Perceptions and Understanding of Transgender Patient Care: A Survey of Practicing Laryngologists.

OBJECTIVES: Transgender individuals face significant health disparities including deficiencies in physician education, knowledge, and comfort with transgender health care. As the prevalence of the transgender population increases more individuals may seek gender-affirming surgery. Herein, we present a survey study which presents data on (1) the current practice patterns, (2) the familiarity with, (3) the perception of, and (4) the future educational goals of transgender health care among laryngologists in the United States. METHODS: A cross-sectional survey study of practicing laryngologists in the United States. RESULTS: A total of 53 laryngologists participated in the study, with 50 (94.3%) coming from an academic practice. Survey response rate was 32.3% (54/167). The number of patients cared for and surgeries performed were significantly associated with self-perceived overall competence (p < 0.001 and p < 0.001), surgical competence (p = 0.013 and p < 0.001), and comfort counseling patients on gender-affirming surgeries (p < 0.001 and p < 0.001). Most obtained training through real-world experience (n = 46, 86.8%), whereas only 11 (20.7%) had formal training in residency or fellowship. Although 37 (70%) of participants felt competent caring for transgender patients, 38 (72%) want to learn more about transgender care, and 49 (93%) support incorporating transgender care into otolaryngology residency/fellowship curricula. CONCLUSION: There is a need for an increased awareness of transgender healthcare issues to address disparities experienced by this diverse population. Many laryngologists report wanting to learn more about this developing part of our field and support incorporating transgender care into training. We attempt to spotlight the degree by which practicing laryngologists are familiar, competent, and comfortable with transgender care. LEVEL OF EVIDENCE: 5 Laryngoscope, 2024.

Glomerular hyperfiltration is an independent predictor of postoperative outcomes: A NSQIP multi-specialty surgical cohort analysis.

AIM: While high estimated glomerular filtration rate (eGFR) has been associated with increased overall mortality, its effect on postoperative outcomes is relatively understudied. We sought to investigate the association between high eGFR and 30-day postoperative outcomes using a multi-specialty surgical cohort. METHODS: Using the National Surgical Quality Improvement Program database, we selected adult for whom eGFR could be calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. Based on sex-specific distributions of eGFR stratified by age quintiles, we classified patients into low (<5th percentile), normal (5-95th percentile) and high eGFR (>95th percentile). The primary outcome was a composite of any 30-day major adverse outcomes, including: death, reoperation, cardiac arrest, myocardial infarction and stroke. Secondary outcomes included 30-day infectious complications, venous thromboembolism (VTE), bleeding requiring transfusion, prolonged length of stay and unplanned readmission. After matching for demographic differences, comorbidity burden and operative characteristics, logistic regression models were used to evaluate the association between extremes of eGFR and the outcomes of interest. RESULTS: Of 1 668 447 patients, 84 115 (5.07%) had a high eGFR. High eGFR was not associated with major adverse outcomes (odds ratio [OR] 1.00 [95% confidence interval (CI): 0.97, 1.03]); however, it was associated with reoperation (OR 1.04 [95% CI: 1.00,1.08]), infectious complications (OR 1.14 [95% CI: 1.11, 1.16]), VTE (OR 1.15 [95% CI: 1.09, 1.22]) and prolonged length of stay (OR 1.19 [95% CI: 1.16, 1.21]). CONCLUSION: Our findings support an association between high eGFR and adverse 30-day postoperative outcomes.

Patient Attitudes and Barriers to Endoscopy During the COVID-19 Pandemic.

BACKGROUND: After COVID-19 restrictions on nonessential procedures were lifted and safety protocols established, utilization rates of endoscopic procedures remained reduced. AIMS: This study assessed patient attitudes and barriers to scheduling endoscopy during the pandemic. METHODS: A survey was administered to patients with ordered procedures at a hospital-based setting (7/21/2020-2/19/2021) collecting demographic data, body mass index, COVID-19 relevant comorbidities, level of procedural urgency (defined by recommended scheduling window), scheduling and attendance, concerns, and awareness of safety measures. RESULTS: The average respondent was female (63.8%), age 57.6 ± 14, White (72.3%), married (76.7%), insured (99.3%), affluent English speakers (92.3%) and highly educated (at least college 90.2%). Most reported moderate to excellent COVID-19 knowledge (96.6%). Of 1039 procedures scheduled, emergent cases accounted for 5.1%, urgent 55.3% and elective 39.4%. Respondents identified appointment convenience (48.53%) as the most frequent factor impacting scheduling, also noting concern for results (28.4%). Age (p = .022), native language (p = .04), education (p = .007), self-reported COVID knowledge (p = .002), and a desire to be COVID tested pre-procedure (p = .023) were associated with arrival, more commonly in an ambulatory surgical center than hospital (p = .008). Diabetes mellitus (p = .004) and an immunocompromised state (p = .009) were adversely related to attendance. Attitudes towards safety protocols did not affect scheduling. Multivariate analysis demonstrated age, education and COVID knowledgeability were associated with procedure completion. CONCLUSIONS: Safety protocols and urgency levels were not associated with procedure completion. Pre-pandemic barriers to endoscopy persisted as dominant factors amid pandemic concerns.

Morbidity and mortality of multivisceral resection with radical nephrectomy for locally advanced renal cell carcinoma: An analysis of the National Surgical Quality Improvement Program (NSQIP) database.

INTRODUCTION: Locally advanced renal cell carcinoma (RCC) can rarely invade into adjacent abdominal viscera without clinical evidence of distant metastases. The role of multivisceral resection (MVR) of involved adjacent organs at the time of radical nephrectomy (RN) remains poorly described and quantified. Using a national database, we aimed to evaluate the association between RN+MVR and 30-day postoperative complications. METHODS AND MATERIALS: We conducted a retrospective cohort study of adult patients undergoing RN for RCC with and without MVR between 2005 and 2020 using the ACS-NSQIP database. The primary outcome was a composite of any of the following 30-day major postoperative complications: mortality, reoperation, cardiac event, and neurologic event. Secondary outcomes included individual components of the composite primary outcome, as well as infectious and venous thromboembolic complications, unplanned intubation and ventilation, transfusion, readmission, and prolonged length of stay (LOS). Groups were balanced using propensity score matching. Likelihood of complications was assessed by conditional logistic regression adjusted for unbalanced total operation time. Postoperative complications were compared by Fisher's exact test among subtypes of resection. RESULTS: A total of 12,417 patients were identified: 12,193 (98.2%) undergoing RN alone and 224 (1.8%) undergoing RN+MVR. Patients undergoing RN+MVR were more likely to experience major complications (odds ratio [OR] 2.46; 95% confidence interval [CI] 1.28-4.74). However, there was no significant association between RN+MVR and postoperative mortality (OR 2.49; 95% CI 0.89-7.01). RN+MVR was associated with higher rates of reoperation (OR 7.85; 95% CI 2.38-25.8), sepsis (OR 5.45; 95% CI 1.83-16.2), surgical site infection (OR 4.41; 95% CI 2.14-9.07), blood transfusion (OR 2.24; 95% CI 1.55-3.22), readmission (OR 1.78; 95% CI 1.11-2.84), infectious complications (OR 2.62; 95% CI 1.62-4.24), and longer hospital stay (5 days [IQR 3-8] vs. 4 days [IQR 3-7]; OR 2.31 [95% CI 2.13-3.03]).  There was no heterogeneity in the association between subtype of MVR and major complication rate. CONCLUSION: Undergoing RN+MVR is associated with an increased risk of 30-day postoperative morbidity, including infectious complications, reoperation, blood transfusion, prolonged LOS, and readmission.

Comparison of keratometry using SS-OCT and dual Scheimpflug-Placido imaging in postmyopic corneal refractive surgery eyes.

PURPOSE: To compare simulated (SimK) and total (True-K) keratometry and corneal astigmatism values between the IOLMaster 700 (IOLM) and Galilei G4 (G4) devices in postmyopic laser refractive surgery eyes. SETTING: Methodist Eye Associates, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas. DESIGN: Retrospective cohort study. METHODS: A chart review was conducted on patients with prior myopic laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK), undergoing phacoemulsification at a single institution from May 2019 through January 2022, who underwent imaging with both the IOLM and G4. Exclusion criteria were prior radial keratotomy, keratoectatic diseases, and inability to obtain a reliable image. Mean, flat, and steep SimK and True-K (TK from the IOLM and TCP IOL from the G4) values and astigmatism magnitude were compared. RESULTS: 50 eyes of 50 patients were included. The mean difference in SimK and True-K between devices (IOLM - G4) was -0.04 (95% CI -0.13 to 0.06; P > .05) diopters (D) and 1.14 (95% CI 1.02 to 1.25; P < .05) D, respectively. The IOLM measured steeper True-K values than the G4. There were no statistically significant differences between devices for all other SimK values, whereas for True-K there were significant differences in flat K and steep K ( P < .05), but not astigmatism magnitude. CONCLUSIONS: Despite an overall good correlation in postmyopic laser refractive surgery eyes in keratometry and astigmatism measurements, there is a significant difference in True-K, with the IOLM measuring steeper values by about 1.0 D compared with the G4, similar to prior studies on nonrefractive surgery eyes.

COVID-19 and communication: A sentiment analysis of US state governors' official press releases.

OBJECTIVES: This study examines the contents of official communication from United States governors' offices related to the COVID-19 pandemic to assess patterns in communication and to determine if they correlate with trends for COVID cases and deaths. METHODS: We collected text data for all COVID-19 related press releases between March 1 and December 31, 2020 from the US governors' office websites in all 50 states. An automated parsing and sentiment analyzer assessed descriptive statistics and trends in tone, including positivity and negativity. RESULTS: We included a total of 7,720 press releases in this study. We found that both positive and negative sentiments were homogenous across states at the beginning of the pandemic but became heterogeneous as the pandemic evolved. The same trend applied to the frequency and tone of press releases. Sentiments across states were overall positive with a small level of negativity. We observed a reactive official communication to the evolution of the number of COVID-19 cases rather than responsive or preventive. CONCLUSIONS: The findings of both positivity and negativity in press communications suggest that the effect of discounted importance was present in official communications. Our findings support a state-dependent optimal communication frequency and tone, agreeing with the curvilinear communication model of organizational theory and implying that feedback cycles between government officials and public response should be shortened to rapidly maximize communication efficacy during the pandemic. Future research should identify and evaluate the drivers of the large differences in communication tone across states and validate the reactive characteristics of COVID-19 official communications.

Pancreatic head vs pancreatic body/tail cancer: Are they different?

BACKGROUND: The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results. AIM: To explore if pancreatic head cancer (PHC) and pancreatic body/tail cancer (PBTC) have different overall survival (OS), molecular signature and response to chemotherapy. METHODS: We retrospectively queried patient records from July 2016 to June 2020 in our institution. Patient demographics, cancer stage on diagnosis, tumor location, somatic mutations, treatment, and survival are recorded and analyzed. A test is considered statistically significant if the P value was < 0.05. RESULTS: We reviewed 101 patients with complete records, among which 67 (66.34%) were PHC and 34 (33.66%) were PBTC. More PHC were diagnosed at younger age [61.49 vs 68.97, P = 0.010], earlier stages (P = 0.006) and underwent surgical resection (P = 0.025). There were no significant differences among all mutations and pathways studied except for TP53 mutations (37.0% in PHC vs 70.0% in PBTC, P = 0.03). OS was not statistically different between PHC and PBTC (P = 0.636) in the overall population and in subgroups according to surgical resection status or stages. In terms of response to chemotherapy, chemotherapy regimens (FOLFIRINOX-based vs gemcitabine-based) didn't impact disease free interval in those who had surgical resection in either PHC (P = 0.546) or PBTC (P = 0.654), or the duration of response to first line palliative treatment in those with advanced disease in PHC (P = 0.915) or PBTC (P = 0.524). CONCLUSION: Even though PHC and PBTC have similar poor OS and response to chemotherapy, the different presentations and molecular profiles indicate they are different diseases. Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.

A non-translational role of threonyl-tRNA synthetase in regulating JNK signaling during myogenic differentiation.

Aminoacyl-tRNA synthetases (aaRSs) are house-keeping enzymes that are essential for protein synthesis. However, it has become increasingly evident that some aaRSs also have non-translational functions. Here we report the identification of a non-translational function of threonyl-tRNA synthetase (ThrRS) in myogenic differentiation. We find that ThrRS negatively regulates myoblast differentiation in vitro and injury-induced skeletal muscle regeneration in vivo. This function is independent of amino acid binding or aminoacylation activity of ThrRS, and knockdown of ThrRS leads to enhanced differentiation without affecting the global protein synthesis rate. Furthermore, we show that the non-catalytic new domains (UNE-T and TGS) of ThrRS are both necessary and sufficient for the myogenic function. In searching for a molecular mechanism of this new function, we find the kinase JNK to be a downstream target of ThrRS. Our data further reveal MEKK4 and MKK4 as upstream regulators of JNK in myogenesis and the MEKK4-MKK4-JNK pathway to be a mediator of the myogenic function of ThrRS. Finally, we show that ThrRS physically interacts with Axin1, disrupts Axin1-MEKK4 interaction and consequently inhibits JNK signaling. In conclusion, we uncover a non-translational function for ThrRS in the maintenance of homeostasis of skeletal myogenesis and identify the Axin1-MEKK4-MKK4-JNK signaling axis to be an immediate target of ThrRS action.

Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins.

Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employ a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. Of 67 human PH domain-containing proteins initially examined, 36 (54%) are found to have affinity for PIPs with various specificity, the majority of which have not been reported before. Further investigation of ARHGEF3 reveals distinct structural requirements for its binding to PI(4,5)P2 and PI(3,5)P2, and functional relevance of its PI(4,5)P2 binding. We generate a recursive-learning algorithm based on the assay results to analyze the sequences of 242 human PH domains, predicting that 49% of them bind PIPs. Twenty predicted binders and 11 predicted non-binders are assayed, yielding results highly consistent with the prediction. Taken together, our findings reveal unexpected lipid-binding specificity of PH domain-containing proteins.

Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers.

Circulating polymers of α1-antitrypsin (α1AT) are neutrophil chemo-attractants and contribute to inflammation, yet cellular factors affecting their secretion remain obscure. We report on a genome-wide CRISPR-Cas9 screen for genes affecting trafficking of polymerogenic α1ATH334D. A CRISPR enrichment approach based on recovery of single guide RNA (sgRNA) sequences from phenotypically selected fixed cells reveals that cells with high-polymer content are enriched in sgRNAs targeting genes involved in "cargo loading into COPII-coated vesicles," where "COPII" is coat protein II, including the cargo receptors lectin mannose binding1 (LMAN1) and surfeit protein locus 4 (SURF4). LMAN1- and SURF4-disrupted cells display a secretion defect extending beyond α1AT monomers to polymers. Polymer secretion is especially dependent on SURF4 and correlates with a SURF4-α1ATH334D physical interaction and with their co-localization at the endoplasmic reticulum (ER). These findings indicate that ER cargo receptors co-ordinate progression of α1AT out of the ER and modulate the accumulation of polymeric α1AT not only by controlling the concentration of precursor monomers but also by promoting secretion of polymers.

Contrast-induced encephalopathy in an infant.

Contrast-induced encephalopathy (CIE) is a well-known but rare complication following contrast media administration. Its nonspecific clinical manifestations hinder diagnosis, particularly in the pediatric population. The majority of cases are reversible, with clinical improvement and resolution of signs noted on diagnostic imaging. Here, we report the case of a 2-month-old patient with a history of complex cardiovascular disease who presented with a single episode of seizure after undergoing cardiac catheterization with nonionic iodinated contrast media. CIE is diagnosed based on the signs and symptoms exhibited by the patient and the findings on plain head computed tomography (CT) scan. Subsequently, the absence of neurological symptoms and disappearance of the imaging alterations on a control CT are documented.

ARHGEF3 Regulates Skeletal Muscle Regeneration and Strength through Autophagy.

Skeletal muscle regeneration after injury is essential for maintaining muscle function throughout aging. ARHGEF3, a RhoA/B-specific GEF, negatively regulates myoblast differentiation through Akt signaling independently of its GEF activity in vitro. Here, we report ARHGEF3's role in skeletal muscle regeneration revealed by ARHGEF3-KO mice. These mice exhibit indiscernible phenotype under basal conditions. Upon acute injury, however, ARHGEF3 deficiency enhances the mass/fiber size and function of regenerating muscles in both young and regeneration-defective middle-aged mice. Surprisingly, these effects occur independently of Akt but via the GEF activity of ARHGEF3. Consistently, overexpression of ARHGEF3 inhibits muscle regeneration in a Rho-associated kinase-dependent manner. We further show that ARHGEF3 KO promotes muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength. Accordingly, ARHGEF3 depletion in old mice prevents muscle weakness by restoring autophagy. Taken together, our findings identify a link between ARHGEF3 and autophagy-related muscle pathophysiology.

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

Complications associated with L4-5 anterior retroperitoneal trans-psoas interbody fusion: a single institution series.

BACKGROUND: Lateral lumbar interbody fusion (LLIF), first described in the literature in 2006 by Ozgur et al., involves direct access to the lateral disc space via a retroperitoneal trans-psoas tubular approach. Neuromonitoring is vital during this approach since the surgical corridor traverses the psoas muscle where the lumbar plexus lies, risking injury to the lumbosacral plexus that could result in sensory or motor deficits. The risk of neurologic injury is especially higher at L4-5 due to the anatomy of the plexus at this level. Here we report our single-center clinical experience with L4-5 LLIF. METHODS: A retrospective chart review of all patients who underwent an L4-5 LLIF between May 2016 and March 2019 was performed. Baseline demographics and clinical characteristics, such as body mass index (BMI), medical comorbidities, surgical history, tobacco status, operative time and blood loss, length of stay (LOS), and post-op complications were recorded. RESULTS: A total of 220 (58% female and 42% male) cases were reviewed. The most common presenting pathology was spondylolisthesis. The average age, BMI, operative time, blood loss, and LOS were 64.6 years, 29 kg/m2, 214 min, 75 cc, and 2.5 days respectively. A review of post-operative neurologic deficits revealed 31.4% transient hip flexor weakness and 4.5% quadricep weakness on the approach side. At 3-week follow-up, 9.1% of patients experienced mild hip flexor weakness (4 or 4+/5), 0.9% reported mild quadricep weakness, and 9.5% reported anterior thigh dysesthesias; 93.2% of patients were discharged home and 2.3% were readmitted within the first 30 days post discharge. Female sex, higher BMI and longer operative time were associated with hip flexor weakness. CONCLUSIONS: LLIF at L4-5 is a safe, feasible, and versatile approach to the lumbar spine with an acceptable approach-related sensory and motor neurologic complication rates.

The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells.

The eukaryotic translation initiation factor 2α (eIF2α) kinase GCN2 is activated by amino acid starvation to elicit a rectifying physiological program known as the Integrated Stress Response (ISR). A role for uncharged tRNAs as activating ligands of yeast GCN2 is supported experimentally. However, mouse GCN2 activation has recently been observed in circumstances associated with ribosome stalling with no global increase in uncharged tRNAs. We report on a mammalian CHO cell-based CRISPR-Cas9 mutagenesis screen for genes that contribute to ISR activation by amino acid starvation. Disruption of genes encoding components of the ribosome P-stalk, uL10 and P1, selectively attenuated GCN2-mediated ISR activation by amino acid starvation or interference with tRNA charging without affecting the endoplasmic reticulum unfolded protein stress-induced ISR, mediated by the related eIF2α kinase PERK. Wildtype ribosomes isolated from CHO cells, but not those with P-stalk lesions, stimulated GCN2-dependent eIF2α phosphorylation in vitro. These observations support a model whereby lack of a cognate charged tRNA exposes a latent capacity of the ribosome P-stalk to activate GCN2 in cells and help explain the emerging link between ribosome stalling and ISR activation.

Lentivirus-Mediated RNAi in Skeletal Myogenesis.

RNA interference (RNAi) has greatly facilitated investigation of gene functions in vitro as well as in vivo. Recombinant lentivirus is widely used to deliver small hairpin RNA (shRNA) because of its high transduction capacity into diverse cell types and tissues. Here, we describe methods of lentivirus-mediated delivery of shRNA for the study of skeletal muscle cell differentiation in vitro and injury-induced muscle regeneration in mice.

Lanthionine synthetase C-like protein 2 (LanCL2) is important for adipogenic differentiation.

Adipogenic differentiation is a highly regulated process that is necessary for metabolic homeostasis and nutrient sensing. The expression of PPARγ and the subsequent activation of adipogenic genes is critical for the process. In this study, we identified lanthionine synthetase C-like protein 2 (LanCL2) as a positive regulator of adipogenesis in 3T3-L1 cells. Knockdown of LanCL2, but not LanCL1, inhibited adipogenic differentiation, and this effect was not mediated through cAMP or Akt signaling pathways. The expression of early adipogenic markers CCAAT enhancer binding protein ß (C/EBPß) and C/EBPδ remained intact in LanCL2 knockdown cells, but levels of late adipogenic markers PPARγ and C/EBPα were suppressed. The addition of the naturally occurring PPARγ activator 15-deoxy-Δ12,14-prostaglandin J2 or conditioned medium from differentiating cells did not restore differentiation, implying that LanCL2 may not be involved in the production of a secreted endogenous PPARγ ligand. Pulldown assays demonstrated a direct physical interaction between LanCL2 and PPARγ. Consistent with a regulatory role of LanCL2, luciferase reporter assays revealed that full transcriptional activation by PPARγ was dependent on LanCL2. Taken together, our study reveals a novel role of LanCL2 in adipogenesis, specifically involved in PPARγ-mediated transactivation of downstream adipogenic genes.