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.

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.

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.