Evaluating Patient Tolerability for Urological Procedures Under Conscious Sedation: A Prospective Study.

OBJECTIVE: To prospectively evaluate patient-reported tolerability and surgical outcomes of urologic procedures with conscious sedation with or without local anesthesia. Administration of general or spinal anesthesia is associated with anesthetic-related complications, long wait times, and high costs. Using intravenous conscious sedation and/or local anesthesia is an emerging alternative for a myriad of urologic procedures. METHODS: Patients were enrolled from June-August 2021 at a tertiary care hospital. All procedures were completed using fentanyl, midazolam, or both with patient and procedural data recorded upon completion. Patients were telephoned 4-6 weeks post-procedure with a standardized patient tolerability questionnaire. A multivariable adjusted logistic regression analysis was performed to evaluate whether a patient would opt for conscious sedation again as opposed to general anesthesia. RESULTS: A total of 196 procedures were performed by 6 attending urologists with an overall success rate of 98.5% and 0% intraoperative complication rate. At 4-6 weeks follow-up, 85.6% of patients reported they would opt for conscious sedation as opposed to general anesthesia. Predictors of opting for conscious sedation in the future were older age (Odds Ratio (OR): 1.049; P = .017) and surgeon perceived level of patient tolerability (OR: 2.124; P <.001, scored 1-10). CONCLUSION: Physician directed, nursing administered IV conscious sedation is a viable alternative for various urologic procedures and has minimal risk of perioperative complications.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

De novo neurogenesis in adult hypothalamus as a compensatory mechanism to regulate energy balance.

The ability to develop counter-regulatory mechanisms to maintain energy balance in response to environmental and physiologic insults is essential for survival, but the mechanisms underlying these compensatory regulations are poorly understood. Agouti-related peptide (AGRP) and Neuropeptide Y are potent orexigens and are coexpressed in neurons in the arcuate nucleus of the hypothalamus. Acute ablation of these neurons leads to severe anorexia and weight loss, whereas progressive degeneration of these neurons has minimal impact on food intake and body weight, suggesting that compensatory mechanisms are developed to maintain orexigenic drive. In this study, we show that cell proliferation is increased in the hypothalamus of adult mutant animals in which AgRP neurons undergo progressive neurodegeneration due to deletion of mitochondrial transcription factor A, and that a subset of these newly generated cells differentiate into AgRP neurons along with other resident neuronal subtypes. Furthermore, some of the newly generated cells are capable of responding to leptin, and a central blockade of cell proliferation in adult animals results in decreases in food intake and body adiposity in mutant but not in control animals. Our study indicates that neurons important for energy homeostasis can be regenerated in adult feeding centers under neurodegenerative conditions. It further suggests that de novo neurogenesis might serve as a compensatory mechanism contributing to the plastic control of energy balance in response to environmental and physiologic insults.

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake.

In female mammals including rodents and humans, feeding decreases during the periovulatory period of the ovarian cycle, which coincides with a surge in circulating estrogen levels. Ovariectomy increases food intake, which can be normalized by estrogen treatment at a dose and frequency mimicking those during the estrous cycle. Furthermore, administration of estrogen to rodents potently inhibits food intake. Despite these well-known effects of estrogen, neuronal subtypes that mediate estrogen's anorexigenic effects have not been identified. In this study, we show that changes in hypothalamic expression of agouti-related protein (Agrp) and neuropeptide Y (Npy) coincide with the cyclic changes in feeding across the estrous cycle. These cyclic changes in feeding are abolished in mice with degenerated AgRP neurons even though these mice cycle normally. Central administration of 17beta-estradiol (E2) decreases food intake in controls but not in mice lacking the AgRP neurons. Furthermore, E2 treatment suppresses fasting-induced c-Fos activation in AgRP and NPY neurons and blunts the refeeding response. Surprisingly, although estrogen receptor alpha (ERalpha) is the key mediator of estrogen's anorexigenic effects, we find that expression of ERalpha is completely excluded from AgRP and NPY neurons in the mouse hypothalamus, suggesting that estrogen may regulate these neurons indirectly via presynaptic neurons that express ERalpha. This study indicates that neurons coexpressing AgRP and NPY are functionally required for the cyclic changes in feeding across estrous cycle and that AgRP and NPY neurons are essential mediators of estrogen's anorexigenic function.