Myringoplasty Using Human Birth Tissue Allografts to Repair Large Tympanic Membrane Perforations.

OBJECTIVE: Examine outcomes among a series of pediatric patients who underwent myringoplasty using human birth tissue (BT) for repair of large tympanic membrane (TM) perforations. STUDY DESIGN: Case series. SETTING: Single-institution pediatric hospital. METHODS: Retrospective chart review of patients treated with BT during a 4-year study period. Subjects who underwent myringoplasty for large (size 40% or greater) TM perforations were included for this study. Patients with a stable perforation of at least 1 month's duration preoperatively who then followed up for at least 3 months postoperatively met inclusion criteria. RESULTS: Six subjects were included in this study. One subject underwent bilateral repair; thus, this series includes a total of 7 perforations. TM perforations ranged from 40% to 70% of the TM. At initial follow-up (median of 2 months), 5 of the 7 perforations had healed. One of these 5 had evidence of a 10% recurrent perforation at 5 months, which subsequently healed. Of the 2 patients not healed at initial follow-up, 1 had only a residual pinpoint perforation that subsequently healed; the other had a persistent 30% perforation that was possibly related to their postoperative recovery period, which was complicated by a respiratory viral illness. CONCLUSION: For large TM perforations, myringoplasty with BT grafts may be a viable alternative to longer, more invasive procedures like tympanoplasty. Larger, randomized, prospective studies are needed.

A Major Facilitator Superfamily Transporter Contributes to Ergot Alkaloid Accumulation but Not Secretion in Aspergillus leporis.

Ergot alkaloids are fungal natural products with important roles in agriculture and medicine. We used heterologous expression and gene knockout approaches to investigate potential roles for the product of a major facilitator superfamily transporter gene (easT) recently found in an ergot alkaloid biosynthetic gene cluster in Aspergillus leporis. A strain of Aspergillus fumigatus previously engineered to accumulate lysergic acid, but which did not convert the precursor agroclavine to lysergic acid efficiently or secrete lysergic acid well, was chosen as an expression host for easT. Expression of easT in this strain resulted in accumulation of significantly more pathway intermediates but no detectable lysergic acid. Secretion of ergot alkaloids was reduced in the easT-expressing strain. EasT localized to discrete vesicle-like structures in the cytosol of A. fumigatus, with no localization detected in the plasma membrane. When easT was knocked out in A. leporis, accumulation of lysergic acid amides was reduced relative to the wild type. There was no negative effect on secretion of ergot alkaloids in the knockout mutant. The data indicate that easT encodes a product that contributes to accumulation of ergot alkaloids, perhaps by transporting intermediates between cellular compartments, but does not have a significant role in secreting ergot alkaloids.

Histopathologic Features of Mucosal Head and Neck Cancer Cachexia.

Objective: Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods: A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results: The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions: Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.

Repair of facial dog bite wound utilizing cryopreserved umbilical cord allograft.

BACKGROUND: In the United States, craniofacial injuries are the most frequently observed traumas in the pediatric population. Human birth tissue products contain growth factors, cytokines, and signaling molecules that can be potentially harnessed for tissue regeneration and wound healing. PURPOSE: A cryopreserved ultra-thick amniotic membrane (AM) allograft wound dressing was used in a patient with significant facial soft tissue loss due to a dog bite injury. METHODS: This is a single case report of a pediatric patient. After obtaining IRB exemption, operative and postoperative clinic notes were reviewed. RESULTS: A 10-year-old female presented to the emergency department after suffering a dog bite to her left cheek and upper lip, resulting in tissue loss. A cryopreserved ultra-thick AM allograft was used to cover the area of tissue loss as part of surgical reconstruction. The patient was followed up at 1 week, 3 weeks, 4 months, and 1 year after the graft was placed, and rapid healing and full epithelialization were achieved in addition to scar contracture due to wound location. CONCLUSION: In the setting of acute trauma and tissue loss, human birth tissue was found to promote epithelialization and regenerative healing of facial tissues.

The Role of Telemedicine in Voice Therapy.

Introduction: During the COVID-19 pandemic, our institution adopted telemedicine for voice therapy (VT) as an alternative to in-person sessions, which has been integrated into our routine practice following the pandemic. This study aims to explore factors influencing completion rates among the 2 methods. Method: A retrospective chart review at a single tertiary care institution between 2019 and 2021 was conducted. Patient zip codes were used to determine Neighborhood Atlas® Area Deprivation Index (ADI) scores and travel distance to our institution. Demographic data, Voice Handicap Index (VHI) scores, and completion status were extracted. Results: Between 2019 and 2021, 521 patients were referred to VT at our institution, with 29% opting for telemedicine VT (TVT) sessions and 71% choosing in-person sessions. Seventy-four percent was female, and average age was 57.1 years (range:10-89 years old). No statistically significant differences were observed between the 2 groups regarding sex, age, employment status, or insurance type. Participants in the TVT group demonstrated notably higher completion rates compared to the in-person group [70.0% vs 31.6% (P < .001)]. The TVT group also comprised of a higher percentage of white patients, reported longer travel distances and times to reach therapy, but had comparable ADI scores to the in-person group. Moreover, there were no significant differences in pretreatment VHI scores between the 2 groups or between those who completed therapy versus those who did not (P = .501). Conclusion: Our findings indicate that patients utilizing the telemedicine platform had significantly higher VT completion rates compared to patients appearing in person. These results highlight the importance of being able to offer telemedicine-based options in the management of voice patients.

Needle Decompression Complicated by Cardiac Injury in a Prehospital Environment.

Needle decompression is a mainstay intervention for tension pneumothorax in trauma medicine. It is used in combat and prehospital medicine when definitive measures are often not available or ideal. It can temporarily relieve increased intrathoracic pressure and treat a collapsed lung or great vessel obstruction. However, when done incorrectly, it can result in underlying visceral organ and vessel trauma. This is a case of an adult male who presented to the emergency department after sustaining multiple stab wounds during an altercation. On arrival, the patient had a 14-gauge angiocatheter inserted at the 4th intercostal space (ICS), left of the parasternal line traversing the right ventricle and interventricular septum and terminating in the left ventricle. The case emphasizes the importance of understanding the landmarks of performing needle decompression in increasing the procedure's efficacy and reducing iatrogenic complications.

Effectiveness of Kinematic Alignment-Total Knee Arthroplasty in Treating Preoperative Varus and Valgus Deformities in Patients With Knee Osteoarthritis.

Knee osteoarthritis (OA) is surgically treated with total knee arthroplasty (TKA). Traditionally, TKA has been performed using a mechanical alignment (MA) philosophy. However, due to significant patient dissatisfaction with surgical outcomes, an alternate alignment approach, kinematic alignment (KA), has gained popularity. KA-TKAs have improved functional patient outcomes by restoring the patient's native joint line orientation and minimizing soft tissue releases compared to neutral alignment in MA-TKAs. This review explores the postoperative effectiveness of utilizing KA-TKA to treat knee OA in patients with preoperative varus and valgus deformities. A comprehensive literature search was conducted on PubMed and Biomed Central databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search focused on studies analyzing the postoperative TKA outcomes in knee OA patients with preoperative varus or valgus deformities whose surgeries followed a KA philosophy and those comparing KA-TKA with MA-TKA. The available clinical evidence indicates that KA-TKA can be a viable treatment option for individuals with knee OA. The alignment of phenotypes has little clinical significance concerning functional outcomes and implant survival rates following KA-TKA. Furthermore, surgery outcomes in patients with preoperative deformities who underwent KA-TKA were similar to those who underwent MA-TKA. KA-TKA produced significantly better functional outcomes than MA-TKA in certain aspects. However, studies with larger sample sizes and more extended follow-up periods that directly compare KA-TKA with MA-TKA in treating knee OA patients are needed to fully demonstrate the efficacy of each technique. Furthermore, further research into the effects of KA-TKA on implant survival rates will provide a better understanding of the benefits of this technique and ultimately lead to improved patient outcomes.

Oncologic Safety of Close Margins in Patients With Low- to Intermediate-Grade Major Salivary Gland Carcinoma.

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. Main Outcomes and Measures: Main outcomes were risk factors for local recurrence. Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Correlating area deprivation index with initial stage at presentation and with follow up and recurrence within an advanced practice provider-led survivorship clinic.

INTRODUCTION: Living in disadvantaged neighborhoods has been shown to result in worse healthcare outcomes. The Area Deprivation Index (ADI) is a metric that ranks neighborhoods by socioeconomic disadvantage utilizing numerous factors including income, education, employment, and housing quality. METHODS: A retrospective review of all patients who underwent surveillance in an APP-led head and neck cancer survivorship clinic from Dec 2016 to Oct 2020 at an academic tertiary care center were included. Tumor characteristics, visit frequency, recurrence, number of missed appointments, loss of follow up, and ADI scores were collected. RESULTS: 543 patients were included in the study. A majority were male (69.9 %) and white race (84.9 %) with an average age of 64.6 years old. Average ADI national percentile score was 71.6(range: 17 to 100). ADI national percentile score was not predictive of tumor characteristics at initial presentation: lymphovascular invasion (p = 0.940; OR 1.0 [95 % CI: 0.9 to 1.1]), extranodal extension (p = 0.576; OR 1.0 [95 % CI: 0.9 to 1.2]), positive margins (p = 0.069; OR 0.9 [95 % CI: 0.9 to 1.0]). ADI national percentile score was not significantly correlated with loss to follow up (p = 0.153; OR 1.2 [95 % CI: 0.9 to 1.7] or cancer recurrence (p = 0.594; OR 1.0 [95 % CI: 0.9 to 1.1]). Missing one or more clinic visits was correlated with loss to follow up (p = 0.029; OR 13.1 [95 % CI: 1.3 to 131.7]. CONCLUSION: Living in a disadvantaged neighborhood did not correlate with negative tumor characteristics, loss to follow up, or recurrence within an APP-led survivorship head and neck cancer clinic.

An integrated framework for examining groundwater vulnerability in the Mekong River Delta region.

The Mekong River provides water, food security, and many other valuable benefits to the more than 60 million Southeast Asian residents living within its basin. However, the Mekong River Basin is increasingly stressed by changes in climate, land cover, and infrastructure. These changes can affect water quantity and quality and exacerbate related hazards such as land subsidence and saltwater intrusion, resulting in multiple compounding risks for neighboring communities. In this study, we demonstrate the connection between climate change, groundwater availability, and social vulnerability by linking the results of a numerical groundwater model to land cover and socioeconomic data at the Cambodia-Vietnam border in the Mekong River Delta region. We simulated changes in groundwater availability across 20 years and identified areas of potential water stress based on domestic and agriculture-related freshwater demands. We then assessed adaptive capacity to understand how communities may be able to respond to this stress to better understand the growing risk of groundwater scarcity driven by climate change and overextraction. This study offers a novel approach for assessing risk of groundwater scarcity by linking the effects of climate change to the socioeconomic context in which they occur. Increasing our understanding of how changes in groundwater availability may affect local populations can help water managers better plan for the future, leading to more resilient communities.

The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change.

PURPOSE: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. METHODS: Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 to 2021. RESULTS: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; P < .0001), whereas the use of GS compared with ES had no impact (22.2% vs 22.6%; P = ns). CONCLUSION: The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources toward important VUS follow-up.

Two Satellite Gene Clusters Enhance Ergot Alkaloid Biosynthesis Capacity of Aspergillus leporis.

Ergot alkaloids are fungal specialized metabolites that are important in agriculture and serve as sources of several pharmaceuticals. Aspergillus leporis is a soil saprotroph that possesses two ergot alkaloid biosynthetic gene clusters encoding lysergic acid amide production. We identified two additional, partial biosynthetic gene clusters within the A. leporis genome containing some of the ergot alkaloid synthesis (eas) genes required to make two groups of clavine ergot alkaloids, fumigaclavines and rugulovasines. Clavines possess unique biological properties compared to lysergic acid derivatives. Bioinformatic analyses indicated the fumigaclavine cluster contained functional copies of easA, easG, easD, easM, and easN. Genes resembling easQ and easH, which are required for rugulovasine production, were identified in a separate gene cluster. The pathways encoded by these partial, or satellite, clusters would require intermediates from the previously described lysergic acid amide pathway to synthesize a product. Chemical analyses of A. leporis cultures revealed the presence of fumigaclavine A. However, rugulovasine was only detected in a single sample, prompting a heterologous expression approach to confirm functionality of easQ and easH. An easA knockout strain of Metarhizium brunneum, which accumulates the rugulovasine precursor chanoclavine-I aldehyde, was chosen as expression host. Strains of M. brunneum expressing easQ and easH from A. leporis accumulated rugulovasine as demonstrated through mass spectrometry analysis. These data indicate that A. leporis is exceptional among fungi in having the capacity to synthesize products from three branches of the ergot alkaloid pathway and for utilizing an unusual satellite cluster approach to achieve that outcome. IMPORTANCE Ergot alkaloids are chemicals produced by several species of fungi and are notable for their impacts on agriculture and medicine. The ability to make ergot alkaloids is typically encoded by a clustered set of genes that are physically adjacent on a chromosome. Different ergot alkaloid classes are formed via branching of a complex pathway that begins with a core set of the same five genes. Most ergot alkaloid-producing fungi have a single cluster of genes that is complete, or self-sufficient, and produce ergot alkaloids from one or occasionally two branches from that single cluster. Our data show that Aspergillus leporis is exceptional in having the genetic capacity to make products from three pathway branches. Moreover, it uses a satellite cluster approach, in which gene products of partial clusters rely on supplementation with a chemical intermediate produced via another gene cluster, to diversify its biosynthetic potential without duplicating all the steps.

Climate resilience of dry season cereals in India.

India is the world's second largest producer of wheat, with more than 40% increase in production since 2000. Increasing temperatures raise concerns about wheat's sensitivity to heat. Traditionally-grown sorghum is an alternative rabi (winter season) cereal, but area under sorghum production has declined more than 20% since 2000. We examine sensitivity of wheat and sorghum yields to historical temperature and compare water requirements in districts where both cereals are cultivated. Wheat yields are sensitive to increases in maximum daily temperature in multiple stages of the growing season, while sorghum does not display the same sensitivity. Crop water requirements (mm) are 1.4 times greater for wheat than sorghum, mainly due to extension of its growing season into summer. However, water footprints (m3 per ton) are approximately 15% less for wheat due to its higher yields. Sensitivity to future climate projections, without changes in management, suggests 5% decline in wheat yields and 12% increase in water footprints by 2040, compared with 4% increase in water footprint for sorghum. On balance, sorghum provides a climate-resilient alternative to wheat for expansion in rabi cereals. However, yields need to increase to make sorghum competitive for farmer profits and efficient use of land to provide nutrients.

Crop switching can enhance environmental sustainability and farmer incomes in China.

Achieving food-system sustainability is a multidimensional challenge. In China, a doubling of crop production since 1990 has compromised other dimensions of sustainability1,2. Although the country is promoting various interventions to enhance production efficiency and reduce environmental impacts3, there is little understanding of whether crop switching can achieve more sustainable cropping systems and whether coordinated action is needed to avoid tradeoffs. Here we combine high-resolution data on crop-specific yields, harvested areas, environmental footprints and farmer incomes to first quantify the current state of crop-production sustainability. Under varying levels of inter-ministerial and central coordination, we perform spatial optimizations that redistribute crops to meet a suite of agricultural sustainable development targets. With a siloed approach-in which each government ministry seeks to improve a single sustainability outcome in isolation-crop switching could realize large individual benefits but produce tradeoffs for other dimensions and between regions. In cases of central coordination-in which tradeoffs are prevented-we find marked co-benefits for environmental-impact reductions (blue water (-4.5% to -18.5%), green water (-4.4% to -9.5%), greenhouse gases (GHGs) (-1.7% to -7.7%), fertilizers (-5.2% to -10.9%), pesticides (-4.3% to -10.8%)) and increased farmer incomes (+2.9% to +7.5%). These outcomes of centrally coordinated crop switching can contribute substantially (23-40% across dimensions) towards China's 2030 agricultural sustainable development targets and potentially produce global resource savings. This integrated approach can inform feasible targeted agricultural interventions that achieve sustainability co-benefits across several dimensions.

A randomized study on the value of self-directed versus traditional mentor-led microsurgical training.

Objective: Analyze efficacy of self-directed resident microvascular training versus a mentor-led course. Study Design: Randomized, single-blinded cohort study. Setting: Academic tertiary care center. Methods: Sixteen resident and fellow participants were randomized into two groups stratified by training year. Group A completed a self-directed microvascular course with instructional videos and self-directed lab sessions. Group B completed a traditional mentor-led microvascular course. Both groups spent equal time in the lab. Video recorded pre and post-course microsurgical skill assessments were performed to assess the efficacy of the training. Two microsurgeons, blinded to participant identity, evaluated the recordings and inspected each microvascular anastomosis (MVA). Videos were scored using an objective-structured assessment of technical skills (OSATS), a global rating scale (GRS), and quality of anastomosis scoring (QoA). Results: The pre-course assessment identified that the groups were well matched with only "Economy of Motion" on the GRS favoring the mentor led group (p = .02). This difference remained significant on the post assessment (p = .02) Both groups significantly improved in OSATS and GRS scoring (p < .05). There was no significant difference in OSATS improvement between the two groups (p = .36) or improvement in MVA quality between groups (p > .99). Time to completion of MVA significantly improved overall by a mean of 8 min and 9 s (p = .005) with no significant difference between post training times to complete (p = .63). Conclusion: Different microsurgical training models have previously been validated as effective methods for improved MVA performance. Our findings indicate that a self-directed microsurgical training model is an effective alternative to a traditional mentor driven models. Level of Evidence: Level 2.

Characterizing Pediatric Bilateral Vocal Fold Dysfunction: Analysis with the Pediatric Health Information System Database.

OBJECTIVES: The purpose of this study was to characterize pediatric bilateral vocal fold dysfunction and to examine the overall inpatient mortality. METHODS: Retrospective cohort analysis. Data from the Pediatric Health Information System was gathered for all pediatric patients with a diagnosis of bilateral vocal fold dysfunction between January 2008 and September 2020. Univariate and multivariate analyses were performed using Cox proportional hazard models. RESULTS: 2395 patients accounted for 4799 hospitalizations with bilateral vocal fold dysfunction. Inpatient mortality occurred in 2.9% of the study sample. Chiari 2 was found in 2.8% of patients. The most common associated diagnoses were related to comorbid respiratory conditions (61.1%). The median adjusted ratio of cost to charges was $76,569. Aspiration was noted in 28 patients (1.2%). Gastrostomy was performed in 607 patients (25.3%). Tracheostomy was performed in 27% of patients. The overall 90-day readmission rate was 61%. On multivariate analysis, prognostic factors associated with increased hospital survival include gastrointestinal comorbidities (hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.18-0.49) and tracheostomy (HR: 0.21; 95% CI: 0.12-0.37). CONCLUSION: This database study represents the largest cohort analysis to date characterizing bilateral vocal fold dysfunction. Favorable prognostic indicators of overall hospital survival include gastrointestinal comorbidities and the presence of tracheostomy. Tracheostomy is associated with an increase in hospital costs, comorbidities, gastrostomy tube placement, and Chiari diagnosis. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1228-1233, 2023.