Combining varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with serious mental illness who smoke: The randomized ACTSLow pilot feasibility trial.

BACKGROUND: People with serious mental illness (SMI; bipolar [BD] or schizophrenia spectrum disorders [SSD]) who smoke have 30-60% lower odds of quitting and are more prone to experience neuropsychiatric adverse events (NPSAEs) when quitting than smokers without SMI. We pilot-tested the feasibility of combining two different dosing strategies of varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with SMI in an attempt to bolster quit rates without increasing NPSAEs. METHODS: Twelve-week, single center, randomized, double-blind, pilot feasibility trial of low (0.5mg twice daily, slower titration) versus standard dose (1.0mg twice daily, standard titration) varenicline in persons with BD or SSD with a 12-week follow-up. All participants received up to 10 sessions of ACT for smoking cessation. Participants were asked to preload with varenicline while still smoking and set a flexible target quit day (TQD) by day 35. RESULTS: Recruitment was hampered by shutdowns related to COVID-19 and the worldwide varenicline recall, respectively. Retention goals were met. Treatment satisfaction was high across both dosing and diagnostic groups. Most participants (92.9%) adhered to preloading instructions and the flexible TQD. Seven-day point prevalence abstinence at week 12 was highest in BD participants (37.5%) but lowest in SSD participants (16.7%) who received the standard dose. Medication was well tolerated. CONCLUSIONS: Although recruitment was hindered by unanticipated world events, feasibility was demonstrated. Participants adhered to and were highly satisfied with the combination of pre-cessation varenicline plus ACT. Findings support testing this combined treatment approach in a fully powered trial of persons with BD who smoke.

Erector spinae plane blocks for analgesia after percutaneous nephrolithotomy A pathway to reduce opioids.

INTRODUCTION: Despite its minimally invasive nature, percutaneous nephrolithotomy (PCNL ) may be associated with significant pain. Challenges in pain control may prevent timely discharge (and expose patients to adverse effects of opioid use). We sought to evaluate whether our patients who underwent erector spinae plane (ESP) regional blocks experienced improved postoperative pain control and decreased opioid use after PCNL (compared with those who did not receive blocks). METHODS: We retrospectively reviewed consecutive PCNL cases on patients admitted for greater than 24 hours without pre-existing opioid regimens for chronic pain. Cases were completed by a single high-volume surgeon. Patients who accepted an ESP block were compared to those who did not receive a block. Patients received either a single injection or a disposable pump delivering intermittent boluses of ropivacaine 0.2%. Demographic and perioperative data were analyzed. The primary outcomes were opioid use measured in morphine milligram equivalent (MME ) and patient-reported pain scores during the first 24 hours of hospitalization. RESULTS: From March 2019 to August 2021, 44 patients were identified who met criteria - 28 of whom received an ESP block (including 14 continuous blocks). The patients who received blocks had significantly decreased opioid use (18.3 vs. 81.3 MME, p=0.004) and a longer mean time to first non-zero pain score (p=0.004). Continuous blocks had similar opioid use to single shot blocks (21.0 vs. 15.6 MME, p=0.952). CONCLUSIONS: ESP regional blocks appear to offer an effective adjunct method for pain control after PCNL and may reduce post-PCNL opioid use while maintaining adequate patient analgesia.

A Tet-Inducible CRISPR Platform for High-Fidelity Editing of Human Pluripotent Stem Cells.

Pluripotent stem cells (PSCs) offer an exciting resource for probing human biology; however, gene-editing efficiency remains relatively low in many cell types, including stem cells. Gene-editing using the CRISPR-Cas9 system offers an attractive solution that improves upon previous gene-editing approaches; however, like other technologies, off-target mutagenesis remains a concern. High-fidelity Cas9 variants greatly reduce off-target mutagenesis and offer a solution to this problem. To evaluate their utility as part of a cell-based gene-editing platform, human PSC lines were generated with a high-fidelity (HF) tetracycline-inducible engineered Streptococcus pyogenes SpCas9 (HF-iCas9) integrated into the AAVS1 safe harbor locus. By engineering cells with controllable expression of Cas9, we eliminated the need to include a large Cas9-expressing plasmid during cell transfection. Delivery of genetic cargo was further optimized by packaging DNA targeting guide RNAs (gRNAs) and donor fragments into a single plasmid backbone. The potential of homology-directed repair (HDR) based gene knock-in at the CLYBL safe harbor site and endogenous SOX2 and SIX6 genes were demonstrated. Moreover, we used non-homologous end-joining (NHEJ) for gene knockout of disease-relevant alleles. These high-fidelity CRISPR tools and the resulting HF-iCas9 cell lines will facilitate the production of cell-type reporters and mutants across different genetic backgrounds.