Educational and Clinical Outcome Measures in an Integrated Hand Service.

Background: We recently sought to integrate our orthopaedic and plastic hand surgeons with the goal of improving education, patient care, and providing seamless, continuous coverage for our trauma center. Our hypothesis was that integration could serve both the orthopaedic and plastic surgery training programs well and provide more consistent care for the trauma patients. Materials and Methods: Program director approval was granted for blinded analysis of case logs from plastic and orthopaedic surgery programs from 2012 through 2019. Data on mean and total number of hand cases were analyzed and compared for both specialties. Institutional Review Board approval was granted for a retrospective review of patient outcomes. Results: For both orthopaedic and plastics resident trainees, the mean number of hand cases increased during this study period suggesting that the integration had a favorable impact on both programs. The mean number of hand cases for orthopaedic residents rose from 163 to 246. The mean number of hand cases for plastic surgery residents rose from 218 to 295. Patient outcomes as reflected in length of stay and time to consultation also improved. Conclusion: To improve hand surgical training and patient care, an integrated orthoplastics approach to hand surgery was implemented at our institution. Plastic surgery trainees are completing more hand surgery cases in an integrated model (p < 0.001), including fracture care (p < 0.047). Orthopaedic surgery trainees have doubled the percentage of integumentary and microsurgery cases in the integrated model (p < 0.001). The educational and clinical changes affected in an integrated model have changed the paradigm for educating future hand surgeons at our institution.

Chemogenetic stimulation of phrenic motor output and diaphragm activity.

Impaired diaphragm activation contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We conducted experiments to determine if expression of an excitatory DREADD (designer receptors exclusively activation by designer drugs) in the mid-cervical spinal cord would enable respiratory-related activation of phrenic motoneurons to increase diaphragm activation. Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive DREADD expression in C4 ventral horn motoneurons, targeting the phrenic motoneuron pool. Diaphragm EMG was recorded during spontaneous breathing at 6-8 weeks post-AAV delivery. The selective DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in a ChAT-Cre rat model were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT assessed using whole-body plethysmography. Subsequently, direct nerve recordings confirmed that J60 evoked a >50% increase in inspiratory phrenic output. The data show that mid-cervical spinal DREADD expression targeting the phrenic motoneuron pool enables ligand-induced, sustained increases in the neural drive to the diaphragm. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

Acute ampakines increase voiding function and coordination in a rat model of SCI.

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague-Dawley rats received a unilateral contusion of the T9 spinal cord (n = 10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed 5 d post-SCI under urethane anesthesia. Data were compared to responses in spinal-intact rats (n = 8). The 'low-impact' ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously. The HPCD vehicle had no discernible impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

Fibrin Glue Acutely Blocks Distal Muscle Contraction after Confirmed Polyethylene Glycol Nerve Fusion: An Animal Study.

Background: Polyethylene glycol (PEG) is a synthetic, biodegradable, and hyperosmotic material promising in the treatment of acute peripheral nerve injuries. Our team set out to investigate the impact of fibrin glue upon PEG fusion in a rat model. Methods: Eighteen rats underwent sciatic nerve transection and PEG fusion. Electrophysiologic testing was performed to measure nerve function and distal muscle twitch. Fibrin glue was applied and testing repeated. Due to preliminary findings, fibrin glue was applied to an uncut nerve in five rodents and testing was conducted before and after glue application. Mann-Whitney U tests were used to compare median values between outcome measures. A Shapiro-Wilk test was used to determine normality of data for each comparison, significance set at a P value less than 0.05. Results: PEG fusion was confirmed in 13 nerves with no significant change in amplitude (P = 0.054), latency (P = 0.114), or conduction velocity (P = 0.114). Stimulation of nerves following PEG fusion produced distal muscle contraction in 100% of nerves. Following application of fibrin glue, there was a significant reduction in latency (P = 0.023), amplitude (P < 0.001), and conduction velocity (P = 0.023). Stimulation of the nerve after application of fibrin glue did not produce distal muscle twitch. Five uncut nerves with fibrin glue application blocked distal muscle contraction following stimulation. Conclusions: Our data suggest that fibrin glue alters the nerve's function. The immediate confirmation of PEG fusion via distal muscle twitch is blocked with application fibrin glue in this experimental model. Survival and functional outcome studies are necessary to understand if this has implications on the long-term functional outcomes.

Medicare Reimbursement in Hand and Upper Extremity Procedures: A 20-Year Analysis.

PURPOSE: Concern exists that Medicare physician fees for procedures have decreased over the past 20 years. The Centers for Medicare & Medicaid Services (CMS) is set to re-evaluate these physician fees in the near future for concern that these procedures are overvalued. Our study sought to analyze trends in Medicare reimbursement rates from 2000 to 2019 for the top 20 most billed hand and upper extremity surgical procedures at our institution. METHODS: The financial database of a single academic tertiary care center was queried to identify the Current Procedural Terminology codes most frequently utilized in orthopedic hand and upper extremity procedures in 2019. The Physician Fee Schedule Look-Up Tool from the CMS was queried for annual physician fee data. Monetary data were adjusted for inflation using the consumer price index of Urban Research Series (CPI-U-RS) and expressed in 2019 constant US dollars (USD). The average annual and total percent change in reimbursement were calculated via linear regression for all procedures (P < .05). RESULTS: Accounting for inflation, the total average physician reimbursement decreased by 20.9% from 2000 to 2019, with 12 of 20 codes decreasing by more than 20%. The greatest decrease pertained to arthrodesis of the wrist at 33.9%. Upon linear regression, all procedures were found to decrease annually, with arthrodesis of the wrist decreasing by an average of 2.3% annually over this period. CONCLUSIONS: Over the past 2 decades, physician reimbursement for hand and upper extremity procedures has significantly decreased.

Current avenues of gene therapy in Pompe disease.

PURPOSE OF REVIEW: Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions. RECENT FINDINGS: Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability. SUMMARY: Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing.

Acute ampakines increase voiding function and coordination in a rat model of SCI.

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The "low impact" ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

Optogenetic activation of the tongue in spontaneously breathing mice.

Inadequate tongue muscle activation contributes to dysarthria, dysphagia, and obstructive sleep apnea. Thus, treatments which increase tongue muscle activity have potential clinical benefit. We hypothesized that lingual injection of an adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) would enable light-induced activation of tongue motor units during spontaneous breathing. An AAV serotype 9 vector (pACAGW-ChR2-Venus-AAV9, 8.29 × 1011 vg) was injected to the posterior tongue in adult C57BL/6J mice. After 12 weeks, mice were anesthetized and posterior tongue electromyographic (EMG) activity was recorded during spontaneous breathing; a light source was positioned near the injection site. Light-evoked EMG responses increased with the intensity and duration of pulses. Stimulus trains (250 ms) evoked EMG bursts that were comparable to endogenous (inspiratory) tongue muscle activation. Histology confirmed lingual myofiber transgene expression. We conclude that intralingual AAV9-ChR2 delivery enables light evoked lingual EMG activity. These proof-of-concept studies lay the groundwork for clinical application of this novel approach to lingual therapeutics.

Effects of Hyperbaric Oxygen Preconditioning on Doxorubicin Cardiorespiratory Toxicity.

Cardiorespiratory dysfunction resulting from doxorubicin (DOX) chemotherapy treatment is a debilitating condition affecting cancer patient outcomes and quality of life. DOX treatment promotes cardiac and respiratory muscle pathology due to enhanced reactive oxygen species (ROS) production, mitochondrial dysfunction and impaired muscle contractility. In contrast, hyperbaric oxygen (HBO) therapy is considered a controlled oxidative stress that can evoke a substantial and sustained increase in muscle antioxidant expression. This HBO-induced increase in antioxidant capacity has the potential to improve cardiac and respiratory (i.e., diaphragm) muscle redox balance, preserving mitochondrial function and preventing muscle dysfunction. Therefore, we determined whether HBO therapy prior to DOX treatment is sufficient to enhance muscle antioxidant expression and preserve muscle redox balance and cardiorespiratory muscle function. To test this, adult female Sprague Dawley rats received HBO therapy (2 or 3 atmospheres absolute (ATA), 100% O2, 1 h/day) for 5 consecutive days prior to acute DOX treatment (20 mg/kg i.p.). Our data demonstrate that 3 ATA HBO elicits a greater antioxidant response compared to 2 ATA HBO. However, these effects did not correspond with beneficial adaptations to cardiac systolic and diastolic function or diaphragm muscle force production in DOX treated rats. These findings suggest that modulating muscle antioxidant expression with HBO therapy is not sufficient to prevent DOX-induced cardiorespiratory dysfunction.

A Tale of Two Centers: Visual Exploration of Health Disparities in Cancer Care.

The annual incidence of head and neck cancers (HNC) worldwide is more than 550,000 cases, with around 300,000 deaths each year. However, the incidence rates and disease-characteristics of HNC differ between treatment centers and different populations, due to undetermined reasons, which may or not include socioeconomic factors. The multi-faceted and multi-variate nature of the data in the context of the emerging field of health disparities research makes automated analysis impractical. Hence, we present a visual analysis approach to explore the health disparities in the data of HNC patients from two different cohorts at two cancer care centers. Our approach integrates data from multiple sources, including census data and city data, with custom visual encodings and with a nearest neighbor approach. Our design, created in collaboration with oncology experts, makes it possible to analyze the patients' demographic, disease characteristics, treatments and outcomes, and to make significant comparisons of these two cohorts and of individual patients. We evaluate this approach through two case studies performed with domain experts. The results demonstrate that this visual analysis approach successfully accomplishes the goal of comparing two cohorts in terms of different significant factors, and can provide insights into the main source of health disparities between the two centers.

Implant Removal Due to Infection After Open Reduction and Internal Fixation: Trends and Predictors.

Background: Implant removal due to infection is one of the major causes failure following open reduction and internal fixation (ORIF). The aim of this study was to determine trends and predictors of infection-related implant removal following ORIF of extremities using a nationally representative database. Methods: Nationwide Inpatient Sample data from 2006 to 2017 was used to identify cases of ORIF following upper and lower extremity fractures, as well as cases that underwent infection-related implant removal following ORIF. Multivariate analysis was performed to identify independent predictors of infection-related implant removal, controlling for patient demographics and comorbidities, hospital characteristics, site of fracture, and year. Results: For all ORIF procedures, the highest rate of implant removal due to infection was the phalanges/hand (5.61%), phalanges/foot (5.08%), and the radius/ulna (4.85%). Implant removal rates due to infection decreased in all fractures except radial/ulnar fractures. Tarsal/metatarsal fractures (odds ratio (OR)=1.45, 95% confidence interval (CI): 1.02-2.05), and tibial fractures (OR=1.82, 95% CI: 1.45-2.28) were identified as independent predictors of infection-related implant removal. Male gender (OR=1.67, 95% CI: 1.49-1.87), Obesity (OR=1.85, 95% CI: 1.34-2.54), diabetes mellitus with chronic complications (OR=1.69, 95% CI: 1.13-2.54, P<0.05), deficiency anemia (OR=1.59, 95% CI: 1.14-2.22) were patient factors that were associated with increased infection-related removals. Removal of implant due to infection had a higher total charge associated with the episode of care (mean: $166,041) than non-infection related implant removal (mean: $133,110). Conclusion: Implant removal rates due to infection decreased in all fractures except radial/ulnar fractures. Diabetes, liver disease, and rheumatoid arthritis were important predictors of infection-related implant removal. The study identified some risk factors for implant related infection following ORIF, such as diabetes, obesity, and anemia, that should be studied further to implement strategies to reduce rate of infection following ORIF.

Chemogenetic activation of hypoglossal motoneurons in a mouse model of Pompe disease.

Pompe disease is a lysosomal storage disease resulting from absence or deficiency of acid α-glucosidase (GAA). Tongue-related disorders including dysarthria, dysphagia, and obstructive sleep apnea are common in Pompe disease. Our purpose was to determine if designer receptors exclusively activated by designer drugs (DREADDs) could be used to stimulate tongue motor output in a mouse model of Pompe disease. An adeno-associated virus serotype 9 (AAV9) encoding an excitatory DREADD (AAV9-hSyn-hM3D(Gq)-mCherry, 2.44 × 1010 vg) was administered to the posterior tongue of 5-7-wk-old Gaa null (Gaa-/-) mice. Lingual EMG responses to intraperitoneal injection of saline or a DREADD ligand (JHU37160-dihydrochloride, J60) were assessed 12 wk later during spontaneous breathing. Saline injection produced no consistent changes in lingual EMG. Following the DREADD ligand, there were statistically significant (P < 0.05) increases in both tonic and phasic inspiratory EMG activity recorded from the posterior tongue. Brainstem histology confirmed mCherry expression in hypoglossal (XII) motoneurons in all mice, thus verifying retrograde movement of the AAV9 vector. Morphologically, Gaa-/- XII motoneurons showed histological characteristics that are typical of Pompe disease, including an enlarged soma and vacuolization. We conclude that lingual delivery of AAV9 can be used to drive functional expression of DREADD in XII motoneurons in a mouse model of Pompe disease.NEW & NOTEWORTHY In a mouse model of Pompe disease, lingual injection of adeno-associated virus (AAV) serotype 9 encoding DREADD was histologically verified to produce transgene expression in hypoglossal motoneurons. Subsequent intraperitoneal delivery of a DREADD ligand stimulated tonic and phase tongue motor output.In a mouse model of Pompe disease, lingual injection of adeno-associated virus (AAV) serotype 9 encoding DREADD was histologically verified to produce transgene expression in hypoglossal motoneurons. Subsequent intravenous delivery of a DREADD ligand stimulated tonic and phase tongue motor output.

A Phase 1 Proof of Concept Study Evaluating the Addition of an LSD1 Inhibitor to Nab-Paclitaxel in Advanced or Metastatic Breast Cancer (EPI-PRIMED).

Objective: Lysine-Specific Demethylase-1 (LSD1) is overexpressed in breast cancer cells and facilitate mesenchymal properties which may contribute to therapeutic resistance and cancer progression. The purpose of this study was to investigate the safety of combination, nab-paclitaxel and phenelzine, an irreversible LSD1 inhibitor in patients with metastatic breast cancer (mBC). Methods: Eligible patients with mBC were treated with nab-paclitaxel (100mg/m2) weekly for 3 weeks with one week break in a 28-day cycle. Dose escalation of phenelzine followed the Cumulative Cohort Design and phenelzine treatment commenced from day 2 of first cycle. Eleven patients were screened, and eligible patients were enrolled in cohorts with the dose of phenelzine ranging from 45mg to 90mg. Results: The Optimum Biological Dose was established at 60mg of phenelzine daily in combination with nab-paclitaxel and considered as the recommended phase 2 dose. Most (95%) of adverse events were grade 1 or 2 with two grade 3 events being diarrhea and neutropenia at 45mg and 60mg phenelzine respectively, with no unexpected toxicity/deaths. Commonly reported toxicities were fatigue (n=4,50%), dizziness (n=6,75%), neutropenia (n=3,37.5%), peripheral neuropathy (n=3,37.5%), diarrhea (n=2,25%), and hallucination (n=2,25%). After a median follow up of 113 weeks, all patients showed disease progression on trial with 4 patients being alive at the time of data cut off, including one patient with triple negative breast cancer. Median progression-free survival was 34 weeks. Significant inhibition of LSD1 and suppression of mesenchymal markers in circulating tumor cells were noted. Conclusion: Phenelzine in combination with nab-paclitaxel was well tolerated, without any unexpected toxicities in patients with mBC and demonstrated evidence of antitumor activity. For the first time, this proof-of-concept study showed in-vivo inhibition of LSD1 suppressed mesenchymal markers, which are known to facilitate generation of cancer stem cells with metastatic potential. Clinical Trial Registration: ClinicalTrials.Gov NCT03505528, UTN of U1111-1197-5518.

Optogenetic activation of the diaphragm.

Impaired diaphragm activation is common in many neuromuscular diseases. We hypothesized that expressing photoreceptors in diaphragm myofibers would enable light stimulation to evoke functional diaphragm activity, similar to endogenous bursts. In a mouse model, adeno-associated virus (AAV) encoding channelrhodopsin-2 (AAV9-CAG-ChR2-mVenus, 6.12 × 1011 vg dose) was delivered to the diaphragm using a minimally invasive method of microinjection to the intrapleural space. At 8-18 weeks following AAV injection, mice were anesthetized and studied during spontaneous breathing. We first showed that diaphragm electromyographic (EMG) potentials could be evoked with brief presentations of light, using a 473 nm high intensity LED. Evoked potential amplitude increased with intensity or duration of the light pulse. We next showed that in a paralyzed diaphragm, trains of light pulses evoked diaphragm EMG activity which resembled endogenous bursting, and this was sufficient to generate respiratory airflow. Light-evoked diaphragm EMG bursts showed no diminution after up to one hour of stimulation. Histological evaluation confirmed transgene expression in diaphragm myofibers. We conclude that intrapleural delivery of AAV9 can drive expression of ChR2 in the diaphragm and subsequent photostimulation can evoke graded compound diaphragm EMG activity similar to endogenous inspiratory bursting.

Vocal-cord Only vs. Complete Laryngeal radiation (VOCAL): a randomized multicentric Bayesian phase II trial.

BACKGROUND: Radiotherapy, along with laser surgery, is considered a standard treatment option for patients with early glottic squamous cell cancer (SCC). Historically, patients have received complete larynx radiotherapy (CL-RT) due to fear of swallowing and respiratory laryngeal motion and this remains the standard approach in many academic institutions. Local control (LC) rates with CL-RT have been excellent, however this treatment can carry significant toxicities include adverse voice and swallowing outcomes, along with increased long-term risk of cerebrovascular morbidity. A recent retrospective study reported improved voice quality and similar local control outcomes with focused vocal cord radiotherapy (VC-RT) compared to CL-RT. There is currently no prospective evidence on the safety of VC-RT. The primary objective of this Bayesian Phase II trial is to compare the LC of VC-RT to that of CL-RT in patients with T1N0 glottic SCC. METHODS: One hundred and fifty-five patients with T1a-b N0 SCC of the true vocal cords that are n ot candidate or declined laser surgery, will be randomized in a 1:3 ratio the control arm (CL-RT) and the experimental arm (VC-RT). Randomisation will be stratified by tumor stage (T1a/T1b) and by site (each site will be allowed to select one preferred radiation dose regimen, to be used in both arms). CL-RT volumes will correspond to the conventional RT volumes, with the planning target volume extending from the top of thyroid cartilage lamina superiorly to the bottom of the cricoid inferiorly. VC-RT volumes will include the involved vocal cord(s) and a margin accounting for respiration and set-up uncertainty. The primary endpoint will be LC at 2-years, while secondary endpoints will include patient-reported outcomes (voice impairment, dysphagia and symptom burden), acute and late toxicity radiation-induced toxicity, overall survival, progression free survival, as well as an optional component of acoustic and objective measures of voice analysis using the Consensus Auditory-Perceptual Evaluation of Voice. DISCUSSION: This study would constitute the first prospective evidence on the efficacy and safety of VC-RT in early glottic cancer. If positive, this study would result in the adoption of VC-RT as standard approach in early glottic cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759431 Registration date: November 30, 2018.

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential.

Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

Designer Receptors Exclusively Activated by Designer Drugs Approach to Treatment of Sleep-disordered Breathing.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.

Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction.

Osteopathic Approach to the Treatment of a Patient With Idiopathic Iliohypogastric Neuralgia.

Iliohypogastric neuralgia is an uncommon etiology of lower abdominal pain caused by entrapment of the iliohypogastric nerve. Conventional management consists of medications, injections, and surgery; previous literature has not explored the use of osteopathic manipulative medicine for management of iliohypogastric neuralgia. Here, the author discusses the case of a 72-year-old woman who presented with 2 years of right lower abdominal pain, having failed multiple treatments, including exploratory laparoscopy and appendectomy. Following management of the patient's somatic dysfunctions with osteopathic manipulative treatment and a heel lift, her iliohypogastric neuralgia was significantly improved.

Analysis of surgical options for patients with bilateral carpal tunnel syndrome.

BACKGROUND: Bilateral endoscopic carpal tunnel release is a modality offered for the treatment of the median nerve compression neuropathy. This retrospective study compares outcomes for patients undergoing open carpal tunnel release versus bilateral endoscopic carpal tunnel release. We hypothesized that there is no significant difference in postoperative complication rates between unilateral open and bilateral endoscopic carpal tunnel release surgery. METHODS: The authors identified all patients who underwent open carpal tunnel release, unilateral endoscopic carpal tunnel release and bilateral endoscopic carpal tunnel release at a university hospital from 2012 to 2014. Cases were identified using CPT billing codes and the data was assessed using an analysis of variance (ANOVA). All endoscopic carpal tunnel releases were done by the same surgeon (AP), and greater than 90% of open procedures were done by a different same surgeon (DF). RESULTS: The total combined complication rate was 24.7% with no significant difference (p > .05) between techniques. There were no major complications necessitating a return to the operating room. Variables that had a statistically significant difference between groups (p < .05) included mean tourniquet time, mean total procedure time, and return to work as determined from the number of follow-up appointments. CONCLUSIONS: The study demonstrates equivocal complication profiles and decreased cost associated with bilateral endoscopic tunnel release as compared to sequential open carpal tunnel release. Endoscopic bilateral carpal tunnel release for patients with bilateral carpal tunnel syndrome offers a safe and effective alternative to open carpal tunnel release.