Intraocular pressure control efficacy and safety of HA-Mg glaucoma drainage plate implantation in the anterior chamber of rabbit eyes.

The current clinical application of glaucoma drainage devices is made of non-degradable materials. These non-degradable drainage devices often trigger inflammatory responses and scar proliferation, possibly leading to surgical failure. We developed a biodegradable material hydroxyapatite-coated magnesium (HA-Mg) as a glaucoma drainage device. Twelve New Zealand white rabbits were randomly assigned to three groups: HA-Mg drainage plate group (6 right eyes), trabeculectomy group (6 right eyes), and control group (12 left eyes). Results showed that all HA-Mg drainage plates were completely degraded ~4 months postoperatively. At the 5th month postoperatively, there was no statistical difference in the corneal endothelium density between the HA-Mg drainage plate group and the control group (p = 0.857). The intraocular pressure (IOP) level in the HA-Mg drainage plate implantation group was lower than in the other two groups. The trypan blue dye still drained from the anterior chamber to the subconjunctiva 5 months after HA-Mg drainage plate implantation. HE staining revealed the scleral linear aqueous humor drainage channel and anterior synechia were observed after drainage plate completely degraded, with no obvious infiltration with the inflammatory cells. This study showed the safety and efficacy of HA-Mg glaucoma drainage plate in controlling IOP after implantation into the anterior chamber of rabbit eyes.

Prospective evaluation of postoperative pain and opioid use after minor urologic surgery.

INTRODUCTION: Filling an opioid prescription after a minor urologic procedure increases patient risk of overdose and misuse. Strategies to reduce the number of opioids reaching the community are critical. This study evaluates opioid use after minor urologic procedures at a Canadian academic center and guides future prescribing recommendations. METHODS: We prospectively evaluated patients over 18 years old undergoing minor urologic procedures (penile, scrotal, urethral, etc.) from September 2020 to May 2022. Consenting participants were given a pain diary and postoperative pain questionnaire. Patients on chronic pain medications or those who had major surgery within six months were excluded. Response rate, pain on visual analog scale, pain control satisfaction, quantity of opioids prescribed, and consumption of opioid and non-opioid medication were collected and analyzed. RESULTS: Ninety-five patients met the inclusion criteria. The mean age was 61.7 years (range 20- 87) and 96% of patients identified as male. The response rate for the opioid diary and pain questionnaire was 57%. Forty-two patients (78%) were offered an opioid prescription following their surgery, but only 12 of those patients (22%) filled and consumed any opioids analgesics. Forty-two patients (78%) used no postoperative opioids, and the mean oral morphine equivalents (OME) consumed was 5.87 (standard deviation 16.7). There was a total of 259 OME unused from post-procedure prescriptions. The mean overall pain score for patients who did and did not fill opioid prescriptions were 3.18/10 and 1.79/10 (p<0.01), respectively, with mean overall pain management satisfaction score of 8.63/10 and 8.58/10 (p=0.94), respectively. CONCLUSIONS: Most patients undergoing minor urologic procedures do not require opioids to manage postoperative pain. Based on our data, we suggest that a prescription for 39 OME would adequately treat postoperative pain in 95% of patients undergoing minor urologic procedures. Education around pain management with non-narcotic modalities is imperative, and practice changes are warranted to address the opioid crisis within our specialty.

Intrinsic ATR signaling shapes DNA end resection and suppresses toxic DNA-PKcs signaling.

Most cancer cells experience oncogene-induced replication stress and, as a result, exhibit high intrinsic activation of the ATR kinase. Although cancer cells often become more dependent on ATR for survival, the precise mechanism by which ATR signaling ensures cancer cell fitness and viability remains incompletely understood. Here, we find that intrinsic ATR signaling is crucial for the ability of cancer cells to promote DNA end resection, the first step in homology-directed DNA repair. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents the engagement of RAD51 as well as RAD52 at nuclear foci, leading to toxic DNA-PKcs signaling and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and engagement of RAD52. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.

Phxnlme: An R package that facilitates pharmacometric workflow of Phoenix NLME analyses.

BACKGROUND AND OBJECTIVE: Pharmacometric analyses are integral components of the drug development process, and Phoenix NLME is one of the popular software used to conduct such analyses. To address current limitations with model diagnostic graphics and efficiency of the workflow for this software, we developed an R package, Phxnlme, to facilitate its workflow and provide improved graphical diagnostics. METHODS: Phxnlme was designed to provide functionality for the major tasks that are usually performed in pharmacometric analyses (i.e. nonlinear mixed effects modeling, basic model diagnostics, visual predictive checks and bootstrap). Various estimation methods for modeling using the R package are made available through the Phoenix NLME engine. The Phxnlme R package utilizes other packages such as ggplot2 and lattice to produce the graphical output, and various features were included to allow customizability of the output. Interactive features for some plots were also added using the manipulate R package. RESULTS: Phxnlme provides enhanced capabilities for nonlinear mixed effects modeling that can be accessed using the phxnlme() command. Output from the model can be graphed to assess the adequacy of model fits and further explore relationships in the data using various functions included in this R package, such as phxplot() and phxvpc.plot(). Bootstraps, stratified up to three variables, can also be performed to obtain confidence intervals around the model estimates. With the use of an R interface, different R projects can be created to allow multi-tasking, which addresses the current limitation of the Phoenix NLME desktop software. In addition, there is a wide selection of diagnostic and exploratory plots in the Phxnlme package, with improvements in the customizability of plots, compared to Phoenix NLME. CONCLUSIONS: The Phxnlme package is a flexible tool that allows implementation of the analytical workflow of Phoenix NLME with R, with features for greater overall efficiency and improved customizable graphics. Phxnlme is freely available for download on the CRAN repository (https://cran.r-project.org/web/packages/Phxnlme/).