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.

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.

Impact of adjuvant treatment on survival in patients with 2023 FIGO stage IIC endometrial cancer: a retrospective analysis from two tertiary centers in Korea and Taiwan.

OBJECTIVE: In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. METHODS: We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. RESULTS: A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. CONCLUSION: In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors.

Prescribed Opioid Dosages, Payer Type, and Self-Reported Outcomes After Surgical Procedures in Michigan, 2018-2020.

Importance: Collaborative quality improvement (CQI) models, often supported by private payers, create hospital networks to improve health care delivery. Recently, these systems have focused on opioid stewardship; however, it is unclear whether reduction in postoperative opioid prescribing occurs uniformly across health insurance payer types. Objective: To evaluate the association between insurance payer type, postoperative opioid prescription size, and patient-reported outcomes in a large statewide CQI model. Design, Setting, and Participants: This retrospective cohort study used data from 70 hospitals within the Michigan Surgical Quality Collaborative clinical registry for adult patients (age ≥18 years) undergoing general, colorectal, vascular, or gynecologic surgical procedures between January 1, 2018, and December 31, 2020. Exposure: Insurance type, classified as private, Medicare, or Medicaid. Main Outcomes and Measures: The primary outcome was postoperative opioid prescription size in milligrams of oral morphine equivalents (OME). Secondary outcomes were patient-reported opioid consumption, refill rate, satisfaction, pain, quality of life, and regret about undergoing surgery. Results: A total of 40 149 patients (22 921 [57.1%] female; mean [SD] age, 53 [17] years) underwent surgery during the study period. Within this cohort, 23 097 patients (57.5%) had private insurance, 10 667 (26.6%) had Medicare, and 6385 (15.9%) had Medicaid. Unadjusted opioid prescription size decreased for all 3 groups during the study period from 115 to 61 OME for private insurance patients, from 96 to 53 OME for Medicare patients, and from 132 to 65 OME for Medicaid patients. A total of 22 665 patients received a postoperative opioid prescription and had follow-up data for opioid consumption and refill. The rate of opioid consumption was highest among Medicaid patients throughout the study period (16.82 OME [95% CI, 12.57-21.07 OME] greater than among patients with private insurance) but increased the least over time. The odds of refill significantly decreased over time for patients with Medicaid compared with patients with private insurance (odds ratio, 0.93; 95% CI, 0.89-0.98). Adjusted refill rates for private insurance remained between 3.0% and 3.1% over the study period; adjusted refill rates among Medicare and Medicaid patients decreased from 4.7% to 3.1% and 6.5% to 3.4%, respectively, by the end of the study period. Conclusions and Relevance: In this retrospective cohort study of surgical patients in Michigan from 2018 to 2020, postoperative opioid prescription size decreased across all payer types, and differences between groups narrowed over time. Although funded by private payers, the CQI model appeared to have benefitted patients with Medicare and Medicaid as well.

Dual inhibition of BTLA and PD-1 can enhance therapeutic efficacy of paclitaxel on intraperitoneally disseminated tumors.

BACKGROUND: Expression of immune checkpoints in the tumor microenvironment is one mechanism underlying paclitaxel (PTX) chemoresistance. This study aimed to investigate whether the addition of checkpoint blockade to PTX can improve the therapeutic efficacy against apparently disseminated intraperitoneal tumors. METHODS: We analyzed the in vivo expression of various immune checkpoints in CD3+CD8+ cytotoxic T cells from tumor-bearing mice treated with or without PTX and validated the tumor-killing activities of selected checkpoint-expressing T-cell subpopulations ex vivo. The regulation of selected checkpoints was investigated in vitro. The therapeutic effects of inhibition of a targeted checkpoint pathway with antibodies added to PTX therapy were examined. RESULTS: CD3+CD8+ T cells expressed with herpes virus entry mediator (HVEM), programmed cell death 1 (PD-1), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) in tumor-bearing hosts treated with PTX had effective tumoricidal activities. In addition to PTX and cytokines, B and T lymphocyte attenuator (BTLA) or homologous to lymphotoxin, exhibits inducible expression and competes with herpes simplex virus (HSV) glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT) interacting with HVEM can regulate the expression of PD-1 on CD3+CD8+ T cells. Interleukin (IL)-15 increased the percentage of HVEMhighgranzyme B (GZMB)+ cells among CD3+CD8+ T cells, which was suppressed by the BTLA/HVEM signal. LIGHT induced the percentage of HVEM+GZMB+ cells but not HVEMhighGZMB+ cells among CD3+CD8+ T cells. Expression of IL-15, BTLA, or LIGHT was detected in CD19+ B cells and regulated by damage-associated molecular patterns/Toll-like receptor interactions. In the tumor-bearing hosts treated with PTX, certain proportions of BTLA+ B or PD-1+ T lymphocytes were still noted. When dual inhibition of BTLA and PD-1 was added to PTX, the antitumor effects on intraperitoneally disseminated tumors can be significantly improved. CONCLUSIONS: Dual blockade of BTLA on B cells and PD-1 on cytotoxic T cells may have clinical potential for enhancing the efficacy of PTX in the treatment of tumors with intraperitoneal spread, including epithelial ovarian carcinomas.

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.

Less is More: Fulfillment of Opioid Prescriptions Before and After Implementation of a Modifier 22 Based Quality Incentive for Opioid-Free Vasectomies.

OBJECTIVE: To examine the percentage of patients who filled peri-procedural opioid prescriptions before and after Blue Cross Blue Shield of Michigan (BCBSM) launched a modifier 22 payment incentive for opioid-sparing vasectomies in Michigan on July 1, 2019. METHODS: We evaluated BCBSM administrative claims data from February 1, 2018 - November 16, 2020 for men 20 - 64 years old who underwent vasectomy or a control office-based urologic procedure (cystourethroscopy, prostate biopsy, circumcision, and transurethral destruction of prostate tissue.) The primary outcome was the percentage of patients who filled opioid prescriptions 30 days before to 3 days after their procedure. We performed an interrupted time series analysis to estimate changes in the percentage of patients who filled opioid prescriptions in the vasectomy and control group before and after July 1, 1019. RESULTS: Our cohort included 4,559 men who had a vasectomy and 4,679 men who had a control procedure. Within each group, demographics and clinical factors were similar before and after July 1, 2019. Before implementation of the modifier 22 policy, 32.5% of men who had a vasectomy filled an opioid prescription whereas only 12.6% of men filled an opioid prescription after July 1, 2019 -a 19.9% absolute reduction and 61.0% relative reduction (P < .001). In the control group, there was no significant change in the percentage of patients who filled opioid prescriptions before and after July 1, 2019 (0.8% absolute increase, P = .671). CONCLUSION: Implementation of modifier 22 based financial incentive for opioid-sparing vasectomies was associated with decrease in the percentage of men who filled opioid prescriptions after vasectomy.

Variation in Opioid Prescribing After Vaginal and Cesarean Birth: A Statewide Analysis.

INTRODUCTION: Our aim was to evaluate variation in opioid prescribing rates and prescription size following childbirth across providers and hospitals. METHODS: This retrospective cohort study analyzed claims data from a single-payer Preferred Provider Organization from June 2014 to May 2019 in 84 hospitals in a statewide quality collaborative. All patients aged 12-55 years, undergoing childbirth, with continuous enrollment in pregnancy were included. The primary outcome was the predicted rate of postpartum opioid fills from 7 days before birth to 3 days after discharge. Secondary outcomes included postpartum opioid prescription size in oral morphine equivalents, a standardized measure that includes the number of pills prescribed times the strength of the medication. Multilevel regression models accounted for clustering. We calculated attributable variation in opioid fills using the intraclass correlation coefficient. RESULTS: Of 41,427 births, 15,459 patients (37.2%) filled a postpartum opioid prescription (vaginal, 4,624/27,536 [16.8%]; cesarean, 10,835/13,891 [78.0%]). The median postpartum prescription size was 150 oral morphine equivalents (interquartile range [IQR], 30) (vaginal, 135; [IQR, 45]; cesarean, 150 [IQR, 75]). In adjusted models, the rates of opioid prescribing after vaginal birth differed from cesarean birth (vaginal median, 12.1% [range, 1.1%-60.0%]; cesarean median, 80.4% [range, 43.6%-90.2%]). More variation in postpartum opioid fills was attributable to providers and hospitals for vaginal (provider, 29%; hospital, 24%) than cesarean birth (provider, 8%; hospital, 6%). Variation in prescription size was driven by providers for vaginal birth (provider, 27%; hospital, 6%) and providers and hospitals for cesarean birth (provider, 29%; hospital, 21%). CONCLUSIONS: Across a statewide quality collaborative, variation in postpartum opioid prescribing is attributable to providers and hospitals. Future efforts at the provider and hospital levels are needed to implement best practices for postpartum opioid prescribing.

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.

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.

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.

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.

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.

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.

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.

Gamma Knife Radiosurgery-Based Combination Treatment Strategies Improve Survival in Patients With Central Nervous System Metastases From Epithelial Ovarian Cancer: A Retrospective Analysis of Two Academic Institutions in Korea and Taiwan.

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p<0.001] significantly impacted survival after diagnosis of CNS metastases. In a subgroup analysis, superior survival was observed in patients with CNS involvement not in first tumor recurrence who underwent GKS-based combination therapeutic regimens. The survival benefit of GKS-based treatment was not significant in patients with CNS involvement in first disease relapse, but a trend for longer survival was still observed. In conclusion, GKS-based combination treatment can be considered for the treatment of EOC patients with CNS metastases. The patients with CNS involvement not in first disease relapse could significantly benefit from GKS-based combination strategies.