Worth the Risk? Standardized Screening to Identify Substance Use Among Patients Prior to Surgery.

OBJECTIVE: We sought to compare identification of unhealthy substance use before surgery using The Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS), a standardized 4-item instrument, versus routine clinical documentation in the electronic medical record (EHR). SUMMARY BACKGROUND DATA: Over 20% of individuals exhibit unhealthy substance use before elective surgery. Routine EHR documentation is often based on non-standard questions that may not fully capture the extent of substance use and is subject to bias. In contrast, brief standardized screening could provide a more efficient and systematic approach. METHODS: We conducted a cross-sectional study among adults (≥18 y) at a preoperative clinic from August to September, 2021. Positive screens for unhealthy substances by TAPS were compared to data from the EHR. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were reported. Receiver operating characteristic curves (ROCs) were used to assess diagnostic ability. Multivariable logistic regression was used to estimate the predictors of positive screens by TAPS. RESULTS: The cohort included 240 surgical patients. TAPS screening identified significantly more positive screens than EHR documentation (43.3% vs. 14.2%). Patients with unhealthy substance use were younger (50.8 vs. 56.7 y; P=0.003), and TAPS revealed alcohol misuse in 30.8% of cases, contrasting with 0% in clinician documentation (P<0.001). Of the 104 TAPS-positive patients, 69.2% were missed by EHR documentation. Sensitivity (31%) and accuracy (AUC=0.65) of clinician documentation for any unhealthy substance use were lower compared to TAPS. CONCLUSION: Standardized TAPS screening detected preoperative unhealthy substance use more frequently than routine clinician documentation, emphasizing the need for integrating standardized measures into surgical practice to ensure safer perioperative care and outcomes.

The Association of Cannabis Use After Discharge From Surgery With Opioid Consumption and Patient-reported Outcomes.

OBJECTIVE: To compare outcomes of patients using versus not using cannabis as a treatment for pain after discharge from surgery. BACKGROUND: Cannabis is increasingly available and is often taken by patients to relieve pain. However, it is unclear whether cannabis use for pain after surgery impacts opioid consumption and postoperative outcomes. METHODS: Using Michigan Surgical Quality Collaborative registry data at 69 hospitals, we analyzed a cohort of patients undergoing 16 procedure types between January 1, 2021, and October 31, 2021. The key exposure was cannabis use for pain after surgery. Outcomes included postdischarge opioid consumption (primary) and patient-reported outcomes of pain, satisfaction, quality of life, and regret to undergo surgery (secondary). RESULTS: Of 11,314 included patients (58% females, mean age: 55.1 years), 581 (5.1%) reported using cannabis to treat pain after surgery. In adjusted models, patients who used cannabis consumed an additional 1.0 (95% CI: 0.4-1.5) opioid pills after surgery. Patients who used cannabis were more likely to report moderate-to-severe surgical site pain at 1 week (adjusted odds ratio: 1.7, 95% CIL 1.4-2.1) and 1 month (adjusted odds ratio: 2.1, 95% CI: 1.7-2.7) after surgery. Patients who used cannabis were less likely to endorse high satisfaction (72.1% vs 82.6%), best quality of life (46.7% vs 63.0%), and no regret (87.6% vs 92.7%) (all P < 0.001). CONCLUSIONS: Patient-reported cannabis use, to treat postoperative pain, was associated with increased opioid consumption after discharge from surgery that was of clinically insignificant amounts, but worse pain and other postoperative patient-reported outcomes.

The Association of Preoperative Opioid Use with Post-Discharge Outcomes: A Cohort Study of the Michigan Surgical Quality Collaborative.

OBJECTIVE: To examine the association of prescription opioid fills over the year prior to surgery with postoperative outcomes. BACKGROUND: Nearly one third of patients report opioid use in the year preceding surgery, yet an understanding of how opioid exposure influences patient-reported outcomes after surgery remains incomplete. Therefore, this study was designed to test the hypothesis that preoperative opioid exposure may impede recovery in the postoperative period. METHODS: This retrospective cohort study used a statewide clinical registry from 70 hospitals linked to opioid fulfillment data from the state's prescription drug monitoring program to categorize patients' preoperative opioid exposure as none (naïve), minimal, intermittent, or chronic. Outcomes were patient-reported pain intensity (primary), as well as 30-day clinical and patient-reported outcomes (secondary). RESULTS: Compared to opioid-naïve patients, opioid exposure was associated with higher reported pain scores at 30 days after surgery. Predicted probabilities was higher among the opioid exposed versus naive group for reporting moderate pain (43.5% [95% CI 42.6 - 44.4%] vs 39.3% [95% CI 38.5 - 40.1%]) and severe pain (13.% [95% CI 12.5 - 14.0%] vs 10.0% [95% CI 9.5 - 10.5%]), and increasing probability was associated increased opioid exposure for both outcomes. Clinical outcomes (incidence of ED visits, readmissions, and reoperation within 30-days) and patient-reported outcomes (reported satisfaction, regret, and quality of life) were also worse with increasing preoperative opioid exposure for most outcomes. CONCLUSIONS: This study is the first to examine the effect of presurgical opioid exposure on both clinical and non-clinical outcomes in a broad cohort of patients, and shows that exposure is associated with worse postsurgical outcomes. A key question to be addressed is whether and to what extent opioid tapering before surgery mitigates these risks after surgery.

Does the diagnostic timing of cancer-associated thromboembolism influence the survival outcome in ovarian cancer patients?

BACKGROUND/PURPOSE: Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. METHODS: We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. RESULTS: These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24 kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI <24 kg/m2 at the diagnosis of ovarian cancer, or primary debulking surgery in the during cancer diagnosis group had longer disease-free survival, and overall survival benefit was observed in cases with stage I/II disease, or primary debulking surgery. CONCLUSION: The diagnostic timing of thromboembolism was not related to disease-free or overall survival of ovarian cancer patients, but associated with that of specific patient subgroups.

Postacute Care Utilization and Episode of Care Payments Following Common Elective Operations.

OBJECTIVE: To describe PAC utilization and associated payments for patients undergoing common elective procedures. SUMMARY OF BACKGROUND DATA: Utilization and costs of PAC are well described for benchmarked conditions and operations but remain understudied for common elective procedures. METHODS: Cross-sectional study of adult patients in a statewide administrative claims database undergoing elective cholecystectomy, ventral or incisional hernia repair (VIHR), and groin hernia repair from 2012 to 2019. We used multivariable logistic regression to estimate the odds of PAC utilization, and multivariable linear regression to determine the association of 90-day episode of care payments and PAC utilization. RESULTS: Among 34,717 patients undergoing elective cholecystectomy, 0.7% utilized PAC resulting in significantly higher payments ($19,047 vs $7830, P < 0.001). Among 29,826 patients undergoing VIHR, 1.7% utilized PAC resulting in significantly higher payments ($19,766 vs $9439, P < 0.001). Among 37,006 patients undergoing groin hernia repair, 0.3% utilized PAC services resulting in significantly higher payments ($14,886 vs $8062, P < 0.001). We found both modifiable and non-modifiable risk factors associated with PAC utilization. Morbid obesity was associated with PAC utilization following VIHR [odds ratio (OR) 1.61, 95% confidence interval (CI) 1.29-2.02, P < 0.001]. Male sex was associated with lower odds of PAC utilization for VIHR (OR 0.43, 95% CI 0.35-0.51, P < 0.001) and groin hernia repair (OR 0.62, 95% CI 0.39-0.98, P = 0.039). CONCLUSIONS: We found both modifiable (eg, obesity) and nonmodifiable (eg, female sex) patient factors that were associated with PAC. Optimizing patients to reduce PAC utilization requires an understanding of patient risk factors and systems and processes to address these factors.

Postoperative Opioid Prescribing and New Persistent Opioid Use: The Risk of Excessive Prescribing.

OBJECTIVE: Evaluate the association between postoperative opioid prescribing and new persistent opioid use. SUMMARY BACKGROUND DATA: Opioid-nave patients who develop new persistent opioid use after surgery are at increased risk of opioid-related morbidity and mortality. However, the extent to which postoperative opioid prescribing is associated with persistent postoperative opioid use is unclear. METHODS: Retrospective study of opioid-naïve adults undergoing surgery in Michigan from 1/1/2017 to 10/31/2019. Postoperative opioid prescriptions were identified using a statewide clinical registry and prescription fills were identified using Michigan's prescription drug monitoring program. The primary outcome was new persistent opioid use, defined as filling at least 1 opioid prescription between post-discharge days 4 to 90 and filling at least 1 opioid prescription between post-discharge days 91 to 180. RESULTS: A total of 37,654 patients underwent surgery with a mean age of 52.2 (16.7) years and 20,923 (55.6%) female patients. A total of 31,920 (84.8%) patients were prescribed opioids at discharge. Six hundred twenty-two (1.7%) patients developed new persistent opioid use after surgery. Being prescribed an opioid at discharge was not associated with new persistent opioid use [adjusted odds ratio (aOR) 0.88 (95% confidence interval (CI) 0.71-1.09)]. However, among patients prescribed an opioid, patients prescribed the second largest [12 (interquartile range (IQR) 3) pills] and largest [20 (IQR 7) pills] quartiles of prescription size had higher odds of new persistent opioid use compared to patients prescribed the smallest quartile [7 (IQR 1) pills] of prescription size [aOR 1.39 (95% CI 1.04-1.86) andaOR 1.97 (95% CI 1.442.70), respectively]. CONCLUSIONS: In a cohort of opioid-naïve patients undergoing common surgical procedures, the risk of new persistent opioid use increased with the size of the prescription. This suggests that while opioid prescriptions in and of themselves may not place patients at risk of long-term opioid use, excessive prescribing does. Consequently, these findings support ongoing efforts to mitigate excessive opioid prescribing after surgery to reduce opioid-related harms.

Sequential Phosphorylation of Hepatitis C Virus NS5A Protein Requires the ATP-Binding Domain of NS3 Helicase.

The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation. Given the ATPase domain in the NS3 COOH terminus, we tested whether NS3 participates in NS5A phosphorylation similarly to the nucleoside diphosphate kinase-like activity of the rotavirus NSP2 nucleoside triphosphatase (NTPase). Mutations in the NS3 ATP-binding motifs blunted NS5A hyperphosphorylation and phosphorylation at serines 225, 232, and 235, whereas a mutation in the RNA-binding domain did not. The phosphorylation events were not rescued with wild-type NS3 provided in trans. When provided with an NS3 ATPase-compatible ATP analog, N6-benzyl-ATP-γ-S, thiophosphorylated NS5A was detected in the cells expressing the wild-type NS3-NS5B polyprotein. The thiophosphorylation level was lower in the cells expressing NS3-NS5B with a mutation in the NS3 ATP-binding domain. In vitro assays with a synthetic peptide and purified wild-type NS3 followed by dot blotting and mass spectrometry found weak NS5A phosphorylation at serines 222 and 225 that was sensitive to an inhibitor of casein kinase Iα but not helicase. When casein kinase Iα was included in the assay, much stronger phosphorylation was observed at serines 225, 232, and 235. We concluded that NS5A sequential phosphorylation requires the ATP-binding domain of the NS3 helicase and that casein kinase Iα is a potent NS5A kinase. IMPORTANCE For more than 20 years, NS3 was known to participate in NS5A sequential phosphorylation. In the present study, we show for the first time that the ATP-binding domain of NS3 is involved in NS5A phosphorylation. In vitro assays showed that casein kinase Iα is a very potent kinase responsible for NS5A phosphorylation at serines 225, 232, and 235. Our data suggest that ATP binding by NS3 probably results in conformational changes that recruit casein kinase Iα to phosphorylate NS5A, initially at S225 and subsequently at S232 and S235. Our discovery reveals intricate requirements of the structural integrity of NS3 for NS5A hyperphosphorylation and HCV replication.

Comparison of Minimally Invasive and Open Surgery for the Treatment of Endometrial Cancer with a High Risk of Recurrence: A Propensity Score Matching Study in Korea and Taiwan.

BACKGROUND: This study compared oncologic outcomes between minimally invasive surgery (MIS) and open surgery for the treatment of endometrial cancer with a high risk of recurrence. METHODS: This study included patients with endometrial cancer who underwent primary surgery at two tertiary centers in Korea and Taiwan. Low-grade advanced-stage endometrial cancer (endometrioid grade 1 or 2) or endometrial cancer with aggressive histology (endometrioid grade 3 or non-endometrioid) at any stage was considered to have a high risk of recurrence. We conducted 1:1 propensity score matching between the MIS and open surgery groups to adjust for the baseline characteristics. RESULTS: Of the total of 582 patients, 284 patients were included in analysis after matching. Compared with open surgery, MIS did not show a difference in disease-free survival [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.67-1.77, P = 0.717] or overall survival (HR 0.67; 95% CI 0.36-1.24, P = 0.198). In the multivariate analysis, non-endometrioid histology, tumor size, tumor cytology, depth of invasion, and lymphovascular space invasion were risk factors for recurrence. There was no association between the surgical approach and either recurrence or mortality in the subgroup analysis according to stage and histology. CONCLUSIONS: MIS did not compromise survival outcomes for patients with endometrial cancer with a high risk of recurrence when compared with open surgery.

Five year trends in surgical technique and outcomes of groin hernia repair in the United States.

INTRODUCTION: Despite being one of the most commonly performed operations in the US, there is a paucity of data on practice patterns and resultant long-term outcomes of groin hernia repair. In this context, we performed a contemporary assessment of operative approach with 5 year follow-up to inform care for the 800000 persons undergoing groin hernia repair annually. METHODS: This was a retrospective cohort study of adult patients undergoing elective groin hernia repair in a 20% representative Medicare sample from 2010-17. Surgical approach [minimally invasive (MIS) vs open] was defined using appropriate CPT codes. The primary outcome was operative recurrence at up to 5 years following surgery. We estimated the overall risk of operative recurrence using a multivariable Cox proportional hazards model. RESULTS: Among 118119 patients, the majority (76.4%) underwent an open repair. Compared to patients who underwent MIS repair, patients in the open surgery cohort were older (mean age 72.7 vs 71.0, p < 0.001), more often female (14.4 vs 10.9%, p < 0.001), less often white (86.9 vs 87.7%, p < 0.001), and had a higher prevalence of nearly all measured comorbidities Patients in the open cohort had a lower incidence of operative recurrence at 1-year (1.0 vs 1.5%, p < 0.001), 3-years, (2.5 vs 3.5%, p < 0.001), and 5-years (3.7 vs 4.7%, p < 0.001). In the Cox proportional hazards model, we found that patients who underwent an open groin hernia repair were significantly less likely to experience operative recurrence (HR 0.86, 95% CI 0.79-0.93). CONCLUSIONS: In this study, we found that open groin hernia repair was associated with a lower risk of operative recurrence over time. While this may be related to patient comorbidity and age at the index operation, future work should focus on the impact of surgeon volume on outcomes in the modern era.

Preoperative Opioid Use and Readmissions Following Surgery.

OBJECTIVE: To assess the association between preoperative opioid exposure and readmissions following common surgery. SUMMARY BACKGROUND DATA: Preoperative opioid use is common, but its effect on opioid-related, pain-related, respiratory-related, and all-cause readmissions following surgery is unknown. METHODS: We analyzed claims data from a 20% national Medicare sample of patients ages ≥ 65 with Medicare Part D claims undergoing surgery between January 1, 2009 and November 30, 2016. We grouped patients by the dose, duration, recency, and continuity of preoperative opioid prescription fills. We used logistic regression to examine the association between prior opioid exposure and 30-day readmissions, adjusted for patient risk factors and procedure type. RESULTS: Of 373,991 patients, 168,579 (45%) filled a preoperative opioid prescription within 12 months of surgery, ranging from minimal to chronic high use. Preoperative opioid exposure was associated with higher rate of opioid-related readmissions, compared with naive patients [low: aOR=1.63, 95% CI=1.26-2.12; high: aOR=3.70, 95% CI=2.71-5.04]. Preoperative opioid exposure was also associated with higher risk of pain-related readmissions [low: aOR=1.27, 95% CI=1.23-1.32; high: aOR=1.62, 95% CI=1.53-1.71] and respiratory-related readmissions [low: aOR=1.10, 95% CI=1.05-1.16; high: aOR=1.44, 95% CI=1.34-1.55]. Low, moderate, and high chronic preoperative opioid exposures were predictive of all-cause readmissions (low: OR 1.09, 95% CI: 1.06-1.12); high: OR 1.23, 95% CI: 1.18-1.29). CONCLUSIONS: Higher levels of preoperative opioid exposure are associated with increased risk of readmissions after surgery. These findings emphasize the importance of screening patients for preoperative opioid exposure and creating risk mitigation strategies for patients.

The Association of Postoperative Opioid Prescriptions with Patient Outcomes.

OBJECTIVE: To compare outcomes after surgery between patients who were not prescribed opioids and patients who were prescribed opioids. SUMMARY OF BACKGROUND DATA: Postoperative opioid prescriptions carry significant risks. Understanding outcomes among patients who receive no opioids after surgery may inform efforts to reduce these risks. METHODS: We performed a retrospective study of adult patients who underwent surgery between January 1, 2019 and October 31, 2019. The primary outcome was the composite incidence of an emergency department visit, readmission, or reoperation within 30 days of surgery. Secondary outcomes were postoperative pain, satisfaction, quality of life, and regret collected via postoperative survey. A multilevel, mixed-effects logistic regression was performed to evaluate differences between groups. RESULTS: In a cohort of 22,345 patients, mean age (standard deviation) was 52.1 (16.5) years and 13,269 (59.4%) patients were female. About 3175 (14.2%) patients were not prescribed opioids, of whom 422 (13.3%) met the composite adverse event endpoint compared to 2255 (11.8%) of patients not prescribed opioids ( P = 0.015). Patients not prescribed opioids had a similar probability of adverse events {11.7% [95% confidence interval (CI) 10.2%-13.2%] vs 11.9% (95% CI 10.6%-13.3%]}. Among 12,872 survey respondents, patients who were not prescribed an opioid had a similar rate of high satisfaction [81.7% (95% CI 77.3%-86.1%) vs 81.7% (95% CI 77.7%- 85.7%)] and no regret [(93.0% (95% CI 90.8%-95.2%) vs 92.6% (95% CI 90.4%-94.7%)]. CONCLUSIONS: Patients who were not prescribed opioids after surgery had similar clinical and patient-reported outcomes as patients who were prescribed opioids. This suggests that minimizing opioids as part of routine postoperative care is unlikely to adversely affect patients.

TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation.

BACKGROUND: Systemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells). METHODS: Lipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain. RESULTS: Some noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection. CONCLUSIONS: The findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.

Does para-aortic lymphadenectomy improve survival in pathologically diagnosed early-stage grade 3 endometrioid and non-endometrioid endometrial cancers? A retrospective cohort study in Korea and Taiwan.

PURPOSE: The therapeutic effect of para-aortic lymphadenectomy in early-stage high-grade endometrial cancer remains controversial. In this study, we investigated whether combined pelvic and para-aortic lymphadenectomy has a survival benefit compared to pelvic lymphadenectomy alone in patients with pathologically diagnosed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. METHODS: We retrospectively reviewed the medical records of 281 patients with histologically confirmed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers who underwent pelvic lymphadenectomy alone or combined pelvic and para-aortic lymphadenectomy in staging surgery at two tertiary centers in Korea and Taiwan. Prognostic factors to predict outcomes in these cases were also analyzed. RESULTS: Among 281 patients, 144 underwent pelvic lymphadenectomy alone and 137 underwent combined pelvic and para-aortic lymphadenectomy. Within a median follow-up of 45 months, there was no significant difference in recurrence-free survival (RFS) and overall survival (OS) between the two groups. In multivariable analysis, age at diagnosis ≥60 years (HR = 2.20, 95% CI 1.25-3.87, p = 0.006) and positive lymph-vascular space invasion (LVSI) (HR = 2.79, 95% CI 1.60-4.85, p < 0.001) were associated with worse RFS, and only non-endometrioid histology was associated with worse OS (HR = 3.18, 95% CI 1.42-7.12, p = 0.005). In further subgroup analysis, beneficial effects of combined pelvic and para-aortic lymphadenectomy on RFS and OS were not observed. CONCLUSIONS: In this study, combined pelvic and para-aortic lymphadenectomy could not improve survival compared to pelvic lymphadenectomy alone in patients with FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. Therefore, para-aortic lymphadenectomy may be omitted for these cases.

The Association Between Preoperative Opioid Exposure and Prolonged Postoperative Use.

OBJECTIVE: To determine the effect of nonchronic, periodic preoperative opioid use on prolonged opioid fills after surgery. BACKGROUND: Nonchronic, periodic opioid use is common, but its effect on prolonged postoperative opioid fills is not well understood. We hypothesize greater periodic opioid use before surgery is correlated with persistent postoperative use. METHODS: We used a national private insurance claims database, Optum's de-identifed Clinformatics Data Mart Database, to identify adults undergoing general, gynecologic, and urologic surgical procedures between 2008 and 2015 (N = 191,043). We described patterns of opioid fills based on dose, recency, duration, and continuity to categorize preoperative opioid exposure. Patients with chronic use were excluded. Our primary outcome was persistent postoperative use, defined as filling an opioid prescription between 91- and 180-days post-discharge. The association between preoperative opioid use and persistent use was determined using multivariable logistic regression, controlling for clinical covariates. RESULTS: In the year before surgery, 41% of patients had nonchronic, periodic opioid fills. Compared with other risk factors, patterns of preoperative fills were most strongly correlated with persistent postoperative opioid use. Patients with recent intermittent use were significantly more likely to have prolonged fills after surgery compared with opioid-naïve patients [minimal use: odds ratio (OR): 2.0, 95% confidence interval (CI) 1.89-2.03; remote intermittent: OR 4.7, 95% CI 4.46-4.93; recent intermittent: OR 12.2, 95% CI 11.49-12.90]. CONCLUSIONS: Patients with nonchronic, periodic opioid use before surgery are vulnerable to persistent postoperative opioid use. Identifying opioid use before surgery is a critical opportunity to optimize care after surgery.

Sequential Phosphorylation of the Hepatitis C Virus NS5A Protein Depends on NS3-Mediated Autocleavage between NS3 and NS4A.

Replication of the genotype 2 hepatitis C virus (HCV) requires hyperphosphorylation of the nonstructural protein NS5A. It has been known that NS5A hyperphosphorylation results from the phosphorylation of a cluster of highly conserved serine residues (S2201, S2208, S2211, and S2214) in a sequential manner. It has also been known that NS5A hyperphosphorylation requires an NS3 protease encoded on one single NS3-5A polyprotein. It was unknown whether NS3 protease participates in this sequential phosphorylation process. Using an inventory of antibodies specific to S2201, S2208, S2211, and S2214 phosphorylation, we found that protease-dead S1169A mutation abrogated NS5A hyperphosphorylation and phosphorylation at all serine residues measured, consistent with the role of NS3 in NS5A sequential phosphorylation. These effects were not rescued by a wild-type NS3 protease provided in trans by another molecule. Mutations (T1661R, T1661Y, or T1661D) that prohibited proper cleavage at the NS3-4A junction also abolished NS5A hyperphosphorylation and phosphorylation at all serine residues, whereas mutations at the other cleavage sites, NS4A-4B (C1715S) or NS4B-5A (C1976F), did not. In fact, any combinatory mutations that prohibited NS3-4A cleavage (T1661Y/C1715S or T1661Y/C1976F) abrogated NS5A hyperphosphorylation and phosphorylation at all serine residues. In the C1715S/C1976F double mutant, which resulted in an NS4A-NS4B-NS5A fusion polyprotein, a hyperphosphorylated band was observed and was phosphorylated at all serine residues. We conclude that NS3-mediated autocleavage at the NS3-4A junction is critical to NS5A hyperphosphorylation at S2201, S2208, S2211, and S2214 and that NS5A hyperphosphorylation could occur in an NS4A-NS4B-NS5A polyprotein.IMPORTANCE For ca. 20 years, the HCV protease NS3 has been implicated in NS5A hyperphosphorylation. We now show that it is the NS3-mediated cis cleavage at the NS3-4A junction that permits NS5A phosphorylation at serines 2201, 2208, 2211, and 2214, leading to hyperphosphorylation, which is a necessary condition for genotype 2 HCV replication. We further show that NS5A may already be phosphorylated at these serine residues right after NS3-4A cleavage and before NS5A is released from the NS4A-5A polyprotein. Our data suggest that the dual-functional NS3, a protease and an ATP-binding RNA helicase, could have a direct or indirect role in NS5A hyperphosphorylation.

Persistent Opioid Use after Ophthalmic Surgery in Opioid-Naive Patients and Associated Risk Factors.

PURPOSE: To determine the rate and risk factors for new persistent opioid use after ophthalmic surgery in the United States. DESIGN: Retrospective claims-based cohort analysis. PARTICIPANTS: Opioid-naive patients 13 years of age and older who underwent incisional ophthalmic surgery between January 1, 2012, and June 30, 2017, and were included in Optum's de-identified Clinformatics Data Mart database. METHODS: New persistent opioid use was defined as filling an opioid prescription in the 90-day and the 91- to 180-day periods after the surgical procedure. The outcome variable was an initial perioperative opioid prescription fill. Rates of new persistent opioid use were calculated, and multivariate logistic regression models were used to identify variables increasing the risk of new persistent use and refill of an opioid prescription after the initial perioperative prescription in first 30 days. MAIN OUTCOME MEASURES: New persistent opioid use and refill. RESULTS: A total of 327 379 opioid-naive patients (mean age, 67 years [standard deviation, 16 years]; 178 067 women [54.4%]) who underwent ophthalmic surgery were examined. Among these patients, 14 841 (4.5%) had an initial perioperative opioid fill. The rate of new persistent opioid use was 3.4% (498 of 14 841 patients) compared with 0.6% (1833 of 312 538 patients) in patients who did not have an initial perioperative opioid fill. After adjusting for patient characteristics, initial perioperative opioid fill was associated independently with increased odds of new persistent use (adjusted odds ratio [OR], 6.21; 95% confidence interval [CI], 5.57-6.91; P < 0.001). Among patients who had filled an initial perioperative prescription, a prescription size of 150 morphine milligram equivalents or more was associated with an increased odds of refill (adjusted OR, 1.87; 95% CI, 1.58-2.22; P < 0.001). CONCLUSIONS: Exposure to opioids in the perioperative period is associated with new persistent use in patients who were previously opioid-naive. This suggests that exposure to opioids is an independent risk factor for persistent use in patients undergoing incisional ophthalmic surgery. Surgeons should be aware of those risks to identify at-risk patients given the current national opioid crisis and to minimize prescribing opioids when possible.

Higher Amounts of Opioids Filled After Surgery Increase Risk of Serious Falls and Fall-Related Injuries Among Older Adults.

BACKGROUND: Despite increasing numbers of older adults undergoing surgery and the known risks of opioids, little is known about the potential association between opioid prescribing and serious falls and fall-related injuries after surgery. OBJECTIVE: To determine the incidence and risk factors of serious falls and fall-related injuries after elective, outpatient surgery. DESIGN: Retrospective cohort study of 20% national sample of Medicare claims among beneficiaries ≥ 65 years of age with Medicare Part D claims and who underwent elective outpatient surgery from January 1, 2009, through December 31, 2014. PARTICIPANTS: Opioid-naïve patients ≥ 65 years undergoing elective, minor, outpatient surgical procedures. The exposure was opioid prescription fills in the perioperative period (i.e., 30 days before up until 3 days after surgery) converted to total oral morphine equivalents (OME) over a period 30 days prior to and 30 days after surgery. MAIN MEASURES: Serious falls and fall-related injuries within 30 days after surgery, examined through Poisson regression analysis with reported fall and fall-related injury rates adjusted for potential confounders. KEY RESULTS: Among 44,247 opioid-naïve surgical patients, 76.3% filled an opioid prescription in the perioperative period. Overall, 0.62% of patients suffered a serious fall or fall-related injury within 30 days after surgery. Risk factors for serious falls or fall-related injuries after surgery included older age (80-84 years: RR 1.64, 95% CI 1.12-2.40; 85 years and older: RR 1.81, 95% CI 1.25-2.86), female sex (RR 3.04, 95% CI 2.29-4.05), Medicaid eligibility (RR 1.63, 95% CI 1.17-2.26), and higher amounts of opioids filled following surgery (≥ 225 OME: RR 2.29, 95% CI 1.72-3.07). CONCLUSIONS: Serious falls after elective, outpatient surgery are uncommon, but correlated with age, sex, Medicaid eligibility, and the amount of opioids filled in the perioperative period. Judicious prescribing of opioids after surgery is paramount and is an opportunity to improve the safety of surgical care among older individuals.

New persistent opioid use after acute opioid prescribing in pregnancy: a nationwide analysis.

OBJECTIVE: To evaluate the association between opioid prescribing during pregnancy and new persistent opioid use in the year following delivery. MATERIALS AND METHODS: This nationwide retrospective cohort study included patients aged 12-55 years in Optum's deidentified Clinformatics Data Mart Database who were undergoing vaginal delivery or cesarean delivery from 2008 to 2016, with continuous enrollment from 2 years before birth to 1 year postdischarge. Women were included if they were opioid naive in pregnancy (ie, did not fill an opioid prescription 2 years to 9 months before delivery) and did not undergo a procedure within the year after discharge. The exposure was filling an opioid prescription in pregnancy. The primary outcome was new persistent opioid use, defined as a pharmacy claim for ≥1 opioid prescription between 4 and 90 days postdischarge and ≥1 prescription between 91 and 365 days postdischarge. Clinical and demographic covariates were included. Analyses included descriptive statistics and multivariable logistic regression, adjusting for clinical and demographic covariates. RESULTS: Of 158,425 childbirths identified, 101,013 (63.8%) were by vaginal delivery and 57,412 (36.2%) cesarean delivery. Among all patients, 6.0% (9429) filled an opioid prescription during pregnancy. The factors associated with filling an opioid in pregnancy were having a nondelivery procedure in pregnancy (adjusted odds ratio, 9.60; 95% confidence interval, 8.81-10.47) and having an emergency room visit during pregnancy (adjusted odds ratio, 2.48; 95% confidence interval, 2.37-2.59). Of women who received an opioid in pregnancy, 4% (379) developed new persistent opioid use. The factors most associated with new persistent opioid use were receiving an opioid prescription during pregnancy (adjusted odds ratio, 3.45; 95% confidence interval, 3.04-3.92) and filling a peripartum opioid prescription (1 week prior to 3 days postdischarge) adjusted odds ratio, 2.28, 95% confidence interval (2.02-2.57). Though having a procedure during pregnancy was associated with increased receipt of an opioid prescription, it was also associated with reduced new persistent opioid use (adjusted odds ratio, 0.72; 95% confidence interval, 0.52-0.99). CONCLUSION: Women who receive an opioid prescription during pregnancy are more likely to experience new persistent opioid use. Maternity care providers must balance pain management in pregnancy with potential risks of opioids.

Outcomes of extended progestin therapy in atypical endometrial hyperplasia patients without an initial response to progestin: a retrospective study from two tertiary centers in Korea and Taiwan.

OBJECTIVE: In this study, we evaluated the role of prolonged progestin treatment on atypical endometrial hyperplasia (AEH) patients who did not achieve complete regression (CR) after at least 3 months of progestin treatment. Possible prognostic factors predicting disease regression and recurrence were also assessed. METHODS: We retrospectively identified patients who had histologically confirmed persistent disease after at least 3 months of progestin treatment at two tertiary centers in Korea and Taiwan. Clinicopathologic factors and clinical outcomes were obtained from medical records. Logistic regression was used to analyze the relationship between covariates and the probability of CR and relapse. RESULTS: Fifty-two patients were included. Thirty-seven of 52 patients (71.2%) achieved CR after prolonged progestin treatment. Median time from starting progestin treatment to CR was 12.0 months. Daily administration of medroxyprogesterone acetate ≥200 mg or megestrol acetate ≥80 mg was associated with higher probability of regression. Nineteen of 37 patients (51.4%) experienced recurrence, with median time from CR to relapse of 15.0 months. Body mass index ≥27 was associated with higher relapse probability. Twelve of 16 patients with disease progression to endometrial carcinoma underwent surgery. The 12 cases had stage I tumors and lived without disease. CONCLUSION: Extension of progestin treatment course is feasible for AEH patients without an initial response to progestin. Higher daily progestin dosage was associated with higher probability of CR, and obesity was associated with higher risk of relapse. The patients without an initial response to progestins and whose AEH progressed to endometrial carcinoma had good prognoses.