Once-weekly semaglutide in people with HIV-associated lipohypertrophy: a randomised, double-blind, placebo-controlled phase 2b single-centre clinical trial.

BACKGROUND: HIV-associated lipohypertrophy, which is characterised by an abnormal accumulation of abdominal visceral adipose tissue, remains problematic in people with HIV. Effective interventions are lacking, despite HIV-associated lipohypertrophy carrying a substantial risk of cardiometabolic comorbidity. The primary aim of this trial was to investigate effects of the GLP-1 receptor agonist, semaglutide, on adipose tissue in HIV-associated lipohypertrophy. METHODS: This randomised, double-blind, placebo-controlled phase 2b clinical trial was conducted at a single US site. Key inclusion criteria included people with HIV aged 18 years or older with controlled HIV-1, a BMI of 25 kg/m2 or more, and lipohypertrophy but without type 1 or type 2 diabetes. Participants were randomly assigned 1:1 to receive 32 weeks of once-weekly subcutaneous semaglutide (8-week dose titration and 24 weeks at 1·0 mg) or placebo; all research personnel and participants remained masked to treatment assignment. Primary outcomes were changes at 32 weeks in adipose tissue quantity by body compartment. Analyses, including safety, were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. FINDINGS: Between June 10, 2019, and July 28, 2022, 108 participants were randomly assigned to receive semaglutide (n=54) or placebo (n=54). Eight (15%) in each group withdrew prematurely. Significant effects of semaglutide were seen over the 32-week study period in sex-adjusted multiplicative regression analyses for the primary outcome, abdominal visceral adipose tissue (ß -30·82 cm2, 95% CI -50·13 to -11·51; % change -30·6%). Decreases were also seen in other key measures, including abdominal subcutaneous adipose tissue (ß -42·01 cm2, 95% CI -75·49 to -8·52; % change -11·2%) and total body fat (natural logarithmic -0·21 kg, 95% CI -0·33 to -0·08; % change -18·9%). There were no statistically significant differences in possibly related or related adverse events (absolute risk difference 0·1111, 95% CI -0·0727 to 0·2869); however, one semaglutide-related grade 4 elevated lipase and two possibly related cases of cholelithiasis (grades 1 and 2) were observed. INTERPRETATION: Semaglutide holds promise as an effective treatment for HIV-associated lipohypertrophy. The potential risk of serious adverse events deserves further scrutiny in large trials in people with HIV. FUNDING: National Institutes of Health.

Local repair of persistent tracheocutaneous fistulas.

Tracheocutaneous fistulas may persist after tracheostomy. Suture closure of the fistula may result in complications, including infection, wound dehiscence, and pneumomediastinum. We present a simplified and relatively safe technique to close persistent fistulas that may be performed under local anesthesia. A retrospective chart review was performed on 13 patients who were successfully treated, including 1 with incomplete closure that was successfully addressed by additional procedures. Our review included analysis of reported risk factors for persistence of tracheocutaneous fistulas: previous irradiation of the neck, an extended duration of cannulation, previous tracheostomies, obesity, and use of a Bjork flap or 4-flap epithelial-lined tracheostomy. All 13 patients in the study were found to have at least 1 of these risk factors.

Ultrasound-guided needle localization of recurrent paratracheal thyroid cancer.

OBJECTIVES: Ultrasound-guided needle localization techniques have been used to direct the resection of targeted axillary lymph nodes in the management of breast cancer. To date, there has been only one other description of this technique as a localization method to direct cancer resection in the neck. We offer further support for the broader application of this technique by reporting its use in the successful identification and resection of recurrent papillary thyroid cancer after a paratracheal node dissection failed to localize the cancer. METHODS: We report a case and discuss the relevant literature regarding ultrasound-guided localization and resection of recurrent well-differentiated thyroid cancer. RESULTS: We were able to achieve successful identification and resection of recurrent papillary thyroid cancer using this technique. CONCLUSIONS: This technique may be useful in the treatment of selected cases of recurrent thyroid cancer to increase the efficacy and safety of surgical resection.

Anterior skull-base surgery: current opinion.

PURPOSE OF REVIEW: The field of anterior skull-base surgery has undergone rapid advancement in the last 10-15 years. As a result, tumors of the anterior skull base that were once considered inoperable are now routinely resected with reliable results and decreasing morbidity. The purpose of this review is to highlight the most up-to-date opinions and advancements within the field, and to evaluate the recent advances in the surgical management of anterior skull-base tumors. RECENT FINDINGS: In the last year, the body of literature in anterior skull-base surgery has been expanded with new anatomic insights, surgical techniques, and data on patient outcomes and quality of life. Much of this literature is focused on minimally invasive, endoscopic techniques, which have expanded greatly in the last decade. SUMMARY: This article summarizes the most current opinion in the field of anterior skull-base surgery. Recent literature regarding new anatomic insights, surgical techniques (resection and reconstruction), and outcomes data are outlined.

Endoscopic transnasal resection of ameloblastoma with intracranial extension.

Ameloblastoma is a rare odontogenic tumor with characteristics of epithelial tissue that produces enamel for the developing tooth. This lesion is generally considered benign, but has malignant forms that invade locally and metastasize. We present a 60-year-old man with maxillary ameloblastoma that after multiple recurrences developed intracranial extension with dural involvement of the middle cranial fossa and was treated by endoscopic transnasal resection followed by radiation therapy. Our technique and intraoperative findings are described with a review of the literature on intracranial ameloblastoma. This patient represents a unique account of endoscopic transnasal resection being utilized in the treatment of intracranial extension of ameloblastoma and demonstrates potential for application in similar cases.

The effect of geniglossal advancement on airway flow using a computational flow dynamics model.

OBJECTIVES/HYPOTHESIS: Obstructive sleep apnea (OSA) is a sleep disorder caused by partial or complete collapse of the pharyngeal airway. Genioglossal advancement (GGA) is a well-tolerated surgical procedure intended to address hypopharyngeal collapse, yet there are few studies that monitor changes in airflow dynamics at this site. Computation fluid dynamics (CFD) utilizes airflow simulation to predict changes in airflow after anatomic manipulation. STUDY DESIGN: We investigated the change in volume and airflow dynamics of the pharyngeal airway after GGA in a cadaveric model. METHODS: We performed serial GGA from 1 mm (control) to 3, 7, and 9 mm on a lightly preserved cadaver. After each intervention, we performed high-resolution computed tomography scans, reconstructed the pharyngeal airway, and quantified airspace volume and CFD analysis with both laminar and large eddy simulation models. RESULTS: Airway volume increased with linear GGA. In both CFD simulation models, velocity increased and pressure decreased after 9-mm advancement secondary to increased airway diameter and less abrupt changes in airway geometry. CONCLUSIONS: These results suggest that GGA may be effective in increasing airway volume and flow to address hypopharyngeal obstruction in OSA.

Factors correlating with burnout in practicing otolaryngologists.

OBJECTIVE: This study sought to determine which demographic and practice characteristics were predictive of professional burnout in otolaryngologists. STUDY DESIGN: Cross-sectional survey. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: Postal mailings, including the Maslach Burnout Inventory (MBI), were sent to alumni of the University of Iowa Hospitals and Clinics otolaryngology program. Participants completed the MBI according to the enclosed instructions. In addition, they answered a brief questionnaire comprising 8 items designed to collect demographic information. The MBI was then scored and subjects were classified according to their degree of burnout. Statistical analysis was then performed, and correlations were used to summarize associations between continuous variables. RESULTS: This study had a response rate of 49% to the survey. Of the respondents, 3.5% met criteria for burnout syndrome, and 16% were classified as having high levels of burnout according to the MBI. Young age, number of hours worked per week, and length of time in practice were found to be statistically significant predictors of burnout. In addition, the length of time married and the presence of children in the home were also significant predictors of burnout. CONCLUSION: The authors report an investigation of burnout in practicing otolaryngologists using a validated instrument with correlation to potentially modifiable risk factors. The experience of burnout was found to correlate significantly with both personal and professional factors, each of which can potentially be addressed to curb the incidence of burnout. Further understanding of the potential risk factors for burnout is necessary to minimize and prevent burnout among practicing otolaryngologists.

Endoscopic resection of calcifying pseudoneoplasm of the neuraxis (CAPNON) of the anterior skull base with sinonasal extension.

We present a calcifying pseudoneoplasm of the neuraxis (CAPNON) of the anterior skull base that was resected endoscopically. The clinical details are reported with a review of the relevant literature. CAPNON, although rare, should be considered in the differential diagnosis of tumors presenting along the anterior skull base with radiographic characteristics consistent with a fibro-osseous lesion. Endoscopic resection of these lesions is feasible in select patients with sinonasal extension.

Activation of a poised RNAPII-dependent promoter requires both SAGA and mediator.

A growing number of promoters have key components of the transcription machinery, such as TATA-binding protein (TBP) and RNA polymerase II (RNAPII), present at the promoter prior to activation of transcription. Thus, while transcriptional output undergoes a dramatic increase between uninduced and induced conditions, occupancy of a large portion of the transcription machinery does not. As such, activation of these poised promoters depends on rate-limiting steps after recruitment of TBP and RNAPII for regulated expression. Little is known about the transcription components required in these latter steps of transcription in vivo. To identify components with critical roles in transcription after recruitment of TBP in Saccharomyces cerevisiae, we screened for loss of gene expression activity from promoter-tethered TBP in >100 mutant strains deleted for a transcription-related gene. The assay revealed a dramatic enrichment for strains containing deletions in genes encoding subunits of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex and Mediator. Analysis of an authentic postrecruitment-regulated gene (CYC1) reveals that SAGA occupies the promoter under both uninduced and induced conditions. In contrast, Mediator is recruited only after transfer to inducing conditions and correlates with activation of the preloaded polymerase at CYC1. These studies indicate the critical functions of SAGA and Mediator in the mechanism of activation of genes with rate-limiting steps after recruitment of TBP.

Detection of metastatic head and neck squamous cell carcinoma using the relative expression of tissue-specific mir-205.

The presence of cervical lymph node metastases in head and neck squamous cell carcinoma (HNSCC) is the strongest determinant of patient prognosis. Owing to the impact of nodal metastases on patient survival, a system for sensitive and accurate detection is required. Clinical staging of lymph nodes is far less accurate than pathological staging. Pathological staging also suffers limitations because it fails to detect micrometastasis in a subset of nodal specimens. To improve the sensitivity of existing means of diagnosing metastatic disease, many advocate the use of molecular markers specific for HNSCC cells. MicroRNA (miRNA) are short noncoding segments of RNA that posttranscriptionally regulate gene expression. Approximately one third of all miRNA will exhibit substantial tissue specificity. Using a quantitative reverse transcription-polymerase chain reaction-based assay, we examined the expression of microRNA-205 (mir-205) across tissues and demonstrated that its expression is highly specific for squamous epithelium. We applied this assay to tissue samples, and we could detect metastatic HNSCC in each positive lymph node specimen, whereas benign specimens did not express this marker. When compared to metastases from other primary tumors, HNSCC-positive lymph nodes were distinguishable by the high expression of this marker. Using an in vitro lymphoid tissue model, we were able to detect as little as one squamous cell in a background of 1 million lymphocytes. By combining the sensitivity of quantitative reverse transcription-polymerase chain reaction with the specificity of mir-205 for squamous epithelium, we demonstrate a novel molecular marker for the detection of metastatic HNSCC.

Spn1 regulates the recruitment of Spt6 and the Swi/Snf complex during transcriptional activation by RNA polymerase II.

We investigated the timing of the recruitment of Spn1 and its partner, Spt6, to the CYC1 gene. Like TATA binding protein and RNA polymerase II (RNAPII), Spn1 is constitutively recruited to the CYC1 promoter, although levels of transcription from this gene, which is regulated postrecruitment of RNAPII, are low. In contrast, Spt6 appears only after growth in conditions in which the gene is highly transcribed. Spn1 recruitment is via interaction with RNAPII, since an spn1 mutant defective for interaction with RNAPII is not targeted to the promoter, and Spn1 is necessary for Spt6 recruitment. Through a targeted genetic screen, strong and specific antagonizing interactions between SPN1 and genes encoding Swi/Snf subunits were identified. Like Spt6, Swi/Snf appears at CYC1 only after activation of the gene. However, Spt6 significantly precedes Swi/Snf occupancy at the promoter. In the absence of Spn1 recruitment, Swi/Snf is constitutively found at the promoter. These observations support a model whereby Spn1 negatively regulates RNAPII transcriptional activity by inhibiting recruitment of Swi/Snf to the CYC1 promoter, and this inhibition is abrogated by the Spn1-Spt6 interaction. These findings link Spn1 functions to the transition from an inactive to an actively transcribing RNAPII complex at a postrecruitment-regulated promoter.