RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions.

The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host's ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.

Host-specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome.

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.

Association of Hospital System Affiliation with Spending and Postoperative Outcomes: A Longitudinal Study of Hospital Mergers And Acquisitions From 2010 To 2018.

OBJECTIVE: To determine whether hospital system affiliation was associated with changes in surgical episode spending or postoperative outcomes. BACKGROUND: Over 70% of US hospitals are now part of a hospital system. The presumed benefits of hospital consolidation include concentrating volume and expertise, care integration, and investment in quality improvement. However, there is conflicting evidence as to whether expanding hospital systems are actually reducing health spending or improving quality. These observations call into question whether systems are leveraging their collective volume and experience to standardize care and maximize efficiencies. METHODS: The American Hospital Association Annual Survey was used to identify whether a hospital was part of a system and in which year a hospital joined the respective system. Using 100% Medicare claims data, we identified fee-for-service Medicare patients undergoing elective inpatient coronary artery bypass graft colon resection, lung resection, hip replacement, or knee replacement from 2010 to 2018. We used a difference-in-differences framework to evaluate hospital spending and outcomes before and after joining a system. The primary outcome was Medicare 30-day episode spending, with specific attention to the total episode payment, index hospitalization, and post-acute care components. Secondary outcomes included serious complications, 30-day mortality, and 30-day readmission. RESULTS: The cohort included 3,395,565 Medicare beneficiaries who underwent surgery between 2010 and 2018. Patients were treated at 3961 hospitals, of which 1097 (27.7%) were never in a system, 2262 (57.1%) were always in a system, and 602 (15.2%) joined a system during the study period. By 1 year after system affiliation, 30-day episode spending had decreased by $303 (95% CI: 63, 454, P=0.01), and after 5 years, 30-day episode spending decreased by $429 (95% CI: 5, 853, P=0.04). One year after system association, index hospitalization spending was not statistically different from before system affiliation ($-30, 95% CI: -160, 100, P=0.65). Conversely, 1 year after system association, postacute care spending decreased by $268 (95% CI: 107, 429, P<0.01) and remained lower for ≥5 years. There was no significant change in hospitals serious complications (-0.14, 95% CI: -0.40, 0.11, P=0.27), 30-day readmission (-0.14, 95% CI:-0.52, 0.25, P=0.48), or 30-day mortality (-0.08, 95% CI: -0.18, 0.03, P=0.17), 1 year after joining a system; similar patterns were observed at three and ≥5 years. CONCLUSIONS: system affiliation was associated with a small decrease in 30-day episode spending, driven by decreased spending in postacute care services. Notably, there was no difference in postoperative outcomes after system affiliation.

Mortality and Severe Complications Among Newly Graduated Surgeons in the United States.

OBJECTIVE: To evaluate severe complications and mortality over years of independent practice among general surgeons. BACKGROUND: Despite concerns that newly graduated general surgeons may be unprepared for independent practice, it is unclear whether patient outcomes differ between early and later career surgeons. METHODS: We used Medicare claims for patients discharged between July 1, 2007 and December 31, 2019 to evaluate 30-day severe complications and mortality for 26 operations defined as core procedures by the American Board of Surgery. Generalized additive mixed models were used to assess the association between surgeon years in practice and 30-day outcomes while adjusting for differences in patient, hospital, and surgeon characteristics. RESULTS: The cohort included 1,329,358 operations performed by 14,399 surgeons. In generalized mixed models, the relative risk (RR) of mortality was higher among surgeons in their first year of practice compared with surgeons in their 15th year of practice [5.5% (95% CI: 4.1%-7.3%) vs 4.7% (95% CI: 3.5%-6.3%), RR: 1.17 (95% CI: 1.11-1.22)]. Similarly, the RR of severe complications was higher among surgeons in their first year of practice compared with surgeons in their 15th year of practice [7.5% (95% CI: 6.6%-8.5%) versus 6.9% (95% CI: 6.1%-7.9%), RR: 1.08 (95% CI: 1.03-1.14)]. When stratified by individual operation, 21 operations had a significantly higher RR of mortality and all 26 operations had a significantly higher RR of severe complications in the first compared with the 15th year of practice. CONCLUSIONS: Among general surgeons performing common operations, rates of mortality and severe complications were higher among newly graduated surgeons compared with later career surgeons.

Identifying Sources of Inter-Hospital Variation in Episode Spending for Sepsis Care.

OBJECTIVE: To evaluate inter-hospital variation in 90-day total episode spending for sepsis, estimate the relative contributions of each component of spending, and identify drivers of spending across the distribution of episode spending on sepsis care. DATA SOURCES/STUDY SETTING: Medicare fee-for-service claims for beneficiaries (n=324,694) discharged from acute care hospitals for sepsis, defined by MS-DRG, between October 2014 and September 2018. RESEARCH DESIGN: Multiple linear regression with hospital-level fixed effects was used to identify average hospital differences in 90-day episode spending. Separate multiple linear regression and quantile regression models were used to evaluate drivers of spending across the episode spending distribution. RESULTS: The mean total episode spending among hospitals in the most expensive quartile was $30,500 compared with $23,150 for the least expensive hospitals ( P <0.001). Postacute care spending among the most expensive hospitals was almost double that of least expensive hospitals ($7,045 vs. $3,742), accounting for 51% of the total difference in episode spending between the most expensive and least expensive hospitals. Female patients, patients with more comorbidities, urban hospitals, and BPCI-A-participating hospitals were associated with significantly increased episode spending, with the effect increasing at the right tail of the spending distribution. CONCLUSION: Inter-hospital variation in 90-day episode spending on sepsis care is driven primarily by differences in post-acute care spending.

Mortality and cancer incidence in perfluorooctanesulfonyl fluoride production workers.

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with several health outcomes, though few occupationally-exposed populations have been studied. We evaluated mortality and cancer incidence in a cohort of perfluorooctanesulfonyl fluoride-based specialty chemical manufacturing workers. METHODS: The cohort included any employee who ever worked at the facility from 1961 to 2010 (N = 4045), with a primary interest in those who had 365 cumulative days of employment (N = 2659). Vital status and mortality records were obtained through 2014 and the cohort was linked to state cancer registries to obtain incident cancer cases from 1995 to 2014. Cumulative exposure was derived from a comprehensive exposure reconstruction that estimated job-specific perfluorooctanesulfonate (PFOS)-equivalents (mg/m3 ) exposure. Overall and exposure-specific standardized mortality ratios (SMR) were estimated in reference to the US population. Hazard ratios (HRs) and 95% confidence interval (CI) for cumulative PFOS-equivalent exposure (log2 transformed) were estimated within the cohort for specific causes of death and incident cancers using a time-dependent Cox model. RESULTS: Death rates were lower than expected except for cerebrovascular disease (SMR = 2.42, 95% CI = 1.25-4.22) and bladder cancer (SMR = 3.91, 95% CI = 1.07-10.02) in the highest exposure quartile. Within the cohort, the incidence of bladder, colorectal, and pancreatic cancer were positively associated with exposure, however except for lung cancer (HR = 1.05, 95% CI = 1.00-1.11) the CIs did not exclude an HR of 1. CONCLUSIONS: This study provides some evidence that occupational exposure to PFOS is associated with bladder and lung cancers and with cerebrovascular disease.

Bundled Payments for Care Improvement Efficacy Across 3 Common Operations.

OBJECTIVE: The aim of this study was to evaluate associations between hospital participation in Bundled Payments for Care Improvement (BPCI) and 30-day total episode and post-acute care spending for lower extremity joint replacement (LEJR), coronary artery bypass graft (CABG), and colec-tomy. SUMMARY BACKGROUND DATA: BPCI has been shown to reduce spending for LEJR episodes largely from reductions in post-acute care. However, BPCI efficacy in other common elective procedures, including CABG and colec-tomy, remains unclear. It is also unknown whether post-acute care spending reductions drive total spending reductions outside of LEJR. METHODS: Retrospective cohort study using 100% Medicare claims data to identify BPCI (312 total) and non-BPCI (1,977 total) acute care hospitals from January 1, 2010 to November 30, 2016 with Medicare-enrolled patient discharges for at least one of the following BPCI episodes: LEJR (454,369 episodes), CABG (107,307 episodes), or colectomy (73,717 episodes). Along with difference-in-differences (DiD) analysis, we constructed generalized synthetic controls in the presence of nonparallel trends to estimate associations between BPCI participation and 30-day total and post-acute care spending. RESULTS: DiD estimates indicated reduced spending for LEJR (-$541.6 [95% confidence interval (CI): -718.0 to -365.3]) and colectomy (-$582.1 [95% CI: -927.3 to -236.8]) but not CABG (-$268.9 [95% CI: -831.5 to 293.7]). Generalized synthetic control estimates indicated reduced spending for LEJR (-$795.3 [95% CI: -10,22.1 to -582.2]) but not colectomy (-$251.3 [95% CI: -997.9 to 335.2]) or CABG (-$257.8 [95% CI: -10,24.6 to 414.8]).Post-acute care comprised 42.6% of LEJR spending reductions and 53.0% of colectomy spending reductions. CONCLUSIONS: BPCI participation was associated with significant spending reductions for LEJR and colectomy but not CABG. We conclude that BPCI has episode-dependent efficacy, largely determined by post-acute care.

Out-of-pocket Costs for Commercially-insured Patients in the Years Following Bariatric Surgery: Sleeve Gastrectomy Versus Roux-en-Y Gastric Bypass.

OBJECTIVE: To compare out-of-pocket (OOP) costs for patients up to 3 years after bariatric surgery in a large, commercially-insured population. SUMMARY OF BACKGROUND DATA: More information on OOP costs following bariatric surgery may affect patients' procedure choice. METHODS: Retrospective study using the IBM MarketScan commercial claims database, representing patients nationally who underwent laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) January 1, 2011 to December 31, 2017. We compared total OOP costs after the surgical episode between the 2 procedures using difference-in-differences analysis adjusting for demographics, comorbidities, operative year, and insurance type. RESULTS: Of 63,674 patients, 64% underwent SG and 36% underwent RYGB. Adjusted OOP costs after SG were $1083, $1236, and $1266 postoperative years 1, 2, and 3. For RYGB, adjusted OOP costs were $1228, $1377, and $1369. In our primary analysis, SG OOP costs were $122 (95% confidence interval [CI]: -$155 to -$90) less than RYGB year 1. This difference remained consistent at -$119 (95%CI: -$158 to -$79) year 2 and -$80 (95%CI: -$127 to -$35) year 3. These amounts were equivalent to relative differences of -7%, -7%, and -5% years 1, 2, and 3. Plan features contributing the most to differences were co-insurance years 1, 2, and 3.The largest clinical contributors to differences were endoscopy and outpatient care year 1, outpatient care year 2, and emergency department use year 3. CONCLUSIONS: Our study is the first to examine the association between bariatric surgery procedure and OOP costs. Differences between procedures were approximately $100 per year which may be an important factor for some patients deciding whether to pursue SG or gastric bypass.

Evidence-Based Opioid Prescribing Guidelines and New Persistent Opioid Use After Surgery.

OBJECTIVE: Evaluate the association of evidence-based opioid prescribing guidelines with new persistent opioid use after surgery. SUMMARY BACKGROUND DATA: Patients exposed to opioids after surgery are at risk of new persistent opioid use, which is associated with opioid use disorder and overdose. It is unknown whether evidence-based opioid prescribing guidelines mitigate this risk. METHODS: Using Medicare claims, we performed a difference-in-differences study of opioid-naive patients who underwent 1 of 6 common surgical procedures for which evidence-based postoperative opioid prescribing guidelines were released and disseminated through a statewide quality collaborative in Michigan in October 2017. The primary outcome was the incidence of new persistent opioid use, and the secondary outcome was total postoperative opioid prescription quantity in oral morphine equivalents (OME). RESULTS: We identified 24,908 patients who underwent surgery in Michigan and 118,665 patients who underwent surgery outside of Michigan. Following the release of prescribing guidelines in Michigan, the adjusted incidence of new persistent opioid use decreased from 3.29% (95% CI 3.15-3.43%) to 2.51% (95% CI 2.35-2.67%) in Michigan, which was an additional 0.53 (95% CI 0.36-0.69) percentage point decrease compared with patients outside of Michigan. Simultaneously, adjusted opioid prescription quantity decreased from 199.5 (95% CI 198.3-200.6) mg OME to 88.6 (95% CI 78.7-98.5) mg OME in Michigan, which was an additional 55.7 (95% CI 46.5-65.4) mg OME decrease compared with patients outside of Michigan. CONCLUSIONS: Evidence-based opioid prescribing guidelines were associated with a significant reduction in the incidence of new persistent opioid use and the quantity of opioids prescribed after surgery.

Comparative Safety of Sleeve Gastrectomy and Gastric Bypass up to 5 Years After Surgery in Patients With Medicaid.

OBJECTIVE: Compare adverse outcomes up to 5 years after sleeve gastrectomy and gastric bypass in patients with Medicaid. BACKGROUND: Sleeve gastrectomy is the most common bariatric operation among patients with Medicaid; however, its long-term safety in this population is unknown. METHODS: Using Medicaid claims, we performed a retrospective cohort study of adult patients who underwent sleeve gastrectomy or gastric bypass from January 1, 2012, to December 31, 2018. Instrumental variables survival analysis was used to estimate the cumulative incidence and heterogeneity of outcomes up to 5 years after surgery. RESULTS: Among 132,788 patients with Medicaid, 84,717 (63.8%) underwent sleeve gastrectomy and 48,071 (36.2%) underwent gastric bypass. A total of 69,225 (52.1%) patients were White, 33,833 (25.5%) were Black, and 29,730 (22.4%) were Hispanic. Compared with gastric bypass, sleeve gastrectomy was associated with a lower 5-year cumulative incidence of mortality (1.29% vs 2.15%), complications (11.5% vs 16.2%), hospitalization (43.7% vs 53.7%), emergency department (ED) use (61.6% vs 68.2%), and reoperation (18.5% vs 22.8%), but a higher cumulative incidence of revision (3.3% vs 2.0%). Compared with White patients, the magnitude of the difference between sleeve and bypass was smaller among Black patients for ED use [5-y adjusted hazard ratios: 1.01; 95% confidence interval (CI), 0.94-1.08 vs 0.94 (95% CI, 0.88-1.00), P <0.001] and Hispanic patients for reoperation [5-y adjusted hazard ratios: 0.95 (95% CI, 0.86-1.05) vs 0.76 (95% CI, 0.69-0.83), P <0.001]. CONCLUSIONS: Among patients with Medicaid undergoing bariatric surgery, sleeve gastrectomy was associated with a lower risk of mortality, complications, hospitalization, ED use, and reoperations, but a higher risk of revision compared with gastric bypass. Although the difference between sleeve and bypass was generally similar among White, Black, and Hispanic patients, the magnitude of this difference was smaller among Black patients for ED use and Hispanic patients for reoperation.

Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection.

Viral infection both activates stress signaling pathways and redistributes ribosomes away from host mRNAs to translate viral mRNAs. The intricacies of this ribosome shuffle from host to viral mRNAs are poorly understood. Here, we uncover a role for the ribosome-associated quality control (RQC) factor ZNF598 during vaccinia virus mRNA translation. ZNF598 acts on collided ribosomes to ubiquitylate 40S subunit proteins uS10 (RPS20) and eS10 (RPS10), initiating RQC-dependent nascent chain degradation and ribosome recycling. We show that vaccinia infection enhances uS10 ubiquitylation, indicating an increased burden on RQC pathways during viral propagation. Consistent with an increased RQC demand, we demonstrate that vaccinia virus replication is impaired in cells that either lack ZNF598 or express a ubiquitylation-deficient version of uS10. Using SILAC-based proteomics and concurrent RNA-seq analysis, we determine that translation, but not transcription of vaccinia virus mRNAs is compromised in cells with deficient RQC activity. Additionally, vaccinia virus infection reduces cellular RQC activity, suggesting that co-option of ZNF598 by vaccinia virus plays a critical role in translational reprogramming that is needed for optimal viral propagation.

Pharmacological Treatment of Disinhibition in Acquired Brain Injury.

PURPOSE/BACKGROUND: Traumatic brain injury is a major universal public health concern and results in chronic neurobehavioral sequelae including disinhibition. Objectives of this study were to review the literature on pharmacological treatment of disinhibition post-acquired brain injury (ABI), describe a snapshot of pharmacotherapy used in ABI at a tertiary neuropsychiatric unit in British Columbia, Canada, and share expert opinion. METHODS/PROCEDURES: A retrospective chart review of 11 patients from October to December 2021 was conducted based on exclusion criteria: age greater than 18 years, primary neurodegenerative conditions, or aphasia. Patient demographics, behavioral and cognitive test results, and disinhibition treatment were recorded. A brief review of the literature was conducted to find the best available evidence of pharmacological interventions to treat disinhibition post-ABI. FINDINGS/RESULTS: In ABI, there was a high utilization of antipsychotics and benzodiazepines, at 91% and 64% respectively, in patients with severe cognitive deficit and disinhibition. Mood stabilizers and nonselective ß-blockers were less prescribed in this population at 73% and 18%. At the point of data collection, all the patients had responded well to treatment and were in the maintenance phase of their pharmacological treatment. IMPLICATIONS/CONCLUSIONS: A limited number of studies with weak methodology suggest that mood stabilizers and ß-blockers should be first line for disinhibition treatment. Our findings are complementary to the literature describing treatment of severe disinhibition. The choice of treatment for disinhibition depends on factors including nature and severity of target symptoms, level of drug evidence, patient-tailored objectives, concurrent psychiatric diagnoses, clinical experience of clinicians, adverse drug reactions, and treatment acuity.

Can 68 Ga-PSMA positron emission tomography and multiparametric MRI guide treatment for biochemical recurrence after radical prostatectomy?

OBJECTIVE: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) and Gallium-68 (68 Ga)-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in guiding salvage therapy for patients with biochemical recurrence (BCR) post-radical prostatectomy. PATIENTS AND METHODS: Patients were evaluated with paired mpMRI and 68 Ga-PSMA PET/CT scans for BCR (prostate-specific antigen [PSA] >0.2 ng/mL). Patient, tumour, PSA and imaging characteristics were analysed with descriptive statistics. RESULTS: A total of 117 patients underwent paired scans to investigate BCR, of whom 53.0% (62/117) had detectable lesions on initial scans and 47.0% (55/117) did not. Of those without detectable lesions, 8/55 patients proceeded to immediate salvage radiotherapy (sRT) and 47/55 were observed. Of patients with negative imaging who were initially observed, 46.8% (22/47) did not reach threshold for repeat imaging, while 53.2% were rescanned due to rising PSA levels. Of these rescanned patients, 31.9% (15/47) were spared sRT due to proven distant disease, or due to absence of disease on repeat imaging. Of the original 117 patients, 53 (45.3%) were spared early sRT due to absence of disease on imaging or presence of distant disease, while those undergoing delayed sRT still maintained good PSA responses. Of note, patients with high-risk features who underwent sRT despite negative imaging demonstrated satisfactory PSA responses to sRT. Study limitations include the observational design and absence of cause-specific or overall survival data. CONCLUSION: Our findings support the use of mpMRI and 68 Ga-PSMA PET/CT in guiding timing and necessity of salvage therapy tailored to detected lesions, with potential to reduce unnecessary sRT-related morbidity. Larger or randomized trials are warranted to validate this.

Legislative and Regulatory Options for Improving Medicare Advantage.

The Medicare Advantage program was created to expand beneficiary choice and to reduce spending through capitated payment to private insurers. However, many stakeholders now argue that Medicare Advantage is failing to deliver on its promise to reduce spending. Three problematic design features in Medicare Advantage payment policy have received particular scrutiny: (1) how baseline payments to insurers are determined, (2) how variation in patient risk affects insurer payment, and (3) how payments to insurers are adjusted for quality performance. The authors analyze the statute underlying these three design features and explore legislative and regulatory strategies for improving Medicare Advantage. They conclude that regulatory approaches for improving risk adjustment and for recouping overpayments from risk-score gaming have the highest potential impact and are the most feasible improvement measures to implement.

Assault Deterrents and Educators' Risk of Physical Assault: A Case-Control Study.

The study purpose was to identify associations between assault deterrent presence in kindergarten through 12th (K-12) grade schools and physical assaults (PAs) against educators. Data collected through a two-phase study identified physical and nonphysical violent events and utilized a nested case-control study to identify PA risk/protective factors. Analyses included multivariable modeling. Adjusted analyses demonstrated a significant decreased risk of PA with routine locker searches (odds ratio [OR] = 0.49, 95% confidence interval [CI] [0.29, 0.82]). Also important, although not statistically significant, were presence of video monitors (OR = 0.72, 95% CI [0.50, 1.03]), intercoms (OR = 0.77, 95% CI [0.55, 1.06]), and required school uniforms/dress codes (OR = 0.74, 95% CI [0.52, 1.07]). These findings are integral to school nursing practice in which there is opportunity to influence application of relevant pilot intervention efforts as a first step in determining the potential efficacy of broad-based interventions that can positively impact the problem of school-related violence.

Bariatric Surgery in Medicare Patients: Examining Safety and Healthcare Utilization in the Disabled and Elderly.

OBJECTIVE: To compare safety and healthcare utilization after sleeve gastrectomy versus Roux-en-Y gastric bypass in a national Medicare cohort. SUMMARY BACKGROUND DATA: Though bariatric surgery is increasing among Medicare beneficiaries, no long-term, national studies examining comparative effectiveness between procedures exist. Bariatric outcomes are needed for shared decision-making and coverage policy concerns identified by the cMS Medicare Evidence Development and Coverage Advisory Committee. METHODS: Retrospective instrumental variable analysis of Medicare claims (2012-2017) for 30,105 bariatric surgery patients entitled due to disability or age. We examined clinical safety outcomes (mortality, complications, and reinterventions), healthcare utilization [Emergency Department (ED) visits, rehospitalizations, and expenditures], and heterogeneity of treatment effect. We compared all outcomes between sleeve and bypass for each entitlement group at 30 days, 1 year, and 3 years. RESULTS: Among the disabled (n = 21,595), sleeve was associated with lower 3-year mortality [2.1% vs 3.2%, absolute risk reduction (ARR) 95% confidence interval (CI): -2.2% to -0.03%], complications (22.2% vs 27.7%, ARR 95%CI: -8.5% to -2.6%), reinterventions (20.1% vs 27.7%, ARR 95%CI: -10.7% to -4.6%), ED utilization (71.6% vs 77.1%, ARR 95%CI: -8.5% to -2.4%), and rehospitalizations (47.4% vs 52.3%, ARR 95%Ci: -8.0% to -1.7%). Cumulative expenditures were $46,277 after sleeve and $48,211 after bypass (P = 0.22). Among the elderly (n = 8510), sleeve was associated with lower 3-year complications (20.1% vs 24.7%, ARR 95%CI: -7.6% to -1.7%), reinterventions (14.0% vs 21.9%, ARR 95%CI: -10.7% to -5.2%), ED utilization (51.7% vs 57.2%, ARR 95%CI: -9.1% to -1.9%), and rehospitalizations (41.8% vs 45.8%, ARR 95%Ci: -7.5% to -0.5%). Expenditures were $38,632 after sleeve and $39,270 after bypass (P = 0.60). Procedure treatment effect significantly differed by entitlement for mortality, revision, and paraesophageal hernia repair. CONCLUSIONS: Bariatric surgery is safe, and healthcare utilization benefits of sleeve over bypass are preserved across both Medicare elderly and disabled subpopulations.

Comparative Safety of Sleeve Gastrectomy and Gastric Bypass: An Instrumental Variables Approach.

OBJECTIVE: To compare the safety of sleeve gastrectomy and gastric bypass in a large cohort of commercially insured bariatric surgery patients from the IBM MarketScan claims database, while accounting for measurable and unmeasurable sources of selection bias in who is chosen for each operation. SUMMARY OF BACKGROUND DATA: Sleeve gastrectomy has rapidly become the most common bariatric operation performed in the United States, but its longer-term safety is poorly described, and the risk of worsening gastroesophageal reflux requiring revision may be higher than previously thought. Prior studies comparing sleeve gastrectomy to gastric bypass are limited by low sample size (in randomized trials) and selection bias (in observational studies). METHODS: Instrumental variables analysis of commercially insured patients in the IBM MarketScan claims database from 2011 to 2018. We studied patients undergoing bariatric surgery from 2012 to 2016. We identified re-interventions and complications at 30 days and 2 years from surgery using Comprehensive Procedural Terminology and International Classification of Disease (ICD)-9/10 codes. To overcome unmeasured confounding, we use the prior year's sleeve gastrectomy utilization within each state as an instrumental variable-exploiting variation in the timing of payers' decisions to cover sleeve gastrectomy as a natural experiment. RESULTS: Among 38,153 patients who underwent bariatric surgery between 2012 and 2016, the share of sleeve gastrectomy rose from 52.6% (2012) to 75% (2016). At 2 years from surgery, patients undergoing sleeve gastrectomy had fewer re-interventions (sleeve 9.9%, bypass 15.6%, P < 0.001) and complications (sleeve 6.6%, bypass 9.6%, P = 0.001), and lower overall healthcare spending ($47,891 vs $55,213, P = 0.003), than patients undergoing gastric bypass. However, at the 2-year mark, revisions were slightly more common in sleeve gastrectomy than in gastric bypass (sleeve 0.6%, bypass 0.4%, P = 0.009). CONCLUSIONS AND RELEVANCE: In a large cohort of commercially insured patients, sleeve gastrectomy had a superior safety profile to gastric bypass up to 2 years from surgery, even when accounting for selection bias. However, the higher risk of revisions in sleeve gastrectomy merits further exploration.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography Maximum Standardized Uptake Value as a Predictor of Gleason Pattern 4 and Pathological Upgrading in Intermediate-Risk Prostate Cancer.

PURPOSE: Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA PET/CT) and the maximum standardized uptake value (SUVmax) may improve risk stratification within this population. MATERIALS AND METHODS: We reviewed men with International Society for Urological Pathology Grade Group (GG) 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per segment at surgery at 3 thresholds: >/<50% GP4, >/<20% GP4, and >/<10% GP4. SUVmax was compared by GP4, and multivariable logistic regression examined the relationship between SUVmax and GP4. Secondary outcome was association between SUVmax and pathological upgrading (GG 1/2 to GG ≥3 from biopsy to surgery). RESULTS: Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/<50% GP4 (p <0.001); 4.77 (3.31-7.00) vs 3.13 (2.64-4.41) >/<20% GP4 (p <0.001); and 4.54 (6.10-3.13) vs 3.03 (2.45-3.70) >/<10% GP4 (p <0.001). SUVmax remained an independent predictor of >50% (OR=1.39 [95%CI 1.18-1.65], p <0.001) and >20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathological upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value 75% and negative predictive value 72%. Threshold 5.4 predicted pathological upgrading with 91% specificity and negative predictive value 94%. CONCLUSIONS: SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.

The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.