Elective Laparoscopic Paraesophageal Hernia Repair Leads to an Increase in Life Expectancy Over Watchful Waiting in Asymptomatic Patients: An Updated Markov Analysis.

OBJECTIVE: The aim of this study was to perform an updated Markov analysis to determine the optimal management strategy for patients with an asymptomatic paraesophageal hernia (PEH): elective laparoscopic hernia repair (ELHR) versus watchful waiting (WW). BACKGROUND: Currently, it is recommended that patients with an asymptomatic PEH not undergo repair based on a 20-year-old Markov analysis. The current recommendation might lead to preventable hospitalizations for acute PEH-related complications and compromised survival. METHODS: A Markov model with updated variables was used to compare life-years (L-Ys) gained with ELHR versus WW in patients with a PEH. One-way sensitivity analyses evaluated the robustness of the analysis to alternative data inputs, while probabilistic sensitivity analysis quantified the level of confidence in the results in relation to the uncertainty across all model inputs. RESULTS: At age 40 to 90, ELHR led to greater life expectancy than WW, particularly in women. The gain in L-Ys (2.6) was greatest in a 40-year-old woman and diminished with increasing age. Sensitivity analysis showed that alternative values resulted in modest changes in the difference in L-Ys, but ELHR remained the preferred strategy. Probabilistic analysis showed that ELHR was the preferred strategy in 100% of 10,000 simulations for age 65, 98% for age 80, 90% for age 85, and 59% of simulations in 90-year-old women. CONCLUSIONS: This updated analysis showed that ELHR leads to an increase in L-Ys over WW in healthy patients aged 40 to 90 years with an asymptomatic PEH. In this new paradigm, all patients with a PEH, regardless of symptoms, should be referred for the consideration of elective repair to maximize their life expectancy.

Intracranial complications of sinogenic and otogenic infections in children: an ESPN survey on their occurrence in the pre-COVID and post-COVID era.

BACKGROUND: COVID-19 pandemic is thought to have changed the epidemiology of some pediatric neurosurgical disease: among them are the intracranial complications of sinusitis and otitis (ICSO). According to some studies on a limited number of cases, both streptococci-related sinusitis and ICSO would have increased immediately after the pandemic, although the reason is not clear yet (seasonal changes versus pandemic-related effects). The goal of the present survey of the European Society for Pediatric Neurosurgery (ESPN) was to collect a large number of cases from different European countries encompassing the pre-COVID (2017-2019), COVID (2020-2021), and post-COVID period (2022-June 2023) looking for possible epidemiological and/or clinical changes. MATERIAL AND METHODS: An English language questionnaire was sent to ESPN members about year of the event, patient's age and gender, presence of immune-deficit or other favoring risk factors, COVID infection, signs and symptoms at onset, site of primary infection, type of intracranial complication, identified germ, type and number of surgical operations, type and duration of medical treatment, clinical and radiological outcome, duration of the follow-up. RESULTS: Two hundred fifty-four cases were collected by 30 centers coming from 14 different European countries. There was a statistically significant difference between the post-COVID period (129 children, 86 cases/year, 50.7% of the whole series) and the COVID (40 children, 20 cases/year, 15.7%) or the pre-COVID period (85 children, 28.3 cases/year, 33.5%). Other significant differences concerned the presence of predisposing factors/concurrent diseases (higher in the pre-COVID period) and previous COVID infection (higher in the post-COVID period). No relevant differences occurred as far as demographic, microbiological, clinical, radiological, outcome, morbidity, and mortality data were concerned. Paranasal sinuses and middle ear/mastoid were the most involved primary site of infection (71% and 27%, respectively), while extradural or subdural empyema and brain abscess were the most common ICSO (73% and 17%, respectively). Surgery was required in 95% of cases (neurosurgical and ENT procedure in 71% and 62% of cases, respectively) while antibiotics in 99% of cases. After a 12.4-month follow-up, a full clinical and radiological recovery was obtained in 85% and 84% of cases, respectively. The mortality rate was 2.7%. CONCLUSIONS: These results suggest that the occurrence of ICSO was significantly increased after the pandemic. Such an increase seems to be related to the indirect effects of the pandemic (e.g., immunity debt) rather than to a direct effect of COVID infection or to seasonal fluctuations. ICSO remain challenging diseases but the pandemic did not affect the management strategies nor their prognosis. The epidemiological change of sinusitis/otitis and ICSO should alert about the appropriate follow-up of children with sinusitis/otitis.

Intensive cholesterol-lowering treatment reduces synovial inflammation during early collagenase-induced osteoarthritis, but not pathology at end-stage disease in female dyslipidemic E3L.CETP mice.

INTRODUCTION: The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. MATERIALS AND METHODS: Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. RESULTS: Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P = 0.008, WTD: 95% CI: 1.4- 2.3; WTD + AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD + AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P = 0.0005, 95% CI: -46.0 to -12.0; P = 2.8 × 10-10, 95% CI: -398.3 to -152.1; P = 2.1 × 10-9, -66.8 to -30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease. CONCLUSION: This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.

Surgeon experience with insurance barriers to offering gastric bypass as an evidence-based operation for pathologic GERD.

INTRODUCTION: Obesity is an increasingly prevalent public health problem often associated with poorly controlled gastroesophageal reflux disease. Fundoplication has been shown to have limited long-term efficacy in patients with morbid obesity and does not address additional weight-related co-morbidities. Roux-en-Y gastric bypass (RYGB) is the gold standard operation for durable resolution of GERD in patients with obesity, and is also used as a salvage operation for GERD after prior foregut surgery. Surgeons report access to RYGB as surgical treatment for GERD is often limited by RYGB-specific benefit exclusions embedded within insurance policies, but the magnitude and scope of this problem is unknown. METHODS: A 9-item survey evaluating surgeon practice and experience with insurance coverage for RYGB for GERD was developed and piloted by a SAGES Foregut Taskforce working group. This survey was then administered to surgeon members of the SAGES Foregut Taskforce and to surgeons participating in the SAGES Bariatrics and/or Foregut Facebook groups. RESULTS: 187 surgeons completed the survey. 89% reported using the RYGB as an anti-reflux procedure. 44% and 26% used a BMI of 35 kg/m2 and 30 kg/m2 respectively as cutoff for the RYGB. 89% viewed RYGB as the procedure of choice for GERD after bariatric surgery. 69% reported using RYGB to address recurrent reflux secondary to failed fundoplication. 74% of responders experienced trouble with insurance coverage at least half the time RYGB was offered for GERD, and 8% reported they were never able to get approval for RYGB for GERD indications in their patient populations. CONCLUSION: For many patients, GERD and obesity are related diseases that are best addressed with RYGB. However, insurance coverage for RYGB for GERD is often limited by policies which run contrary to evidence-based medicine. Advocacy is critical to improve access to appropriate surgical care for GERD in patients with obesity.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

The alarmins high mobility group box protein 1 and S100A8/A9 display different inflammatory profiles after acute knee injury.

OBJECTIVE: To compare the concentrations of high mobility group box 1 protein (HMGB1) and S100A8/A9 in synovial fluid between patients with knee injuries and osteoarthritis (OA), and knee healthy subjects. To investigate associations of alarmin levels with different joint injuries and with biomarkers of inflammation, Wnt signaling, complement system, bone and cartilage degradation. METHODS: HMGB1 and S100A8/A9 were measured in synovial fluid by immunoassays in patients with knee injuries, with OA and from knee healthy subjects, and were related to time from injury and with biomarkers obtained from previous studies. Hierarchical cluster and enrichment analyses of biomarkers associated to HMGB1 and S100A8/A9 were performed. RESULTS: The synovial fluid HMGB1 and S100A8/A9 concentrations were increased early after knee injury; S100A8/A9 levels were negatively associated to time after injury and was lower in the old compared to recent injury group, while HMGB1 was not associated to time after injury. The S100A8/A9 levels were also increased in OA. The initial inflammatory response was similar between the alarmins, and HMGB1 and S100A8/A9 shared 9 out of 20 enriched pathways. The alarmins displayed distinct response profiles, HMGB1 being associated to cartilage biomarkers while S100A8/A9 was associated to proinflammatory cytokines. CONCLUSIONS: HMGB1 and S100A8/A9 are increased as an immediate response to knee trauma. While they share many features in inflammatory and immunoregulatory mechanisms, S100A8/A9 and HMGB1 are associated to different downstream responses, which may have impact on the OA progression after acute knee injuries.

A single dose of anti-IL-1ß antibodies prevents Western diet-induced immune activation during early stage collagenase-induced osteoarthritis, but does not ameliorate end-stage pathology.

OBJECTIVE: Metabolic dysfunction can cause IL-1ß mediated activation of the innate immune system, which could have important implications for the therapeutic efficacy of IL-1ß neutralizing drugs as treatment for OA in the context of metabolic syndrome (MetS). In the present study, we investigated whether early treatment with a single dose of IL-1ß blocking antibodies could prevent Western diet (WD) induced changes to systemic monocyte populations and their cytokine secretion profile and herewith modulate collagenase induced osteoarthritis (CiOA) pathology. METHODS: CiOA was induced in female C57Bl/6 mice fed either a standard diet (SD) or WD and treated with a single dose of either polyclonal anti-IL-1ß antibodies or control. Monocyte subsets and granulocytes in bone marrow and blood were analyzed with flow cytometry, and cytokine expression by bone marrow cells was analyzed using qPCR. Synovial cellularity, cartilage damage and osteophyte formation were assessed on histology. RESULTS: WD feeding of C57Bl/6 mice led to increased serum levels of low-density lipoprotein (LDL) and innate immune activation in the form of an increased number of Ly6Chigh cells in bone marrow and blood and increased cytokine expression of IL-6 and TNF-α by bone marrow cells. The increase in monocyte number and activity was ameliorated by anti-IL-1ß treatment. However, anti-IL-1ß treatment did not significantly affect synovial lining thickness, cartilage damage and ectopic bone formation during WD feeding. CONCLUSIONS: Single-dose systemic anti-IL-1ß treatment prevented WD-induced innate immune activation during early stage CiOA in C57Bl/6 mice, but did not ameliorate joint pathology.

Analysis of trimodal and bimodal therapy in a selective-surgery paradigm for locally advanced oesophageal squamous cell carcinoma.

BACKGROUND: Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. METHODS: Patients with stage II-III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. RESULTS: Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001). CONCLUSION: In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

TROPHY registry - status report.

INTRODUCTION: The TROPHY registry has been established to conduct an international multicenter prospective data collection on the surgical management of neonatal intraventricular hemorrhage (IVH)-related hydrocephalus to possibly contribute to future guidelines. The registry allows comparing the techniques established to treat hydrocephalus, such as external ventricular drainage (EVD), ventricular access device (VAD), ventricular subgaleal shunt (VSGS), and neuroendoscopic lavage (NEL). This first status report of the registry presents the results of the standard of care survey of participating centers assessed upon online registration. METHODS: On the standard of treatment forms, each center indicated the institutional protocol of interventions performed for neonatal post-hemorrhagic hydrocephalus (nPHH) for a time period of 2 years (Y1 and Y2) before starting the active participation in the registry. In addition, the amount of patients enrolled so far and allocated to a treatment approach are reported. RESULTS: According to the standard of treatment forms completed by 56 registered centers, fewer EVDs (Y1 55% Y2 46%) were used while more centers have implemented NEL (Y1 39%; Y2 52%) to treat nPHH. VAD (Y1 66%; Y2 66%) and VSGS (Y1 42%; Y2 41%) were used at a consistent rate during the 2 years. The majority of the centers used at least two different techniques to treat nPHH (43%), while 27% used only one technique, 21% used three, and 7% used even four different techniques. Patient data of 110 infants treated surgically between 9/2018 and 2/2021 (13% EVD, 15% VAD, 30% VSGS, and 43% NEL) were contributed by 29 centers. CONCLUSIONS: Our results emphasize the varying strategies used for the treatment of nPHH. The international TROPHY registry has entered into a phase of growing patient recruitment. Further evaluation will be performed and published according to the registry protocol.

Structured Digital Self-Assessment of Patient Anamnesis Prior to Computed Tomography: Performance Evaluation and Added Value.

The aim of this study was to evaluate the performance of a tablet-based, digitized structured self-assessment (DSSA) of patient anamnesis (PA) prior to computed tomography (CT). Of the 317 patients consecutively referred for CT, the majority (n = 294) was able to complete the tablet-based questionnaire, which consisted of 67 items covering social anamnesis, lifestyle factors (e.g., tobacco abuse), medical history (e.g., kidney diseases), current symptoms, and the usability of the system. Patients were able to mark unclear questions for a subsequent discussion with the radiologist. Critical issues for the CT examination were structured and automatically highlighted as "red flags" (RFs) in order to improve patient interaction. RFs and marked questions were highly prevalent (69.5% and 26%). Missing creatinine values (33.3%), kidney diseases (14.4%), thyroid diseases (10.6%), metformin (5.5%), claustrophobia (4.1%), allergic reactions to contrast agents (2.4%), and pathological TSH values (2.0%) were highlighted most frequently as RFs. Patient feedback regarding the comprehensibility of the questionnaire and the tablet usability was mainly positive (90.9%; 86.2%). With advanced age, however, patients provided more negative feedback for both (p = 0.007; p = 0.039). The time effort was less than 20 min for 85.1% of patients, and faster patients were significantly younger (p = 0.046). Overall, the DSSA of PA prior to CT shows a high success rate and is well accepted by most patients. RFs and marked questions were common and helped to focus patients' interactions and reporting towards decisive aspects.

Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. PATIENTS AND METHODS: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. RESULTS: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. CONCLUSIONS: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.

More recent, better designed studies have weakened links between antidiabetes medications and cancer risk.

BACKGROUND: An increasing number of studies have investigated associations of antidiabetes medications with cancer risk. Antidiabetes medications are classified by their mechanisms of action on tissues and organs. They potentially act as both causative and confounding factors in the temporal association of diabetes and cancer. AIM: To present the current evidence regarding both the carcinogenic and anti-carcinogenic effects of antidiabetes medications on cancer in humans. METHODS: A review of the scientific literature. RESULTS: The most conclusive evidence shown of an association of antidiabetes medication with a specific cancer was for that of the thiazolidinedione pioglitazone with bladder cancer. Currently, there is inconclusive evidence regarding a possible association of incretin therapies, drugs of the dipeptidyl peptidase-4 inhibitor class, with the risk of pancreatic cancer. Insulin, sulfonylureas, metformin and sodium-glucose co-transporter-2 inhibitors appear not to be associated with increased risk of any cancer. Sparse evidence suggests possible protective effects against cancer incidence of metformin, sulfonylureas, thiazolidinediones, incretin-based drugs and sodium-glucose co-transporter-2 inhibitors. CONCLUSION: The conflicting evidence regarding associations of antidiabetes medications with cancer risk is apparently attributable to both methodological issues and to the complexity of the subject. More recent and better-designed studies have weakened the evidence for links between antidiabetes medications and cancer risk.

Enhanced value with implementation of an ERAS protocol for ventral hernia repair.

BACKGROUND: Open ventral hernia repair (VHR) is associated with postoperative complications and hospital readmissions. A comprehensive Enhanced Recovery after Surgery (ERAS) protocol for VHR contributes to improved clinical outcomes including the rapid return of bowel function and reduced infections. The purpose of this study was to compare hospital costs for patients cared for prior to ERAS implementation with patients cared for with an ERAS protocol. METHODS: With IRB approval, clinical characteristics and postoperative outcomes data were obtained via retrospective review of consecutive VHR patients 2 years prior to and 14 months post ERAS implementation. Hospital cost data were obtained from the cost accounting system inclusive of index hospitalization. Clinical data and hospital costs were compared between groups. RESULTS: Data for 178 patients (127 pre-ERAS, 51 post-ERAS) were analyzed. Preoperative and operative characteristics including gender, ASA class, comorbidities, and BMI were similar between groups. ERAS patients had faster return of bowel function (p = 0.001) and decreased incidence of superficial surgical site infection (p = 0.003). Hospital length of stay did not vary significantly pre and post ERAS implementation. Inpatient pharmacy costs were increased in ERAS group ($2673 vs. $1176 p < 0.001), but total hospital costs (14,692 vs. 15,151, p = 0.538) were similar between groups. CONCLUSIONS: Standardization of hernia care via ERAS protocol improves clinical outcomes without impacting total costs.

Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

Professional fee payments by specialty for inpatient open ventral hernia repair: who gets paid for treating comorbidities and complications?

BACKGROUND: The purpose of this study was to determine perioperative professional fee payments to providers from different specialties for the care of patients undergoing inpatient open ventral hernia repair (VHR). METHODS: Perioperative data of patients undergoing VHR at a single center over 3 years were selected from our NSQIP database. 180-day follow-up data were obtained via retrospective review of records and phone calls to patients. Professional fee payments (PFPs) to all providers were obtained from our physician billing system for the VHR hospitalization, the 180 days prior to operation (180Prior) and the 180 days post-discharge (180Post). RESULTS: PFPs for 283 cases were analyzed. Average total 360-day PFPs per patient were $3409 ± SD 3294, with 14.5% ($493 ± 1546) for services in the 180Preop period, 72.5% ($2473 ± 1881) for the VHR hospitalization, and 13.0% ($443 ± 1097) in the 180Postop period. The surgical service received 62% of PFPs followed by anesthesia (18%), medical specialties (9%), radiology (6%), and all other provider services (5%). Medical specialties received increased PFPs for care of patients with COPD and HCT < 38% ($90 and $521, respectively) and for the pulmonary complications ($2471) and sepsis ($2714) that correlated with those patient comorbidities; surgeons did not. Operative duration, mesh size, and separation of components were associated with increased surgeon PFPs (p < .05). At 6 months, wound complications were associated with increased surgeon and radiology payments (p < .01). CONCLUSIONS: Management of acute comorbid conditions and the associated higher postoperative morbidity is not reimbursed to the surgeon under the 90-day global fee. These represent opportunity costs of care that pressure busy surgeons to select against these patients or to delegate more management to their medical specialty colleagues, thereby increasing total system costs. A comorbid risk adjustment of procedural reimbursement is warranted. In negotiating bundled payments, surgeon groups should keep in mind that surgeon reimbursement, unlike medical specialty and hospital reimbursement, have been bundled since the 1990s.

A comparison of short-term outcomes between laparoscopic and open emergent repair of perforated peptic ulcers.

BACKGROUND: We compared 30-day outcomes in patients undergoing emergent open and laparoscopic repair of perforated peptic ulcers in a large multicenter cohort. METHODS: Prospectively obtained data in the American College of Surgeons National Surgical Quality Improvement Program public use files from 2010 to 2016 were reviewed. Perioperative risks and outcomes were compared in unmatched and propensity-matched groups using parametric/non-parametric statistical tests as appropriate. RESULTS: A total of 4210 procedures were identified 345 (8.2%) laparoscopic and 3865 (91.8%) open. Laparoscopic repairs increased from 4.5% of 2010 cases to 11.4% of 2016 cases (p < .001). Open repair patients had more acute presentation including higher rates of ASA class, hypoalbuminemia, preoperative septic shock, dyspnea, and mechanical ventilation (all p < .01). Laparoscopic operations were longer than open procedures (p < .001). Mortality (8.5 vs. 3.5%), median length of stay (7 vs. 5 days), transfusion rates (13.7 vs. 7.0%), renal failure (3.7 vs. 1.2%), and respiratory failure (15.5 vs. 5.2%) were all worse in the unmatched open group (all p < .01). Propensity matching resulted in 342 laparoscopic and 626 open cases of similar ulcer type, demographics, ASA class, preoperative SIRS/sepsis, hypoalbuminemia, and wound class. Mortality was similar between matched groups (5.0 vs. 3.5%, p = .331). Median length of stay was longer in the open group (6 vs. 5 days, p < .001), which also had higher rates of prolonged ventilation/reintubation (9.6 vs. 5.3%, p = .019) and abdominal wall wound occurrences (6.2 vs. 2.3%, p = .042). Return to the operating room and 30-day readmissions did not differ between the matched groups. CONCLUSIONS: Emergent laparoscopic repair of perforated peptic ulcer is increasingly being performed, is safe relative to open repair (in patients without preoperative septic shock), and confers a modest benefit in terms of length of stay, respiratory, and abdominal wall wound complications.

The role of NOX2-derived reactive oxygen species in collagenase-induced osteoarthritis.

OBJECTIVE: Synovitis in collagenase-induced osteoarthritis (CiOA) is driven by locally released S100A8/A9 proteins and enhances joint destruction. S100A8/A9 can induce reactive oxygen species (ROS) release by phagocytes in OA synovium via neutrophil cytosolic factor-1 (Ncf1)-regulated NOX2 activation. In the present study we investigated whether NOX2-derived ROS affect joint pathology during CiOA. METHODS: CiOA was induced in knee joints of wild type (WT) and Ncf1-deficient (Ncf1**) mice. Synovial gene expression of NOX2-subunits was measured with quantitative real-time polymerase chain reaction (qRT-PCR). Joint pathology was assessed using histology and immunohistochemistry for aggrecan neo-epitope VDIPEN. Levels of inflammatory proteins were measured with Luminex or ELISA. Phagocytes in synovium, blood, bone marrow (BM) and spleen were analyzed with flow cytometry. ROS release by phagocytes was measured with a ROS detection kit. RESULTS: CiOA induction in knee joints of WT mice caused significantly increased synovial gene expression of NOX2 subunits. On day 7 of CiOA, cartilage damage and MMP activity, as measured by VDIPEN, were comparable between WT and Ncf1** mice. Synovial thickening, synovial S100A8/A9 levels and percentages of synovial macrophages, polymorphonuclear cells (PMNs), and monocytes were not different, as were levels of inflammatory mediators in serum and phagocyte percentages in blood, BM and spleen. On day 42 of CiOA, synovitis, cartilage damage, and osteophyte formation in Ncf1** mice were unaltered when compared to WT mice. ROS detection confirmed that Ncf1** PMNs lack functional NOX2, but in vitro macrophages showed ROS production, suggesting activation of compensatory mechanisms. CONCLUSIONS: Absence of Ncf1-mediated ROS production does not alter joint pathology in CiOA.

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

Brewer's yeast is a potent inducer of fever, sickness behavior and inflammation within the brain.

Brewer's yeast, derived from the yeast species Saccharomyces cerevisiae (S. cerevisiae), is commonly used for inducing pyrexia in pharmacological studies screening antipyretics in rats. Despite its widespread use, the peripheral and central inflammatory response associated with Brewer's yeast-induced fever and sickness behavior in rats has not been investigated. Thus, we injected male Sprague-Dawley rats (150-200 g) subcutaneously with a high (4 g/kg, n = 9), medium (2 g/kg, n = 5) or low (0.4 g/kg, n = 6) dose of Brewer's yeast solution or saline (0.9%, n = 6) and measured core body temperature, cage activity, food intake and body mass for six days after injection. Blood and brain samples were collected at 2, 8, 18 and 72 h after injection; n = 5-7 per time point. Brewer's yeast administration dose-dependently induced fever, lethargy, anorexia and body mass stunting that was accompanied by increased blood plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and activation of inflammatory transcription factors (nuclear factor (NF) for interleukin-6, signal transducer and activator of transcription (STAT)-3, and NF-κB)) in the hypothalamus and circumventricular organs. The increased activation of transcription factors following Brewer's yeast administration was accompanied by increased hypothalamic mRNA expression of TNF-α, IL-1ß and IL-6 and rate-limiting enzymes for prostaglandin synthesis. Our results show that subcutaneous administration of S. cerevisae induces prolonged fever, anorexia and lethargy that is accompanied by a pronounced increase in the synthesis of pro-inflammatory cytokines, key prostaglandin synthesizing enzymes and transcription factors, in the periphery and brain.

Buccal Respiratory Chain Complexes I and IV Quantities in Huntington's Disease Patients.

Alterations in mitochondrial parameters are an important hallmark of Huntington's disease (HD). The ubiquitous expression of mutant huntingtin raises the prospect that mitochondrial disturbances can also be detected and monitored through buccal epithelial cells. In a group of 34 patients with Huntington's disease and a group of 22 age-related healthy volunteers, respiratory complex I and IV protein quantities in buccal epithelial cells were measured using the dipstick immunocapture assay. The protein quantity of respiratory complex I correlates with age (r = 0.427, P = 0.026, FWE-P = 0.156) in the patient group, but not in the group of healthy subjects. Our non-invasive approach allows us to obtain valuable information for the studies of mitochondrial biochemical parameters in patients with neurodegenerative diseases and could also be useful in epidemiological studies.