Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.

To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.

Pain and Pain Control With Opioid and Nonopioid Medications After Otologic Surgery.

OBJECTIVE: To prospectively analyze pain and pain medication use following otologic surgery. STUDY DESIGN: Prospective cohort study with patient reported pain logs and medication use logs. SETTING: Tertiary academic hospital.Patients: Sixty adults who underwent outpatient otologic surgeries. INTERVENTIONS: Surveys detailing postoperative pain levels, nonopioid analgesic (NOA) use, and opioid analgesic use. MAIN OUTCOME MEASURES: Self-reported pain scores, use of NOA, and use of opioid medications normalized as milligrams morphine equivalents (MME). RESULTS: Thirty-two patients had surgery via a transcanal (TC) approach, and 28 patients had surgery via a postauricular (PA) approach. TC surgery had significantly lower reported pain scores than PA surgery on both postoperative day (POD) 1 (median pain score 2.2, IQR 0-5 vs. median pain score 4.8, IQR 3.4-6.3, respectively; p = 0.0013) and at POD5 (median pain score 0, IQR 0-0 vs. median pain score 2.0, IQR 0-3, respectively; p = 0.0002). Patients also used significantly fewer opioid medications with TC approach than patients who underwent PA approach at POD1 (median total MME 0, IQR 0-5 vs. median total MME 5.0, IQR 0-15, respectively; p = 0.03) and at POD5 (median total MME 0, IQR 0-0 vs. median total MME 0, IQR 0-5, respectively; p = 0.0012). CONCLUSIONS: Surgery with a postauricular approach is associated with higher pain and opioid use following otologic surgery. Patient- and approach-specific opioid prescribing is feasible following otologic surgery.

Is mandibular osteomyelitis a sequela of SSRI-induced dental implant failure? A systematic review & case report.

BACKGROUND: To determine if the utilization of selective serotonin reuptake inhibitors (SSRIs) increases the risk of osteomyelitis as a sequela of dental implant failure. We also report the case of a patient on long-term SSRIs who presented with dental implant failure and subsequently developed mandibular osteomyelitis. METHODS: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) in PubMed, Google Scholar and Embase, for all records pertaining to SSRIs, dental implants, and mandibular osteomyelitis. RESULTS: SSRIs are associated with increased risk of dental implant failure, and our results suggest that they may be independently associated with mandibular osteomyelitis in the setting of implant failure. Though there was no evidence of mandibular osteomyelitis specifically following SSRI-related dental implant failure, there were a few case reports on osteomyelitis resulting from failed dental implant osseointegration. CONCLUSIONS: In the context of long-term SSRI utilization, our findings suggest that osteomyelitis should be considered in the differential diagnosis of patients with recent dental implant placement or failure.

Readmissions and mortality in pediatric tracheostomy patients: Are we doing enough?

OBJECTIVES: Pediatric patients who undergo tracheostomy tube placement are medically complex with a high risk of morbidity and mortality. They are often premature with multiple cardiopulmonary comorbidities. This study reviews the demographics and outcomes within this population to identify at-risk patient groups at our hospital. METHODS: A retrospective chart review of those with pediatric tracheostomy placement from 2015 to 2016 at our hospital was performed (n = 92). Demographic and post-discharge data were collected at 30, 60, and 90-days during the global period. RESULTS: Ventilator dependence was the most common reason for placement. 79.3% of patients had two or more major comorbidities. 44% had an emergency department (ED) visit and subsequent hospital admission within the first 90 days post-discharge, with 36% being trach/respiratory-related. The 90-day mortality was 19.6%; however, at the time of chart review, mortality was 35% with only 1 (1.1%) being from trach-related complications. Patients with longer admissions were more likely to die prior to discharge, p = .001. Lastly, patients who died were 3 times more likely to have > 25% no-shows to their outpatient appointments compared to those living throughout the study period. CONCLUSION: Our population had a high incidence of ED visits, readmission rates, and mortality; however, trach-related causes remained low. Mortality risk increased with more no-show appointments and residing a further distance from our hospital. Furthermore, multiple co-morbidities, with longer hospital stays also increased risk of mortality. Identifying those with the highest risk for complications will enable us to target families for increased home-care education to decrease readmissions and mortality. LEVEL OF EVIDENCE: 4.

Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations.

Midbrain dopamine neurons recorded in vivo pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (IA) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (IH), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of IA completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from in vivo experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons.SIGNIFICANCE STATEMENT Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain in vivo observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.