Citations

Abstract Purpose: Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract, we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology. Experimental Design: We identified tumor-specific acK13-HOXB13 signal enriched super enhancer (SE)-regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity, and CRPC tumor growth by employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids, we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth. Results: acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA, Angiopoietins) genes early in prostate cancer development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE-regulated targets is insensitive to enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide, and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b. Conclusions: In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13–ACK1 axis regulated prostate cancers.

Purpose The PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial was a multicenter prospective trial conducted to develop a risk prediction score for opioid-induced respiratory depressive (OIRD) episodes. Several subjects in the PRODIGY trial developed critical respiratory depressive events, which were qualified as reportable adverse events (AEs). In this study, we determine whether those patients also had an episode of OIRD as detected by continuous capnography and pulse oximetry leading up to the critical clinical event. Methods Blinded capnography and pulse oximetry data from PRODIGY patients who had critical respiratory depressive AE were reviewed. The occurrence and timing of OIRD episodes were recorded in relationship to the AE. Results Of the 1335 subjects in PRODIGY, 7 patients had 8 reportable pulmonary AE and 187 OIRDs (150 apnea episodes, 14 bradypnea episodes, 23 hypoxic episodes) with median 12 (5–19.5) OIRDs per patient. Five patients were monitored before the AE, and multiple preceding OIRD episodes were detected. One patient had 2 AE, the first (hypoxemia) was recognized upon application of pulse oximetry. This patient subsequently had multiple OIRDs until the second AE occurred (somnolence requiring naloxone administration). Another patient’s AE (hypotension and bradypnea) was recognized upon monitor application and subsequently had many OIRD episodes. Conclusions In the PRODIGY trial, patients who had a pulmonary AE had multiple preceding OIRDs detected by continuous capnography and pulse oximetry. When monitoring was initiated before the AE, numerous OIRDs, mostly apneic episodes preceded AE, suggesting continuous monitoring of both ventilation and oxygenation may allow for early detection and possible prediction of future clinical decompensation.

AbstractBackgroundHospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration.MethodsIncluded were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression.ResultsOf 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change −0.003 mm [95% confidence interval (CI) −0.005 to −0.001], p = .002), but not amyloid accumulation (0.003 [95% CI −0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI −0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (−0.004 mm [95% CI −0.008 to −0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565).ConclusionsMedical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.

Background Non-depolarizing neuromuscular blockade can be reversed with neostigmine/glycopyrrolate or sugammadex. We test the hypothesis that sugammadex is associated with earlier postoperative recovery of bowel function (first bowel movement, BM). Methods In adult patients undergoing craniotomy from 2016 to 2019, we identified time of first postoperative BM after receiving neostigmine/glycopyrrolate or sugammadex to reverse neuromuscular blockade. Logistic and proportional hazard regression, with and without inverse probability of treatment weighting (IPTW), were used to assess whether sugammadex is associated with earlier recovery of bowel function. Results Seven hundred and thirty-one patients underwent craniotomy, 323 (44.2%) received neostigmine/glycopyrrolate, and 408 (55.8%) sugammadex. From logistic regression analysis, the proportion of patients having a BM within the first 24 and 48 hours was higher in sugammadex group (unadjusted OR [95% CI]) 1.79 [1.16 to 2.77] P = .009; and 1.45 [1.08 to 1.94] P = .014; IPTW adjusted OR [95% CI]) 1.58 [.95, 2.61] P = .078; and 1.38 [.95 to 2.02] P = .095 for 24 and 48 h, respectively). From proportional hazards regression, sugammadex was associated with improved bowel function recovery (unadjusted hazard ratio (HR) [95% CI] 1.35 [1.08, 1.68], P = .008; IPTW adjusted HR 1.29 [.97 to 1.71], P = .076). Conclusion Patients undergoing craniotomy who had neuromuscular blockade reversed with sugammadex may have earlier recovered bowel function compared to patients reversed with neostigmine/glycopyrrolate.

Abstract Background We describe the clinical course of medical and surgical patients who received naloxone on general hospital wards for suspected opioid-induced respiratory depression (OIRD). Methods From May 2018 through October 2020, patients who received naloxone on hospital wards were identified and their records reviewed for incidence and clinical course. Results There were 86,030 medical and 106,807 surgical admissions. Naloxone was administered to 99 (incidence 11.5 [95% confidence interval 9.4–14.0] per 10,000 admissions) medical and 63 (5.9 [95% confidence interval 4.5–7.5]) surgical patients (P < 0.001). Median oral morphine equivalents administered within 24 hours before naloxone were 32 [15, 64] and 60 [32, 88] mg for medical and surgical patients, respectively (P = 0.002). The rapid response team was activated in 69 (69.7%) vs 42 (66.7%) and critical care transfers in 51 (51.5%) vs 30 (47.6%) medical and surgical patients respectively. The number of in-hospital deaths was 21 (21.2%) vs two (3.2%) and the number of discharges to hospice 12 (12.1%) vs one (1.6%) for medical and surgical patients, respectively (P = 0.001). Naloxone did not reverse OIRD in 38 (23%) patients, and these patients had more transfers to the intensive care unit and a higher 30-day mortality rate. Conclusion Medical inpatients are more likely to suffer OIRD than are surgical inpatients despite lower opioid doses. Definitive OIRD was confirmed in 77% of patients because of immediate naloxone response, whereas 23% of patients did not respond, and this subset was more likely to need a higher level of care and had a higher 30-day mortality rate. Careful monitoring of mental and respiratory variables is necessary when opiates are used in hospital.

Background: Nondepolarizing neuromuscular blockade is reversed with neostigmine/glycopyrrolate or sugammadex. Anticholinergic glycopyrrolate decreases bladder detrusor muscle contractility, potentially leading to postoperative urinary retention (POUR). POUR commonly complicates inguinal herniorrhaphy. In this study we assess association between reversal technique and POUR. Methods: Records of adult patients undergoing unilateral inguinal herniorrhaphy with neuromuscular blockade from January 2013 to September 2020 were reviewed for POUR (unplanned postoperative insertion of urinary catheter). A propensity-adjusted analysis was performed to assess POUR in neostigmine/glycopyrrolate versus sugammadex using inverse probability of treatment weighting (IPTW) to adjust for potential confounding. Results: We identified 181 patients who underwent herniorrhaphy with amnio-steroidal neuromuscular blockers, 75 (41.4%) who received sugammadex and 106 (58.6%) neostigmine/glycopyrrolate. Compared with sugammadex, neostigmine/glycopyrrolate group had longer surgical course [unweighted standardized difference (USTD)=0.38, P=0.004], received more intraoperative opioids (USTD=0.704, P<0.001), more often performed via laparoscopic approach (USTD=0.407, P=0.012), and less often with periprocedural urinary catheter insertion (USTD=0.452, P=0.003). POUR was observed in 2 (3%) of patients in the sugammadex group, and 16 (15%) in neostigmine/glycopyrrolate [unadjusted odds ratio (OR)=0.15; 95% confidence interval (CI): 0.03-0.69; P=0.015, and IPTW OR=0.13; 95% CI: 0.03-0.64; P=0.012]. Results remained similar with further analysis adjusted for opioid administration in the postanesthesia care unit (adjusted IPTW OR=0.18; 95% CI: 0.04-0.88; P=0.034). Of the POUR patients, 9 required unplanned overnight admission and 4 emergency room visit. Conclusion: These results suggest that neuromuscular blockade reversal with sugammadex is associated with lower rates of POUR following unilateral inguinal herniorrhaphy. Our results need to be reconfirmed in a randomized prospective study.

Background Postoperative falls are preventable complications. The study aims were to describe the rate and circumstances surrounding postoperative falls and explore potential associations with patient and procedural characteristics with emphasis on the use of sedative medications. Methods Medical records of hospitalized patients undergoing non-lower extremity surgery under general anesthesia from January 1, 2010, through April 30, 2018 were reviewed for falls within 72 postoperative hours. Perioperative use of sedatives, sleep aids, gabapentinoids, and opioids were abstracted. Each fall case was matched with two controls on age, sex, and procedure type. Descriptive statistics and multivariable analysis accounting for the matched design were performed. Results There were 343 falls among 200 186 hospitalized surgical patients (incidence of 17.1 [95% CI: 15.4, 19.0] falls per 10 000 procedures) with largest proportion of falls occurring on postoperative day 2 (n = 134, 39.1%). Most falls occurred in the general hospital wards (n = 304, 88.6%) and were unwitnessed (n = 186, 55.9%). The incidence of major injuries was 1.0 (95% CI: .1 – 3.6) per 100 000 procedures. Home use of non-benzodiazepine hypnotics (odds ratio 2.68, 95% CI: 1.47, 4.88, P=.001) and blood transfusions were associated with increased fall risk. Hospital stay was longer in patients who fall (7 [4, 15] vs. 5 [3, 9] days, P < .001). Conclusions The rate of postoperative falls in our institution was low and frequently unwitnessed. The use of non-benzodiazepine hypnotics is a modifiable risk factor associated with postoperative falls. Serious complications after falls were rare.