerings, and presence of a reference list or review process. RESULTS: Of the 100 most popular medical podcasts, 91 are educational. Of those, 51 are podcasts intended for physician education (PIPEs) while 40 are intended for other audiences, including the general public, nurses, and physical therapists. Compared with podcasts intended for other audiences, PIPEs engage higher levels of Bloom's taxonomy (p < 0.001). Among PIPEs, 18 (35.2%) are affiliated with an individual, 16 (31.4%) with a company, and 12 (23.5%) with a professional journal. 38 PIPEs (74.5%) are targeted toward all levels of medical learners. PIPEs are significantly more likely to list references or have a peer review process in place (n = 37, 72.5% vs. n = 15, 37.5%, p = 0.001) and offer CME credits (n = 20, 39.2% vs. n = 2, 5.0%, p < 0.001) than podcasts intended for other audiences. CONCLUSIONS: Medical podcasts employ a variety of didactic methods, including those ranked highly on Bloom's taxonomy. Unlike traditional medical education, PIPEs are commonly produced by individuals or companies and targeted to all levels of medical learners.

Higher urate in LRRK2 mutation carriers resistant to Parkinson disease.

OBJECTIVE: LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS: Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS: Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004). INTERPRETATION: These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.

Reactive oxygen species and bacterial biofilms in diabetic wound healing.

Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics. We review these recent findings and discuss mouse models that are being utilized to enhance our understanding of these potentially important contributors to chronic wound formation in diabetic patients.

Compensation of spectral and RF errors in swept-source OCT for high extinction complex demodulation.

We provide a framework for compensating errors within passive optical quadrature demodulation circuits used in swept-source optical coherence tomography (OCT). Quadrature demodulation allows for detection of both the real and imaginary components of an interference fringe, and this information separates signals from positive and negative depth spaces. To achieve a high extinction (∼60 dB) between these positive and negative signals, the demodulation error must be less than 0.1% in amplitude and phase. It is difficult to construct a system that achieves this low error across the wide spectral and RF bandwidths of high-speed swept-source systems. In a prior work, post-processing methods for removing residual spectral errors were described. Here, we identify the importance of a second class of errors originating in the RF domain, and present a comprehensive framework for compensating both spectral and RF errors. Using this framework, extinctions >60 dB are demonstrated. A stability analysis shows that calibration parameters associated with RF errors are accurate for many days, while those associated with spectral errors must be updated prior to each imaging session. Empirical procedures to derive both RF and spectral calibration parameters simultaneously and to update spectral calibration parameters are presented. These algorithms provide the basis for using passive optical quadrature demodulation circuits with high speed and wide-bandwidth swept-source OCT systems.

Hereditary hemorrhagic telangiectasia may be the most morbid inherited bleeding disorder in women.

ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is the second-most common inherited bleeding disorder (BD) worldwide and remains without approved therapies. HHT causes serious mucosal bleeding resulting in severe iron-deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in the brain, lung, and liver, which can cause life-threatening hemorrhagic complications. No study has examined the relative morbidity of HHT and von Willebrand disease (VWD), which is the most common inherited BD in women. We performed an observational cohort study of women with HHT or VWD, comparing a representative sample of 100 randomly selected women with HHT to 100 randomly selected age-matched women with VWD. In HHT vs VWD, recurrent epistaxis and gastrointestinal bleeding were more likely (odds ratio [OR], 32.73 [95% confidence interval, 13.81-71.80]; P < .0001 and 5.69 [2.59-12.89]; P < .0001) and heavy menstrual bleeding was less likely (OR, 0.32 [0.18-0.57]; P < .0001). Iron-deficiency anemia was significantly more likely, and the lowest hemoglobin was significantly lower in HHT than in VWD. The odds of iron infusion dependence, requirement for red cell transfusion, and hemostatic surgical procedures were significantly higher-17-fold, threefold, and eightfold higher, respectively-and hospital admissions to manage disease complications were both ∼14 times more frequent in women with HHT vs those with VWD. In conclusion, much higher disease-related morbidity, mortality, and health care use were observed in women with HHT vs VWD, providing evidence that HHT may be the most clinically significant inherited BD in women. Given the vast gap in research funding for HHT compared with both hemophilia (a disease primarily of men) and VWD, these findings have significant implications for gender equity in hematology.

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia.

ABSTRACT: No US Food and Drug Administration- or European Medicines Agency-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti-vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

Numerical compensation of system polarization mode dispersion in polarization-sensitive optical coherence tomography.

Polarization mode dispersion (PMD), which can be induced by circulators or even moderate lengths of optical fiber, is known to be a dominant source of instrumentation noise in fiber-based PS-OCT systems. In this paper we propose a novel PMD compensation method that measures system PMD using three fixed calibration signals, numerically corrects for these instrument effects and reconstructs an improved sample image. Using a frequency multiplexed PS-OFDI setup, we validate the proposed method by comparing birefringence noise in images of intralipid, muscle, and tendon with and without PMD compensation.

Spectral binning for mitigation of polarization mode dispersion artifacts in catheter-based optical frequency domain imaging.

Polarization mode dispersion (PMD) has been recognized as a significant barrier to sensitive and reproducible birefringence measurements with fiber-based, polarization-sensitive optical coherence tomography systems. Here, we present a signal processing strategy that reconstructs the local retardation robustly in the presence of system PMD. The algorithm uses a spectral binning approach to limit the detrimental impact of system PMD and benefits from the final averaging of the PMD-corrected retardation vectors of the spectral bins. The algorithm was validated with numerical simulations and experimental measurements of a rubber phantom. When applied to the imaging of human cadaveric coronary arteries, the algorithm was found to yield a substantial improvement in the reconstructed birefringence maps.

Artifacts in polarization-sensitive optical coherence tomography caused by polarization mode dispersion.

Polarization mode dispersion (PMD) severely degrades images of biological tissue measured with polarization-sensitive optical coherence tomography. It adds a bias to the local retardation value that can be spatially confined, resulting in regions of seemingly high sample birefringence that are purely artificial. Here, we demonstrate and analyze this effect, both experimentally and with numerical simulations, and show that artifacts can be avoided by limiting the system PMD to less than the system axial resolution. Even then, spatial averaging over a dimension larger than that characteristic of speckle is required to remove a PMD-induced bias of the local retardation values.

Early Termination of Oncology Clinical Trials in the United States.

PURPOSE: The aim of this study was to evaluate the rate of early trial discontinuation of oncology trials and reasons for early termination, to assess potential trends in rates of oncology trial termination, and to perform a comprehensive analysis of predictors of early termination. This study intends to inform efforts in improving efficiency of the oncology clinical trial enterprise. METHODS: We conducted a cross-sectional study of interventional cancer clinical trials registered in ClinicalTrials.gov database from September 27, 2007 to June 30, 2015, with at least one site listed in the United States. We evaluated predictors of early trial termination using Fisher exact or χ2 tests and logistic regression. RESULTS: Of 8687 trials, 22.74% (n = 1975) were terminated trials. Rates of early trial termination appeared stable over the study. Statistically significant univariate predictors of early termination for any reason include cancer category, phase, funding source, location, and age. In multivariable analysis, trials spanning multiple cancer categories and international trials were less likely to terminate early whereas phase 2 trials and trials funded by academia/foundation were more likely to terminate early. The most common reason for early termination was "Other, Multiple Reasons, or Unknown" (36.9%), followed by accrual issues (34.5%). In multivariate analysis among all terminated trials, supportive care trials, phase 2 trials, and non-industry funded trials had significantly higher odds of trial discontinuation specifically due to poor accrual. CONCLUSION: In this national sample of cancer clinical trials, early trial discontinuation was common. Many factors influenced early trial termination with poor accrual being a common reason. Specific trial features are associated with differential likelihood of early trial termination for any reason and for early trial termination due to poor accrual.

Anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia: A scoping review.

INTRODUCTION: Data describing safety and tolerability of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia (HHT), the second-most-common inherited bleeding disorder, is limited. METHODS: We performed a scoping review, searching MEDLINE and EMBASE from inception to March 2023 for eligible studies reporting detailed clinical data describing antithrombotic use in HHT. Data extracted included study design, patient population, and characteristics and outcomes of antithrombotic therapy. RESULTS: Of 625 unique manuscripts identified through database search, 77 were included: 64 case reports/case series describing 65 patients and 13 cohort studies. Data were extracted on a total of 466 patients with HHT, covering 587 episodes of antithrombotic therapy. The most common reasons for antithrombotic therapy were venous thromboembolism (VTE) (44.6 %), atrial arrhythmias (17.8 %) and stroke (10.5 %). anticoagulation was used in in 356 episodes (61.9 %), antiplatelet therapy in 140 episodes (24.3 %), and both together in 50 episodes (8.7 %). Complications of therapy included worsened HHT-associated bleeding (primarily epistaxis and gastrointestinal bleeding) in 198 antithrombotic treatment episodes (38.9 %) and premature antithrombotic therapy discontinuation in 142 episodes (28.9 %). Bleeding-directed therapy (local ablative therapy and systemic therapies) were employed to address worsening bleeding in 14.6 % of episodes. No specific complications of therapy were reported in 322 total antithrombotic events (58.4 %). Rates of bleeding (8.3 % to 80 %), therapy discontinuation (14.3 % to 57.1 %), and other complications ranged considerably from study to study. CONCLUSION: Current publications vary widely on the outcomes and tolerability of antithrombotics in HHT, but confirm the clinical challenge of adequate antithrombotic therapy in this population. More formal studies are needed to better guide optimal antithrombotic use in HHT.

Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia.

BACKGROUND: Antithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed in patients with hereditary hemorrhagic telangiectasia (HHT); however, data describing and guiding its use are very limited. OBJECTIVES: To investigate the safety, tolerability, and effectiveness of antithrombotic therapy in HHT in a cohort large enough to compare agents, evaluate for baseline predictors of premature discontinuation, and evaluate hematologic support requirements and healthcare utilization before and after antithrombitc therapy initiation. METHODS: We performed a multicenter observational cohort study characterizing the outcomes of antithrombic therapy in adults with HHT. RESULTS: A total of 119 patients with HHT with 187 discrete antithrombotic therapy episodes were included. Of these, 59 patients (50%) dose-reduced and/or prematurely discontinued therapy (including 52 patients [44%] who discontinued) due to worsened bleeding complications. Initiation at reduced dose intensity had a similar premature discontinuation rate (49%) as initiation at standard dose intensity (43%). In a multivariable logistic model, a history of gastrointestinal bleeding was associated with 3.25-fold odds of discontinuation (p = .001). Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, p < .001), and the need for hematologic support (intravenous iron and/or red blood cell transfusion) was significantly higher (29 patients vs 12 patients, p = .004) in the 3 months after antithrombotic therapy initiation vs the 3 months before; emergency department visits and hospital admissions due to bleeding also increased. The rates of dose-reduction and/or premature discontinuation were similar regardless of the anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulants, 44%) or with multiple simultaneous agents (44%) but were slightly lower with single-agent antiplatelet therapy (37%). Thromboembolism despite receiving antithrombotic therapy was common (18 patients, 15%) with varying outcomes. CONCLUSION: Antithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and health care utilization from worsened bleeding. Discontinuation rates approached 50% regardless of the dose intensity at initiation or type of antithrombotic agent used and were higher in patients with a gastrointestinal bleeding history.

Polarimetry noise in fiber-based optical coherence tomography instrumentation.

High noise levels in fiber-based polarization-sensitive optical coherence tomography (PS-OCT) have broadly limited its clinical utility. In this study we investigate contribution of polarization mode dispersion (PMD) to the polarimetry noise. We develop numerical models of the PS-OCT system including PMD and validate these models with empirical data. Using these models, we provide a framework for predicting noise levels, for processing signals to reduce noise, and for designing an optimized system.