Natural food intake patterns have little synchronizing effect on peripheral circadian clocks.

BACKGROUND: Circadian rhythms across mammalian tissues are coordinated by a master clock in the suprachiasmatic nucleus (SCN) that is principally entrained by light-dark cycles. Prior investigations have shown, however, that time-restricted feeding (TRF)-daily alternation of fasting and food availability-synchronizes peripheral clocks independent of the light-dark cycle and of the SCN. This has led to the idea that downstream peripheral clocks are entrained indirectly by food intake rhythms. However, TRF is not a normal eating pattern, and it imposes non-physiologic long fasts that rodents do not typically experience. Therefore, we tested whether normal feeding patterns can phase-shift or entrain peripheral tissues by measuring circadian rhythms of the liver, kidney, and submandibular gland in mPer2Luc mice under different food schedules. RESULTS: We employed home cage feeders to first measure ad libitum food intake and then to dispense 20-mg pellets on a schedule mimicking that pattern. In both conditions, PER2::LUC bioluminescence peaked during the night as expected. Surprisingly, shifting the scheduled feeding by 12 h advanced peripheral clocks by only 0-3 h, much less than predicted from TRF protocols. To isolate the effects of feeding from the light-dark cycle, clock phase was then measured in mice acclimated to scheduled feeding over the course of 3 months in constant darkness. In these conditions, peripheral clock phases were better predicted by the rest-activity cycle than by the food schedule, contrary to expectation based on TRF studies. At the end of both experiments, mice were exposed to a modified TRF with food provided in eight equally sized meals over 12 h. In the light-dark cycle, this advanced the phase of the liver and kidney, though less so than in TRF with ad libitum access; in darkness, this entrained the liver and kidney but had little effect on the submandibular gland or the rest-activity cycle. CONCLUSIONS: These data suggest that natural feeding patterns can only weakly affect circadian clocks. Instead, in normally feeding mice, the central pacemaker in the brain may set the phase of peripheral organs via pathways that are independent of feeding behavior.

Endoscopic transsphenoidal drainage of a petrous apex cholesterol granuloma using a frontal sinus nasal stent: a case report with long term follow up.

BACKGROUND: Cholesterol granulomas of the petrous apex are benign cysts affecting 0.6 patients per 1 million. The pathophysiology involves cholesterol crystals and lipids that are surrounded by giant cells. The cholesterol deposits induce an inflammatory response likely from acute hemorrhage leading to the formation of a fibrous capsule. The capsule expands over time compressing nearby cranial nerves (VI-VIII), which can cause worsening symptoms. Surgical resection has been shown to provide excellent improvement in symptoms. Historically, open approaches such as the infracochlear, infralabyrinthine, and middle fossa have been used. Herein we present a case showing the feasibility and clinical utility of using an endoscopic endonasal transclival approach for treatment of these tumors. CASE: A 44-year-old female presented with history of intermittent double vision, dizziness, nausea, and headaches for 3 years. She developed a partial left CN6 palsy with significant diplopia and episodes of left facial weakness. The worsening symptoms prompted presentation to the ED where MRI and CT scan revealed a left petrous apex lesion (1.8 × 1.7 cm) with hyperintensity on T1 and T2 imaging, suggestive of cholesterol granuloma. She underwent an endoscopic transclival resection of the lesion: drainage of left petrous apex cholesterol granuloma and stent placement from left petrous apex into sphenoid sinus (novel technique). This was done to allow continued communication and drainage of the tumor bed from the petrous apex into the sphenoid sinus with the intent to minimize the risk of recurrence. At the postop visit both 6th nerve palsy and diplopia had resolved. Imaging is stable 2 years after the surgery. DISCUSSION: The placement of the stent in this case was done to prevent symptom recurrence. 11% of patients that do not receive a stent will have symptom recurrence within one year. From the historical literature, only 4% of patients who had stent placement developed cyst recurrence or expansion on follow-up imaging. Stent placement has been shown to prevent cyst enlargement within the first few months after surgery. We demonstrate that the endoscopic endonasal transclival approach provided good visualization of the tumor, allowed for an adequate working window for resection, and provided a sufficient approach for stent placement.

Circadian disruption of food availability significantly reduces reproductive success in mice.

Circadian disruptions impair reproductive health in human populations and in animal models. We tested the hypothesis that mistimed food, a common disruptive feature of shift work, impairs reproductive success in mice. Male and female mPer2Luc mice on a C57BL/6 background were fed during the light or dark phase in two experiments. Food-induced internal misalignment of the liver clock was verified by in vivo bioluminescence in anesthetized mice in both experiments. In Experiment 1, food-restricted pairs were monitored for litters for 18 weeks. In the light-fed group, birth of the first litter was significantly delayed, and total reproductive output was significantly reduced by 38%. In Experiment 2, estrous cycling was monitored for 3 weeks, and then after pairing, copulatory plugs, pregnancy, litter sizes, and uterine implantation sites were measured. Fewer light-fed females birthed litters (25% versus 73%). This was attributable to a difference in behavior as mating success was significantly reduced in light-fed mice: 42% were observed with a copulatory plug compared to 82% for dark-fed mice. The proportion of mice displaying uterine implantation sites was the same as the proportion observed with copulatory plugs, suggesting no deficit in initiating pregnancy after mating. Estrous cycling and pregnancy maintenance did not differ between the groups. We conclude that mistimed feeding inhibits reproduction in mice by reducing successful mating behavior.

Nerve Conduction Studies of the Larynx: Porcine Model and Human Application.

OBJECTIVE: There is a paucity of information in the literature about how electromyography (EMG) with nerve conduction studies (NCS) can be utilized in the field of neurolaryngology. The goal of this study was two-part: (1) to identify the NCS test parameters that best reflect underlying neurolaryngeal pathophysiology in a porcine model, and (2) to determine if comparable NCS parameters can be used to assess clinical laryngeal denervation injuries in patients. METHODS: Yukatan minipigs underwent general anesthesia with EMG and recurrent laryngeal NCS assessment. Recurrent laryngeal nerve (RLN) transection injury and uninjured RLN cases were included to determine NCS neuropathologic and normative findings, respectively. Our porcine analytic model was then applied to a clinical scenario of seven patients with RLN injury. RESULTS: The porcine model was able to differentiate and characterize normative and neuropathologic NCS changes. Clinical outcomes suggest that RLN NCS can be performed clinically and is overall well tolerated by in patients. Findings may serve as a useful tool to differentiate normal nerve function, neuropraxia, axonotmesis, and irreversible RLN injuries. CONCLUSION: This novel study is the first to demonstrate the feasibility and applicability of EMG with NCS in the evaluation of vocal fold function in a porcine model in addition to the clinical setting. Further studies are needed to better understand the clinical utility and predictive value in recovery of vocal fold paralysis.

Tissue-Engineered Implant for Hemilaryngectomy Reconstruction with Recurrent Laryngeal Nerve Injury.

OBJECTIVE: Laryngeal cancer resections often require excision of portions of the larynx along with sacrifice of the ipsilateral recurrent laryngeal nerve (RLN). In such cases, there are no reconstructive options that reliably restore laryngeal function, rendering patients with severe functional impairment. To address this unmet clinical need, we extend our evaluation of a 3-implant mucosal, muscle, cartilage reconstruction approach aimed at promoting functional laryngeal restoration in a porcine hemilaryngectomy model with ipsilateral RLN transection. METHODS: Six Yucatan mini-pigs underwent full-thickness hemilaryngectomies with RLN transection followed by transmural reconstruction using fabricated collagen polymeric mucosal, muscle, and cartilage replacements. To determine the effect of adding therapeutic cell populations, subsets of animals received collagen muscle implants containing motor-endplate-expressing muscle progenitor cells (MEEs) and/or collagen cartilage implants containing adipose stem cell (ASC)-derived chondrocyte-like cells. Acoustic vocalization and laryngeal electromyography (L-EMG) provided functional assessments and histopathological analysis with immunostaining was used to characterize the tissue response. RESULTS: Five of six animals survived the 4-week postoperative period with weight gain, airway maintenance, and audible phonation. No tracheostomy or feeding tube was required. Gross and histological assessments of all animals revealed implant integration and regenerative remodeling of airway mucosa epithelium, muscle, and cartilage in the absence of a material-mediated foreign body reaction or biodegradation. Early voice and L-EMG data were suggestive of positive functional outcomes. CONCLUSION: Laryngeal reconstruction with collagen polymeric mucosa, muscle, and cartilage replacements may provide effective restoration of function after hemilaryngectomy with RLN transection. Future preclinical studies should focus on long-term functional outcomes. LEVEL OF EVIDENCE: NA Laryngoscope, 134:4604-4613, 2024.

Eliciting and Characterizing Porcine Vocalizations: When Pigs Fly.

BACKGROUND/OBJECTIVES: While voice-related therapeutic interventions are often researched preclinically in the porcine model, there are no well-established methods to induce porcine glottic phonation. Described approaches, such as training animals to phonate for positive reinforcement are time-consuming and plagued by inherent variability in the type of phonation produced and contamination of background noise. Thus, a reliable method of assessing glottic phonation in the porcine model is needed. METHODS: In this study, we have created a novel pulley-based apparatus with harness for "pig-lifting" with surrounding acoustic insulation and high-directional microphone with digital recorder for recording phonation. Praat and Matlab were used to analyze all porcine vocalizations for fundamental frequency (F0), intensity, duration of phonation and cepstral peak prominence (CPP). Glottic phonation was detected using F0 (≥2000 hz), duration (≥3 seconds) and researcher perceptual judgment. Partial-glottic phonations were also analyzed. Reliability between researcher judgment and acoustic measures for glottic phonation detection was high. RESULTS: Acoustic analysis demonstrated that glottic and partial-glottic phonation was consistently elicited, with no formal training of the minipigs required. Glottic vocalizations increased with multiple lifts. Glottic phonation continued to be elicited after multiple days but became less frequent. Glottic and partial-glottic phonations had similar CPP values over the 6 experimental days. CONCLUSION: Our cost-effective, reliable method of inducing and recording glottic phonation in the porcine model may provide a cost effective, preclinical tool in voice research.

Safety practices for in-office laryngology procedures during clinical reintroduction amidst COVID-19.

Objective: Describe safety practices for performing in-office laryngology procedures during clinical re-introduction amidst the coronavirus disease 2019 (COVID-19) pandemic. Methods: An anonymous survey in Qualtrics was created to evaluate demographics, preprocedure testing, practice settings, anesthesia, and personal protective equipment (PPE) use for five procedure categories (non-mucosal-traversing injections, mucosal-traversing injections, endoscopy without suction, endoscopy with suction/mucosal intervention via working channel, and laser via working channel). The survey was emailed to the Fall Voice Community on Doc Matter and to members of the American Broncho-Esophagological Association (ABEA) from May to June 2020. Results: Eighty-two respondents were analyzed (response rate: 10%). Respondents represented diverse locations, including international. Most reported academic (71%) or private practices (16%), laryngology fellowship training (76%), and a significant practice devotion to laryngology and broncho-esophagology. During the early re-introduction, most continued to perform all procedure categories. The office was preferred to the OR setting for most, though 36% preferred the OR for laser procedures. There was a preference for preprocedural SARS-Cov2 testing for procedures involving a working channel (>67%), and these procedures had the highest proportion of respondents discontinuing the procedure due to COVID-19. Various types of topical anesthesia were reported, including nebulizer treatments. The most common forms of personal protective equipment utilized were gloves (>95%) and N95 masks (>67%). Powered-air purifying respirators and general surgical masks were used infrequently. Conclusions: During the early re-introduction, respondents reported generally continuing to perform office laryngology procedures, while greater mucosal manipulation affected decisions to stop procedures due to COVID-19, perform preprocedural SARS-Cov2 testing, and alter topical anesthesia. Gloves and N95 masks were the predominate PPE. Level of Evidence: N/A.

Incidence of inadequate perforators and salvage options for the anterior lateral thigh free flap.

OBJECTIVE: The anterolateral thigh (ALT) free flap is a soft tissue flap used in head and neck reconstruction. Occasionally, its perforators to the skin paddle are absent or too small to support the flap. Salvage options in this scenario have not been well described for head and neck reconstruction. METHODS: Multicenter review of 1,079 cases of planned ALT flaps where 28 initial flaps (2.6%) were discarded for nonviable skin paddle or lack of cutaneous perforators. Iatrogenic perforator injury was calculated separately. The total flap loss rate was 3.2%. RESULTS: In 12 cases, no perforators were noted after performing the anterior incision (early). Sixteen ALT flaps were discarded immediately before pedicle ligation (late). Reconstruction was salvaged by seven anteromedial thigh (AMT), six radial forearm, five contralateral ALT, four rectus abdominus myocutaneous, three vastus lateralis, three profunda artery perforator, two tensor fascia lata, one rectus femoris, two pectoralis major, one cervicofacial rotational, and one fibula flap. Of the 28 cases, 12 salvage cases did not involve an additional wound for the patient. Five of the seven AMT flaps were harvested after the ALT was identified as nonviable in the early time point. Two patients had no viable ALT flaps on bilateral lower extremities. CONCLUSION: The ALT flap is a reliable soft tissue flap, and rarely cutaneous perforators are not adequate to support the skin paddle. Multiple options exist to salvage the reconstruction without significant additional morbidity to the patient if said inadequacy is identified early. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:343-346, 2020.

Efficacy of Dextromethorphan/Quinidine for Patients With Psychosis-Related Aggression: A Retrospective Case Series.

BACKGROUND: Treatment-resistant aggressive behavior is a complex psychoneurological phenomenon with high health care and societal costs commonly observed in mental illnesses involving psychosis. Here, we report a preliminary evaluation of treatment with dextromethorphan/quinidine in 4 adult patients with significant history of psychosis-related aggression and impulsive behaviors. METHODS: The files of 4 inpatients with DSM-5-defined psychotic disorder and treatment-resistant aggression treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were retrospectively analyzed. The patients (age: mean ± SD = 59.8 ± 7.6) received open-label treatment with dextromethorphan/quinidine (final dose 20 mg/10 mg twice daily) for at least 12 weeks. Outcome was measured on the basis of patient self-report, treatment team evaluation, and physical examination by psychiatrists and primary care physicians. RESULTS: Three of the 4 patients were considered responders to dextromethorphan/quinidine based on clinical impressions of reduction in aggression and impulsive behavior. The nonresponder, who had a history of multiple traumatic brain injuries, showed mild improvement in agitation but continued to display impulsive self-harm behavior despite treatment. Dextromethorphan/quinidine was generally well-tolerated. No metabolic, gastrointestinal, or cardiovascular side effects were observed. CONCLUSIONS: These preliminary findings support dextromethorphan/quinidine as a potential alternative to conventional regimens for treating aggression and impulsive behavior in patients with psychotic disorder. These results should be interpreted cautiously, as extended, double-blinded, placebo-controlled studies with a larger sample size are needed to validate findings from this retrospective case series.

Integrated Otolaryngology and Anesthesia Simulation Model for Crisis Management of Cavernous Carotid Artery Injury.

Simulation training is emerging as a cost-effective way to train residents on the skill sets necessary to excel as fully functioning physicians. Until recently, the simulated resident training environments have primarily focused on handling a medical crisis with learners from the same specialty. A dual otolaryngology and anesthesiology simulation was established to improve teamwork and communication skills between specialties. One otolaryngology resident was paired with one anesthesia resident per trial in our study. The multispecialty team addressed three clinical simulation scenarios to manage a cavernous carotid artery-bleeding crisis with an endoscopic endonasal approach. An independent reviewer evaluated each individual based on situation awareness, decision-making, communications and teamwork, as well as leadership. Residents improved on blood loss, pre and post anatomical exam scores, and communication measures through the course of the scenarios. Residents from both specialties rated the simulation highly and wanted further simulation training in the future. Multidisciplinary simulation training is a novel approach for improving communication skills between specialties prior to entering the wards, clinic, or operative arena. The lessons learned from this multidisciplinary simulation transcend the individual experience by allowing trainees to develop algorithms for crisis management and to improve on aspects of teamwork, leadership, and communication skills that can be applied throughout their careers.