Validating a Curvature-Based Marker of Cervical Carotid Tortuosity for Risk Assessment in Heritable Aortopathies.

BACKGROUND: Cervical arterial tortuosity is associated with adverse outcomes in Loeys-Dietz syndrome and other heritable aortopathies. METHODS AND RESULTS: A method to assess tortuosity based on curvature of the vessel centerline in 3-dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys-Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow-up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow-up). Logistic regression was performed to assess the likelihood of clinical end point according to baseline carotid tortuosity. Total absolute curvature at baseline was 11.13±5.76 and was relatively unchanged at 8 to 10 years (fold change: 0.026±0.298, P=1.00), whereas tortuosity index at baseline was 0.262±0.131, with greater variability at 8 to 10 years (fold change: 0.302±0.656, P=0.818). Baseline total absolute curvature correlated with aortic root diameter (r=0.456, P=0.004) and was independently associated with aortic events during the 4-year follow-up (adjusted odds ratio [OR], 2.64 [95% CI, 1.02-6.85]). Baseline tortuosity index correlated with age (r=0.532, P<0.001) and was not associated with events (adjusted OR, 1.88 [95% CI, 0.79-4.51]). Finally, baseline total absolute curvature had good discrimination of 4-year outcomes (area under the curve=0.724, P=0.014), which may be prognostic or predictive. CONCLUSIONS: Here we introduce cervical carotid tortuosity as a promising quantitative biomarker with validated, standardized characteristics. Specifically, we recommend the adoption of a curvature-based measure, total absolute curvature, for early detection or monitoring of disease progression in Loeys-Dietz syndrome.

Trends and Frequencies of Antibiotic Prescriptions for Acute Sinusitis Outpatient Visits in Adults.

OBJECTIVE: The objective of this study was to analyze the trends and frequency in which recommended first-line therapy, amoxicillin with or without clavulanate, was prescribed for acute sinusitis based on current otolaryngology and other gold standard guidelines, as well as analyze differences in prescription behaviors of otolaryngologists compared with non-otolaryngologists for outpatient adult acute sinusitis visits. METHODS: Weighted patient data from the National Ambulatory Medical Care Survey were analyzed to calculate visit rates and trends of antibiotic prescriptions for adults diagnosed with acute sinusitis from 2007 to 2019. Visits with multiple prescribed antibiotics or concomitant diagnoses requiring antibiotics were excluded. Each visit was classified based on the type of antibiotic prescribed. RESULTS: Acute sinusitis was diagnosed in 0.63% of all outpatient visits from 2007 to 2019 (95% confidence interval: 0.56%-0.71%). Amoxicillin had the greatest increase in prescription frequency (13.4%), whereas macrolides had the largest decrease in prescription frequency (13.9%). Among adult acute sinusitis outpatient visits in which antibiotics were prescribed, recommended first-line antibiotic therapy of amoxicillin-clavulanate or amoxicillin alone was prescribed in 40.4% of visits. The most common antibiotic prescribed was amoxicillin-clavulanate at otolaryngologist visits (20.5%) and macrolides at non-otolaryngologist visits (26.0%). A greater proportion of otolaryngologist visits resulted in no antibiotics prescribed for acute sinusitis (36.8% vs. 22.5%, p < 0.001). CONCLUSION: Otolaryngologists engage in watchful waiting more than non-otolaryngologists. Broader dissemination of existing guidelines for acute sinusitis treatment to non-Otolaryngologist (ENT) primary care specialties that take care of acute sinusitis to improve antibiotic stewardship and appropriate antibiotic selection is needed. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:2622-2625, 2024.

Stability of navigation in catheter-based endovascular procedures.

Endovascular procedures provide surgeons and other interventionalists with minimally invasive methods to treat vascular diseases by passing guidewires, catheters, sheaths and treatment devices into the vasculature to and navigate toward a treatment site. The efficiency of this navigation affects patient outcomes, but is frequently compromised by catheter "herniation", in which the catheter-guidewire system bulges out from the intended endovascular pathway so that the interventionalist can no longer advance it. Here, we showed herniation to be a bifurcation phenomenon that can be predicted and controlled using mechanical characterizations of catheter-guidewire systems and patientspecific clinical imaging. We demonstrated our approach in laboratory models and, retrospectively, in patients who underwent procedures involving transradial neurovascular procedures with an endovascular pathway from the wrist, up in the arm, around the aortic arch, and into the neurovasculature. Our analyses identified a mathematical navigation stability criterion that predicted herniation in all of these settings. Results show that herniation can be predicted through bifurcation analysis, and provide a framework for selecting catheter-guidewire systems to avoid herniation in specific patient anatomy.

Surgical Instrument Designers and Inventors-Where are the Women?

Historically, surgical instruments were designed by men for male surgeons. Although instrumentation has changed with the changing paradigms of surgery, it has failed to adapt to the changing surgical workforce. Almost 30% of surgeons are female and nearly 90% of surveyed female surgeons report poor instrument design and associated musculoskeletal injuries from use. Understanding the current state of handheld surgical instrument design, published literature was reviewed, surgical instrument collections were contacted, and the U.S. Patent and Trademark databases were queried to identify public patents and pre-granted applications of female inventors of handheld surgical instruments. Twenty-five female inventors were identified from published literature and 1551 unique females hold patents. This number pales when the denominator of male inventors is considered. Hence, to address the female surgeon's lack of instrumentation and design, there is a critical need for participatory ergonomics whereby both the female surgeon and engineer collaborate on design.

Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial.

OBJECTIVE: To evaluate the impact of N-acetyl-cysteine (NAC) on amputation stump perfusion and healing in patients with critical limb-threatening ischemia (CLTI). BACKGROUND: Patients with CLTI are at increased risk of poor amputation site healing leading to increased procedure-associated morbidity. METHODS: In a pilot, double-blind, placebo-controlled, randomized controlled trial, patients with CLTI undergoing major elective lower extremity amputation were randomized 1:1 to intravenous NAC (1200 mg twice-daily) or placebo for up to 5 days postoperatively. Primary outcomes were change in stump perfusion at postoperative day 3 (POD3) and POD5, and healing at POD30. Stumps were serially evaluated for wound healing, and tissue perfusion was evaluated using noninvasive laser-assisted fluorescent angiography. RESULTS: Thirty-three patients were randomized to NAC (n = 16) or placebo (n = 17). Thirty-one patients were eligible for intent-to-treat analysis (NAC14; placebo17). Twenty patients (NAC7; placebo13) had amputation stump perfusion defects at POD0 and were considered high-risk for poor healing. Intent-to-treat analysis revealed no significant differences between treatment groups. Subgroup analysis of high-risk patients revealed differences in stump perfusion defect size (NAC-0.53-fold, placebo +0.71-fold; 95% confidence interval -2.11 to-0.35; P < 0.05) and healing (NAC [100%], placebo [46%]; P < 0.01) between study treatments. CONCLUSIONS: Postoperative NAC administration may improve amputation stump perfusion and healing in patients with CLTI and tissue perfusion defects at the time of amputation. Intraoperative laser-assisted fluorescent angiogra-phy may help surgeons identify high-risk patients with stump perfusion defects and provide early adjunctive interventions. Future studies can further explore the therapeutic benefits of NAC in the healing and perfusion of other surgical operative sites in high-risk individuals. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03253328.

Otolaryngology Resident Education and Perceptions of e-cigarettes.

OBJECTIVE: To date, there are no reports of otolaryngology residents' knowledge and confidence in discussing e-cigarette use. The purpose of this study was to evaluate otolaryngology resident e-cigarette knowledge and confidence in counseling patients on e-cigarette use. STUDY DESIGN: Cross-sectional national survey. SETTING: Accreditation Council for Graduate Medical Education otolaryngology residents in the United States. METHODS: US otolaryngology residents were distributed surveys electronically in September 2020. RESULTS: A total of 150 participants replied for a response rate of 8.88%. The majority, 93.10% have not received formal education on e-cigarettes during their residency training. The most common resource of e-cigarette information overall was social media (78.46%). Within academia, the most common resources of e-cigarette education were patient interactions (63.16%) and colleagues (54.74%). Patients commonly inquire residents about e-cigarettes for smoking cessation (85.07%) and their long-term health effects (83.58%). Almost 67% of residents rarely or never ask patients about e-cigarette use. Only 4.35% of residents are not confident discussing traditional cigarette use, while 58.70% are not confident discussing e-cigarettes. CONCLUSION: Otolaryngology residents have not received formal education in e-cigarettes and are not confident discussing e-cigarettes with their patients. This highlights the need for e-cigarette education during otolaryngology residency to improve patient e-cigarette counseling.

Impact of Stroke Call on Career Satisfaction and Burnout for Academic Neurointerventionalists: A Grounded Theory Model.

BACKGROUND: The demand of thrombectomy treatment for acute ischemic stroke increased dramatically in the United States after the publication of 5 pivotal trials in 2015. The impact of call burden on career satisfaction and burnout in neurointerventionalists has not been explored. METHODS: A qualitative approach was chosen to obtain rich, detailed accounts of physician experiences. From July 2018 to July 2019, we conducted in-depth, semistructured interviews (mean duration, 43 minutes) with 16 academic neurointerventionalists from various institutions in the United States. Participants were chosen from the Society of Neurointerventional Surgery to include multiple specialties, career stages, and geographic locations. Key themes/subthemes were organized into a conceptual model and shown by exemplary quotes. RESULTS: Participants report a diverse range of previously uncharacterized ways in which stroke call responsibilities affect their lives. Unrealistic performance expectations, discipline-based inequalities, poor organizational workflow, limited opportunities for growth and advancement, and lack of control over call conditions are some of the key themes identified. Participants describe a need for interventions that address both the issues of workload stress (i.e., resources for stroke call and administrative work) and their ability to accomplish professional goals (i.e., flexible work arrangements, leadership autonomy support, and organizational value congruence). CONCLUSIONS: The burden of stroke call has strong implications for career satisfaction and burnout in neurointerventionalists. This model can be used by hospitals, departments, and physician groups to better conceptualize conditions that facilitate burnout and attrition. Changes to hospital management practices and culture may be the most productive focal areas for intervention.

PSORTdb 4.0: expanded and redesigned bacterial and archaeal protein subcellular localization database incorporating new secondary localizations.

Protein subcellular localization (SCL) is important for understanding protein function, genome annotation, and aids identification of potential cell surface diagnostic markers, drug targets, or vaccine components. PSORTdb comprises ePSORTdb, a manually curated database of experimentally verified protein SCLs, and cPSORTdb, a pre-computed database of PSORTb-predicted SCLs for NCBI's RefSeq deduced bacterial and archaeal proteomes. We now report PSORTdb 4.0 (http://db.psort.org/). It features a website refresh, in particular a more user-friendly database search. It also addresses the need to uniquely identify proteins from NCBI genomes now that GI numbers have been retired. It further expands both ePSORTdb and cPSORTdb, including additional data about novel secondary localizations, such as proteins found in bacterial outer membrane vesicles. Protein predictions in cPSORTdb have increased along with the number of available microbial genomes, from approximately 13 million when PSORTdb 3.0 was released, to over 66 million currently. Now, analyses of both complete and draft genomes are included. This expanded database will be of wide use to researchers developing SCL predictors or studying diverse microbes, including medically, agriculturally and industrially important species that have both classic or atypical cell envelope structures or vesicles.

Estimating Implicit and Explicit Gender Bias Among Health Care Professionals and Surgeons.

Importance: The Implicit Association Test (IAT) is a validated tool used to measure implicit biases, which are mental associations shaped by one's environment that influence interactions with others. Direct evidence of implicit gender biases about women in medicine has yet not been reported, but existing evidence is suggestive of subtle or hidden biases that affect women in medicine. Objectives: To use data from IATs to assess (1) how health care professionals associate men and women with career and family and (2) how surgeons associate men and women with surgery and family medicine. Design, Setting, and Participants: This data review and cross-sectional study collected data from January 1, 2006, through December 31, 2017, from self-identified health care professionals taking the Gender-Career IAT hosted by Project Implicit to explore bias among self-identified health care professionals. A novel Gender-Specialty IAT was also tested at a national surgical meeting in October 2017. All health care professionals who completed the Gender-Career IAT were eligible for the first analysis. Surgeons of any age, gender, title, and country of origin at the meeting were eligible to participate in the second analysis. Data were analyzed from January 1, 2018, through March 31, 2019. Main Outcomes and Measures: Measure of implicit bias derived from reaction times on the IATs and a measure of explicit bias asked directly to participants. Results: Almost 1 million IAT records from Project Implicit were reviewed, and 131 surgeons (64.9% men; mean [SD] age, 42.3 [11.5] years) were recruited to complete the Gender-Specialty IAT. Healthcare professionals (n = 42 991; 82.0% women; mean [SD] age, 32.7 [11.8] years) held implicit (mean [SD] D score, 0.41 [0.36]; Cohen d = 1.14) and explicit (mean [SD], 1.43 [1.85]; Cohen d = 0.77) biases associating men with career and women with family. Similarly, surgeons implicitly (mean [SD] D score, 0.28 [0.37]; Cohen d = 0.76) and explicitly (men: mean [SD], 1.27 [0.39]; Cohen d = 0.93; women: mean [SD], 0.73 [0.35]; Cohen d = 0.53) associated men with surgery and women with family medicine. There was broad evidence of consensus across social groups in implicit and explicit biases with one exception. Women in healthcare (mean [SD], 1.43 [1.86]; Cohen d = 0.77) and surgery (mean [SD], 0.73 [0.35]; Cohen d = 0.53) were less likely than men to explicitly associate men with career (B coefficient, -0.10; 95% CI, -0.15 to -0.04; P < .001) and surgery (B coefficient, -0.67; 95% CI, -1.21 to -0.13; P = .001) and women with family and family medicine. Conclusions and Relevance: The main contribution of this work is an estimate of the extent of implicit gender bias within surgery. On both the Gender-Career IAT and the novel Gender-Specialty IAT, respondents had a tendency to associate men with career and surgery and women with family and family medicine. Awareness of the existence of implicit biases is an important first step toward minimizing their potential effect.

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8Cre/+ PTENflox/flox mice. MOE PTENshRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTENshRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.

Exposure of the extracellular matrix and colonization of the ovary in metastasis of fallopian-tube-derived cancer.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE), but the role of the ovary in these tumors is unclear. Tumorigenic murine oviductal epithelial (MOE) cells allografted in the ovarian bursa resulted in aggressive tumors that spread throughout the peritoneum whereas intraperitoneal xenografting the same number of cells did not form tumors, indicating that colonization of the ovary may play a role in metastasis. Physical tearing of the ovarian surface to mimic rupture of the ovary during ovulation (independent of hormonal changes) resulted in more MOE and HGSOC cells adhering to the ovary compared with intact ovaries. More MOE cells also adhered to three-dimensional (3D) collagen and primary ovarian stromal cells than to ovarian surface epithelia, indicating that FTE cells adhered to the extracellular matrix exposed during ovulation. However, plating cells on 3D collagen reduced the viability of normal FTE but not cancer cells. Mutation of p53 (R273H or R248W) and activation of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) (G12V) did not increase the viability of MOE cells on 3D collagen. In contrast, loss of phosphatase and tensin homolog (PTEN) allowed MOE cells to retain normal viability on 3D collagen. Loss of PTEN activated AKT and RAC1/c-jun N-terminal kinase signaling that each contributed to the increased viability, invasion and attachment in the collagen rich ovarian microenvironment. These results show that loss of PTEN activates multiple pathways that together enhance colonization of the ovary due to access to 3D collagen, which is a critical organ in the colonization of FTE-derived HGSOC.

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody.

Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ∼10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth.

Hereditary hemochromatosis: patient experiences of the disease and phlebotomy treatment.

BACKGROUND: Hereditary hemochromatosis (HH) is a genetic disorder resulting in increased accumulation of dietary iron. It is associated with various clinical complications such as liver cirrhosis and diabetes. The aim of this study was to explore patients' experiences of living with HH, the diagnosis process, and phlebotomy treatment. STUDY DESIGN AND METHODS: An online survey was developed and completed by a total of 210 HH patients across the United States (n = 70), France (n = 50), Ireland (n = 40), and the United Kingdom (n = 50). RESULTS: Of the 210 patients, 30% were induction patients, 49% were maintenance patients, and 22% had never received phlebotomy. The most common route to diagnosis was by chance (42%), although most patients (87%) reported experiencing symptoms they now associated with HH at the time of diagnosis. Fatigue (60%) and joint pain (50%) were the most frequently reported current symptoms. While 87% of patients felt that treatment with phlebotomy was "quite worthwhile" or "very worthwhile," 52% of induction patients and 37% of maintenance patients experienced side effects "always" or "most of the time" after phlebotomy and 16% of patients would "definitely" or "probably" decide not to receive phlebotomy if alternative options were available. CONCLUSION: Diagnosis of HH is likely made late in many patients and subsequent phlebotomy treatment, while considered worthwhile by most, leads to concerns over side effects and inconvenience, often impacting patients' lives. Greater efforts to promote awareness of the disease and reduce the treatment burden associated with phlebotomy are required to improve detection and management of this disease.