Sex Comparisons in Opioid Use and Pain After Colorectal Surgery Using Enhanced Recovery Protocols.

BACKGROUND: Differences in nociception and use of opioids between sexes are of particular interest, considering higher rates of persistent opioid use among women after surgery. Although enhanced recovery protocols (ERPs) have improved postoperative pain control in colorectal surgery, sex-based comparisons of inpatient opioid use after surgery in an ERP remain understudied. METHODS: This retrospective study analyzed data from adults after colorectal surgery using an ERP at a single hospital between 2015 and 2017. The main outcome was the rate of opioid consumption measured as oral morphine equivalents per inpatient day. Poisson regression determined association between sex and opioid consumption, accounting for early discharge, using inverse probability weighting and adjusting for covariates that retained significance on univariate analysis. Linear regression assessed the association between sex and pain scores on postoperative days 0-5 adjusting for covariates. RESULTS: Of 588 patients included, 43% were men and 57% were women. In the unadjusted model, malignancy, prehospital psychiatric medication and analgesic use, tobacco, ileostomy creation, operative time, and postoperative complications were associated with increased opioid consumption. In multivariate analyses, prehospital opioid and nonopioid analgesic use, operative time, anastomotic leak, and postoperative ileus remained significantly associated with increased inpatient opioid consumption. However, there was no significant association between sex and opioid use in crude or adjusted analysis (incidence rate ratio: 1.09; 95% confidence interval: 0.90, 1.32). Women reported higher average daily pain scores (coefficient: 0.29; 95% confidence interval: 0.04, 0.55) in adjusted analyses. CONCLUSIONS: Among patients undergoing colorectal surgery using an ERP, sex-based differences exist in pain scores but not early postoperative opioid consumption. Identification of intragroup differences in postoperative pain and opioid use among patients managed with an ERP serves as targets for customization and enhancement of current protocols. Furthermore, incongruence between reported pain and analgesic administration may have important implications for sex-related differences in persistent opioid use.

Genetically encoded fluorescent probe to visualize intracellular phosphatidylinositol 3,5-bisphosphate localization and dynamics.

Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a low-abundance phosphoinositide presumed to be localized to endosomes and lysosomes, where it recruits cytoplasmic peripheral proteins and regulates endolysosome-localized membrane channel activity. Cells lacking PI(3,5)P2 exhibit lysosomal trafficking defects, and human mutations in the PI(3,5)P2-metabolizing enzymes cause lysosome-related diseases. The spatial and temporal dynamics of PI(3,5)P2, however, remain unclear due to the lack of a reliable detection method. Of the seven known phosphoinositides, only PI(3,5)P2 binds, in the low nanomolar range, to a cytoplasmic phosphoinositide-interacting domain (ML1N) to activate late endosome and lysosome (LEL)-localized transient receptor potential Mucolipin 1 (TRPML1) channels. Here, we report the generation and characterization of a PI(3,5)P2-specific probe, generated by the fusion of fluorescence tags to the tandem repeats of ML1N. The probe was mainly localized to the membranes of Lamp1-positive compartments, and the localization pattern was dynamically altered by either mutations in the probe, or by genetically or pharmacologically manipulating the cellular levels of PI(3,5)P2. Through the use of time-lapse live-cell imaging, we found that the localization of the PI(3,5)P2 probe was regulated by serum withdrawal/addition, undergoing rapid changes immediately before membrane fusion of two LELs. Our development of a PI(3,5)P2-specific probe may facilitate studies of both intracellular signal transduction and membrane trafficking in the endosomes and lysosomes.

Targets for Intervention? Preoperative Predictors of Postoperative Ileus After Colorectal Surgery in an Enhanced Recovery Protocol.

BACKGROUND: Postoperative ileus occurs in up to 30% of colorectal surgery patients and is associated with increased length of stay, costs, and morbidity. While Enhanced Recovery Protocols seek to accelerate postoperative recovery, data on modifiable preoperative factors associated with postoperative ileus in this setting are limited. We aimed to identify preoperative predictors of postoperative ileus following colorectal surgery in Enhanced Recovery Protocols, to determine new intervention targets. METHODS: We performed a retrospective single-center cohort study of patients ≥ 18 years old who underwent colorectal surgery via Enhanced Recovery Protocols (7/2015-7/2017). Postoperative ileus was defined as nasogastric tube insertion postoperatively or nil-per-os by postoperative day 4. Preoperative risk factors including comorbidities and medication use were identified using multivariable stepwise logistic regression. RESULTS: Of 530 patients, 14.9% developed postoperative ileus. On univariate analysis of perioperative and postoperative factors, postoperative ileus patients had increased psychiatric illness, antidepressant and antipsychotic use, American Society of Anesthesiologists classification, ileostomy creation, postoperative opioid use, complications, surgery duration, and length of stay (p < 0.05). Multivariable logistic regression model for preoperative factors identified psychiatric illness, preoperative antipsychotic use, and American Society of Anesthesiologists classification ≥ 3 as significant predictors of postoperative ileus (p < 0.05). DISCUSSION: Postoperative ileus remains a common complication following colorectal surgery under Enhanced Recovery Protocols. Patients with pre-existing psychiatric comorbidities and preoperative antipsychotic use may be a previously overlooked cohort at increased risk for postoperative ileus. Additional research and preoperative interventions within Enhanced Recovery Protocols to reduce postoperative ileus for this higher-risk population are needed.

The intracellular Ca²âº channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy.

The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis.