An Evaluation of the Efficacy and Safety of Timolol Maleate 0.5% Microdrops Administered with the Nanodropper.

PURPOSE: To examine if 12.5 µl timolol maleate 0.5% microdrops dispensed with the Nanodropper Adaptor provide noninferior intraocular pressure (IOP) reduction compared with conventional 28 µl drops in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). DESIGN: Prospective, noninferiority, parallel, multicenter, single-masked, active-controlled, randomized trial. PARTICIPANTS: Treatment-naïve subjects who were recently diagnosed with OAG and OHT at the Aravind Eye Care System. METHODS: Both eyes of subjects received 1 commercially available drop or both eyes of subjects received 1 microdrop of timolol maleate 0.5%. We measured IOP, resting heart rate (HR), and blood pressure (BP) at baseline and 1, 2, 5, and 8 hours after timolol administration. MAIN OUTCOME MEASURES: The IOP was the primary outcome measure. Secondary outcomes were resting HR, systolic BP (sBP), and diastolic BP (dBP). RESULTS: Adaptor-mediated microdrops and conventional drops of timolol significantly decreased IOP compared with baseline at all timepoints. Noninferiority was established at 3 of 4 timepoints. Heart rate decreases with Nanodropper were approximately 3 beats per minute (bpm) less than with conventional drops. CONCLUSIONS: Timolol microdrops appear to be as effective in ocular hypotensive action as conventional drops with a slightly attenuated effect on resting HR and BP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Detecting and Avoiding Problems When Using the Cre-lox System.

The Cre-lox recombination approach is commonly used to generate cell-specific gene inactivation (or activation). We have noticed that the breeding and genotyping sections of papers utilizing Cre-lox techniques are frequently incomplete. While seemingly straightforward, there are important considerations that need to be implemented in the breeding and genotyping methods to prevent the introduction of experimental confounds. Germline recombination and transient expression of Cre recombinase during development are some examples of the complications that can occur, and conventional genotyping methods may fail to identify these events. In this opinion article, we highlight the importance of testing for unexpected recombination events, suggest strategies to isolate and minimize adverse recombination events, and encourage editors and reviewers to expect more definitive statements regarding the validation of genotyping.

Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion.

Activation of κ opioid receptors (KORs) produces analgesia and aversion via distinct intracellular signaling pathways, but whether G protein-biased KOR agonists can be designed to have clinical utility will depend on a better understanding of the signaling mechanisms involved. We found that KOR activation produced conditioned place aversion and potentiated CPP for cocaine in male and female C57BL/6N mice. Consistent with this, males and females both showed arrestin-mediated increases in phospho-p38 MAPK following KOR activation. Unlike in males, however, KOR activation had inconsistent analgesic effects in females and KOR increased Gßγ-mediated ERK phosphorylation in males, but not females. KOR desensitization was not responsible for the lack of response in females because neither Grk3 nor Pdyn gene knock-out enhanced analgesia. Instead, responsiveness was estrous cycle dependent because KOR analgesia was evident during low estrogen phases of the cycle and in ovariectomized (OVX) females. Estradiol treatment of OVX females suppressed KOR-mediated analgesia, demonstrating that estradiol was sufficient to blunt Gßγ-mediated KOR signals. G protein-coupled receptor kinase 2 (GRK2) is known to regulate ERK activation, and we found that the inhibitory, phosphorylated form of GRK2 was significantly higher in intact females. GRK2/3 inhibition by CMPD101 increased KOR stimulation of phospho-ERK in females, decreased sex differences in KOR-mediated inhibition of dopamine release, and enhanced mu opioid receptor and KOR-mediated analgesia in females. In OVX females, estradiol increased the association between GRK2 and Gßγ. These studies suggest that estradiol, through increased phosphorylation of GRK2 and possible sequestration of Gßγ by GRK2, blunts G protein-mediated signals.SIGNIFICANCE STATEMENT Chronic pain disorders are more prevalent in females than males, but opioid receptor agonists show inconsistent analgesic efficacy in females. κ opioid receptor (KOR) agonists have been tested in clinical trials for treating pain disorders based on their analgesic properties and low addictive potential. However, the molecular mechanisms underlying sex differences in KOR actions were previously unknown. Our studies identify an intracellular mechanism involving estradiol regulation of G protein-coupled receptor kinase 2 that is responsible for sexually dimorphic analgesic responses following opioid receptor activation. Understanding this mechanism will be critical for developing effective nonaddictive opioid analgesics for use in women and characterizing sexually dimorphic effects in other inhibitory G protein-coupled receptor signaling responses.

No Increase in Complications With Intravenous Tranexamic Acid Use in Vaginoplasty: A Retrospective Study.

Background: Across surgical specialties, tranexamic acid (TXA) is applied to reduce intraoperative and postoperative bleeding. Within plastic surgery, both topical and intravenous routes are used. The application of TXA has yet to be examined in vaginoplasties. Methods: The authors performed a retrospective chart review of Mayo Clinic patients receiving penile inversion vaginoplasty from January 2017 through July 2021. Incidence of hematoma formation was assessed as the primary outcome. Secondary outcomes included perioperative hemoglobin, vaginoplasty complications, and possible TXA complications. These outcomes were compared across topical only (t-TXA), any intravenous (IV- TXA), and no TXA groups. Results: Of the 124 vaginoplasties, 21 patients received t-TXA only and 43 received any IV-TXA. Only 4 patients developed a hematoma; 2 were from the no TXA group and 2 were from the any IV-TXA group. There was no significant change in perioperative hemoglobin across groups. Analysis showed lower incidence of divergent urine stream (odds ratio [OR], 0.499 [95% confidence interval (CI)], 0.316-0.789], P = .003) and neovaginal stenosis (OR, 0.435 [95% CI, 0.259-0.731], P = .002) within the any IV-TXA group and no increased incidence of other complications. Conclusions: The use of either t-TXA or IV-TXA in vaginoplasty cases did not result in an increased rate of complications. There was no significant reduction in hematoma formation or postoperative hemoglobin decrease across groups.

Patient Experience and Clinical Outcomes after Same-day Outpatient Mastectomy and Immediate Breast Reconstruction Protocol during the Global Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic provoked rapid changes in clinical practice to accommodate mandated restrictions within healthcare delivery. This study reviewed patient-reported experiences and clinical outcomes after implementation of a same-day discharge protocol after mastectomy with immediate alloplastic breast reconstruction compared with our historical overnight stay protocol. Methods: This is a retrospective single-institution study of consecutive patients who underwent mastectomy and immediate alloplastic reconstruction between July 2019 and November 2020. A postoperative survey was completed by patients to evaluate satisfaction with perioperative communications, recovery, and their overall experience. Results: A total of 302 patients (100% women) underwent mastectomy and immediate alloplastic reconstruction (174 pre-COVID-19, 128 during COVID-19). During COVID-19, 71% of patients were scheduled for a same-day discharge, among which 89% were successfully discharged the same day. Compared with pre-COVID-19, there were no differences in type of surgery, operative times, pain scores, 30-day readmission, or unplanned visits (all P > 0.05) during the COVID-19 pandemic. Compared with pre-COVID-19, patients during the pandemic reported comparable satisfaction with their care experience and postoperative recovery (56% survey response rate). Patient satisfaction was also similar between those discharged the same day (n = 81) versus the next day (n = 47) during COVID-19. Conclusions: Same-day discharge is feasible, safe, and can provide similar patient-reported satisfaction and outcomes compared with traditional overnight stay. These data highlight the ability to deliver adaptable, high-quality breast cancer care, within the constraints of a global pandemic.

Efficacy and safety of blepharoptosis repair after incisional glaucoma surgery.

PURPOSE: There is an increased risk for development of blepharoptosis after incisional glaucoma surgery. Data on safety and efficacy of ptosis repair in this group of patients in limited. The goal of this study is to evaluate outcomes and identify potential risk factors for failure of ptosis repair in eyes with history of incisional glaucoma surgery. METHODS: A retrospective chart review was performed of all patients who underwent incisional glaucoma surgery, specifically trabeculectomy or implantation of glaucoma drainage device (GDD), and subsequent ptosis repair at a single institution from 2009 to 2019. Ptosis surgery outcomes were compared to a control group who underwent ptosis repair after cataract surgery. RESULTS: Seventy-eight eyes of 64 patients were included in the glaucoma surgery group. The rate of severe ptosis (margin reflex distance 1 ⩽ 0 mm) among glaucoma surgery patients was higher compared to control (35 of 78 (44.9%) vs 23 of 82 (28.6%). Ptosis repair was successful in 59 of 78 eyes (75.6%), which was similar to control. Risk for revision surgery was increased more than five-fold in the GDD group compared to control. There were no cases of early or late bleb-related complications. CONCLUSIONS: Ptosis repair can be performed safely in patients after incisional glaucoma surgery. Müller muscle conjunctival resection and external levator advancement are equally effective. Patients with history of GDD should be advised about the potentially increased risk of need for revision surgery.

κ-Opioid Receptor Activation in Dopamine Neurons Disrupts Behavioral Inhibition.

The dynorphin/κ-opioid receptor (KOR) system has been previously implicated in the regulation of cognition, but the neural circuitry and molecular mechanisms underlying KOR-mediated cognitive disruption are unknown. Here, we used an operational test of cognition involving timing and behavioral inhibition and found that systemic KOR activation impairs performance of male and female C57BL/6 mice in the differential reinforcement of low response rate (DRL) task. Systemic KOR antagonism also blocked stress-induced disruptions of DRL performance. KOR activation increased 'bursts' of incorrect responses in the DRL task and increased marble burying, suggesting that the observed disruptions in DRL performance may be attributed to KOR-induced increases in compulsive behavior. Local inactivation of KOR by injection of the long-acting antagonist nor-BNI in the ventral tegmental area (VTA), but not the infralimbic prefrontal cortex (PFC) or dorsal raphe nucleus (DRN), prevented disruption of DRL performance caused by systemic KOR activation. Cre-dependent genetic excision of KOR from dopaminergic, but not serotonergic neurons, also blocked KOR-mediated disruption of DRL performance. At the molecular level, we found that these disruptive effects did not require arrestin-dependent signaling, because neither global deletion of G-protein receptor kinase 3 (GRK3) nor cell-specific deletion of GRK3/arrestin-dependent p38α MAPK from dopamine neurons blocked KOR-mediated DRL disruptions. We then showed that nalfurafine, a clinically available G-biased KOR agonist, could also produce DRL disruptions. Together, these studies demonstrate that KOR activation in VTA dopamine neurons disrupts behavioral inhibition in a GRK3/arrestin-independent manner and suggests that KOR antagonists could be beneficial for decreasing stress-induced compulsive behaviors.

Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor.

Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38α MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radioligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5'-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38α MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics.