Defining the patient acceptable symptom state using PROMIS following reconstruction of the progressive collapsing foot deformity.

BACKGROUND: The patient acceptable symptom state (PASS) represents the threshold beyond which patients are satisfied with their outcome. This study aimed to define PASS thresholds for progressive collapsing foot deformity (PCFD) reconstruction using Patient-Reported Outcomes Measurement Information System (PROMIS) scores and anchor question responses. METHODS: This retrospective study consisted of 109 patients who underwent flexible PCFD reconstruction, had preoperative and 2-year postoperative PROMIS scores, and 2-year postoperative anchor question responses. ROC curve analyses were performed to quantify PASS thresholds. RESULTS: PASS thresholds for the PROMIS Physical Function (PF) and Pain Interference (PI) domains were found to be lower and higher, respectively, than population norms. Furthermore, patients with higher preoperative PROMIS PF scores or lower preoperative PROMIS PI scores had a significantly higher likelihood of achieving the PASS thresholds. CONCLUSION: In addition to guiding future outcomes research, these results may help surgeons optimize treatment for PCFD and better manage patient expectations. LEVEL OF EVIDENCE: III, retrospective cohort study.

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.

Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice.

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a µ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.

Preoperative Degenerative Changes at the Tibial Sesamoid-Metatarsal Joint in Hallux Valgus: Association With Postoperative Patient-Reported Outcomes After Modified Lapidus Procedure.

Background: Degenerative changes at the sesamoid-metatarsal joints (SMJs) may be a source of pain following hallux valgus surgery. The aims of this study were to describe degenerative changes at the SMJs on weightbearing computed tomography (WBCT) scans and, secondarily, investigate their association with 1-year patient-reported outcome scores following a modified Lapidus procedure for hallux valgus. We hypothesized that reduced joint space in the SMJs would correlate with worse patient-reported outcomes. Methods: Fifty-seven hallux valgus patients who underwent a modified Lapidus procedure had preoperative and minimum 5-month postoperative WBCT scans, and preoperative and at least 1-year postoperative PROMIS physical function (PF), pain interference, and pain intensity scores were included. Degenerative changes at the SMJs were measured using distance mapping between the sesamoids and first metatarsal head on preoperative and postoperative WBCT scans. The minimum and average distances between the first metatarsal head and tibial sesamoid (tibial-SMJ) for each patient preoperatively and postoperatively were measured. Sesamoid station was measured on WBCT scans using a 0 to 3 grading system. Linear regression was used to investigate the correlations between minimum preoperative and postoperative tibial-SMJ distances and 1-year postoperative PROMIS scores. Results: The median minimum and average tibial-SMJ distances increased from 0.82 mm (interquartile range [IQR] 0.40-1.03 mm) and 1.62 mm (IQR 1.37-1.75 mm) preoperative to 1.09 mm (IQR 0.96-1.23 mm) and 1.73 mm (IQR 1.60-1.91 mm) postoperative (P < .001 and P < .001), respectively. In a subset of patients with complete sesamoid reduction, we found an association between preoperative minimum tibial-SMJ distance and 1-year postoperative PROMIS PF scores (coefficient 7.2, P = .02). Conclusion: Following the modified Lapidus procedure, there was a statistically significant increase in the tibial-SMJ distance. Additionally, in patients with reduced sesamoids postoperatively, reduced preoperative tibial-SMJ distance correlated with worse PROMIS PF scores. Level of Evidence: Level IV, case series.

Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice.

STUDY OBJECTIVES: Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin's respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. METHODS: We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. RESULTS: Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. CONCLUSION: Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.