The prognostic value of the Merkel cell polyomavirus serum antibody test: A dual institutional observational study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.

A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity.

BACKGROUND: Infection with parasitic nematodes (helminths), particularly those of the order Strongylida (such as Haemonchus contortus), can cause significant and burdensome diseases in humans and animals. Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development. METHODS: We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite H. contortus, and the free-living comparator nematode Caenorhabditis elegans. Hit compounds were further validated via dose-response assays, with lead candidates then assessed for nematocidal activity against H. contortus adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells. RESULTS: The primary screen against H. contortus and C. elegans revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as 'flufenerim', as a significant inhibitor of H. contortus larval motility (half-maximal inhibitory concentration [IC50] = 18 µM) and development (IC50 = 1.2 µM), H. contortus adult female motility (100% after 12 h of incubation) and C. elegans larval motility (IC50 = 0.22 µM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC50] < 0.7 µM) and mitotoxic (half-maximal mitotoxic concentration [MC50] < 0.7 µM). CONCLUSIONS: The in vitro efficacy of MMV1794206 against the most pathogenic stages of H. contortus, as well as the free-living C. elegans, suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein-drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure-activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity.

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.

BACKGROUND: The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1fl/fl mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages. METHODS: AlbuminCre + Cc1fl/fl mice were fed a regular or a high-fat diet before their insulin metabolism and action were assessed during IPGTT, and their livers excised for histochemical, immunohistochemical and Western blot analysis. Sirius red staining was used to assess fibrosis, and media transfer was employed to examine whether mutant hepatocytes activated hepatic stellate cells (HSCs). Hepatic CEACAM1 protein levels in patients with varying disease stages were assessed by ELISA. RESULTS: Hepatocytic deletion of Ceacam1 caused hyperinsulinemia-driven insulin resistance emanating from reduced hepatic insulin clearance. AlbuminCre + Cc1fl/fl livers showed inflammation, fibrosis and hepatic injury, with more advanced bridging and chicken-wire hepatic fibrosis under high-fat conditions. Media transferred from hepatocytes isolated from mutant mice activated control HSCs, likely owing to their elevated endothelin1 content. Interestingly, hepatic CEACAM1 levels were lower in the livers of patients with MASH and declined gradually with advanced fibrosis stage. CONCLUSIONS: Hepatic CEACAM1 levels declined with progression of MASH in humans. The phenotype of AlbuminCre + Cc1fl/fl mice assigned a key role to CEACAM1 loss from hepatocytes in hepatic fibrosis independently of other liver cells.

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Structure activity relationship and target prediction for ABX464 analogues in Caenorhabditis elegans.

Global challenges with treatment failures and/or widespread resistance in parasitic worms against commercially available anthelmintics lend impetus to the development of new anthelmintics with novel mechanism(s) of action. The free-living nematode Caenorhabditis elegans is an important model organism used for drug discovery, including the screening and structure-activity investigation of new compounds, and target deconvolution. Previously, we conducted a whole-organism phenotypic screen of the 'Pandemic Response Box' (from Medicines for Malaria Venture, MMV) and identified a hit compound, called ABX464, with activity against C. elegans and a related, parasitic nematode, Haemonchus contortus. Here, we tested a series of 44 synthesized analogues to explore the pharmacophore of activity on C. elegans and revealed five compounds whose potency was similar or greater than that of ABX464, but which were not toxic to human hepatoma (HepG2) cells. Subsequently, we employed thermal proteome profiling (TPP), protein structure prediction and an in silico-docking algorithm to predict ABX464-target candidates. Taken together, the findings from this study contribute significantly to the early-stage drug discovery of a new nematocide based on ABX464. Future work is aimed at validating the ABX464-protein interactions identified here, and at assessing ABX464 and associated analogues against a panel of parasitic nematodes, towards developing a new anthelmintic with a mechanism of action that is distinct from any of the compounds currently-available commercially.

Review of Cutaneous Repairs on the Hand and Fingers Following Dermatologic Surgery.

Removal of cutaneous malignancies on the hand and fingers can result in challenging surgical defects to close. The dermatologic surgeon must not only be highly skilled, but also be knowledgeable regarding the complex anatomy of this area to perform reconstruction that provides optimal functional and cosmetic results. This review highlights key anatomic factors that must be considered when operating in this region. Wound management options discussed below include secondary intention, primary linear repair, local skin flaps, interpolation flaps, and skin grafting. The surgeon's choice is based on defect size, the presence/absence of adjacent skin laxity, and other patient-specific factors that may impact healing such as medical comorbidities, utilization of anticoagulant medications, and smoking status. This manuscript serves as an up-to-date review of closure considerations and techniques for physicians who surgically treat cutaneous malignancies of the hand and fingers.

Cholesterol depletion decreases adhesion of non-small cell lung cancer cells to E-selectin.

Lipid microdomains, ordered membrane phases containing cholesterol and glycosphingolipids, play an essential role in cancer cell adhesion and ultimately metastasis. Notably, elevated levels of cholesterol-rich lipid microdomains are found in cancer cells relative to their normal counterparts. Therefore, alterations of lipid microdomains through cholesterol modulation could be used as a strategy to prevent cancer metastasis. In this study, methyl-beta-cyclodextrin (MßCD), sphingomyelinase (SMase), and simvastatin (Simva) were used to investigate the effects of cholesterol on the adhesive behaviors of four non-small cell lung cancer (NSCLC) cell lines (H1299, H23, H460, and A549) and a small cell lung cancer (SCLC) cell line (SHP-77) on E-selectin, a vascular endothelial molecule that initiates circulating tumor cell recruitment at metastatic sites. Under hemodynamic flow conditions, the number of adherent NSCLC cells on E-selectin significantly decreased by MßCD and Simva treatments, whereas SMase treatment did not show a significant effect. Significant increases in rolling velocities were detected only for H1299 and H23 cells after MßCD treatment. In contrast, cholesterol depletion did not affect SCLC cell attachment and rolling velocities. Moreover, cholesterol depletion by MßCD and Simva induced CD44 shedding and resulted in an enhanced membrane fluidity in the NSCLC cells, whereas it did not affect the membrane fluidity of the SCLC cells which lacked detectable expression of CD44. Our finding suggests that cholesterol regulates the E-selectin-mediated adhesion of NSCLC cells by redistributing the CD44 glycoprotein and thus modulating the membrane fluidity.NEW & NOTEWORTHY This study investigates the effects of cholesterol on the adhesive behaviors of lung cancer cells in recruitment at metastatic sites. Using cholesterol-modulating compounds, we found that reducing cholesterol decreases the adhesion of non-small cell lung cancer (NSCLC) cells while having no significant effect on small cell lung cancer (SCLC) cells. The study suggests that cholesterol regulates NSCLC cell metastasis by redistributing the adhesion proteins on the cells and modulating cells' membrane fluidity.

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis.

OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target. METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant. RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage. CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.

Molecular dynamics simulations and in vitro studies of hybrid decellularized leaf-peptide-polypyrrole composites for potential tissue engineering applications.

Tissue engineering (TE) aims to repair and regenerate damaged tissue by an assimilation of optimal combination of cells specific to the tissue with an appropriate biomaterial. In this work, a new biomaterial for potential cardiac TE applications was developed by utilizing a combination of in silico studies and in vitro experiments. Molecular dynamics (MD) simulations for the formation of the novel composite prepared from the decellularized leaf components cellulose and pectin along with the VEGF derived peptide (NYLTHRQ) and polypyrrole (PPy) was carried out to assess self-assembly, mechanical properties, and interactions with integrin and NPR-C receptors which are commonly found in cells of cardiac tissue. Results of molecular dynamics simulations indicated the successful formation of stable assemblies. MD simulations also revealed that the scaffold successfully interacted with integrin and NPR-C receptors. As a proof of concept, beet leaves were decellularized (DC) and cross-linked with NYLTHRQ and PPy using layer-by-layer assembly. Decellularization (DC) was confirmed by DNA and protein quantification. Incorporation of the NYLTHRQ peptide and polypyrrole was confirmed by FTIR spectroscopy and SEM imaging. The DC-NYLTHRQ-PPy scaffold was seeded with co-cultured cardiomyocytes and vascular smooth muscle cells. The scaffold promoted cell proliferation and adhesion. Actin and Troponin T immunofluorescence staining showed the presence of these critical cardiomyocyte markers. Thus, for the first time we have developed a decellularized leaf-peptide-PPy composite scaffold by a combination of in silico studies and laboratory analyses that may have potential applications in cardiac TE.Communicated by Ramaswamy H. Sarma.

A novel approach to joint prediction of preeclampsia and delivery timing using semicompeting risks.

BACKGROUND: Preeclampsia is a pregnancy complication that contributes substantially to perinatal morbidity and mortality worldwide. Existing approaches to modeling and prediction of preeclampsia typically focus either on predicting preeclampsia risk alone, or on the timing of delivery following a diagnosis of preeclampsia. As such, they are misaligned with typical healthcare interactions during which the 2 events are generally considered simultaneously. OBJECTIVE: This study aimed to describe the "semicompeting risks" framework as an innovative approach for jointly modeling the risk and timing of preeclampsia and the timing of delivery simultaneously. Through this approach, one can obtain, at any point during the pregnancy, clinically relevant summaries of an individual's predicted outcome trajectories in 4 risk categories: not developing preeclampsia and not having delivered, not developing preeclampsia but having delivered because of other causes, developing preeclampsia but not having delivered, and developing preeclampsia and having delivered. STUDY DESIGN: To illustrate the semicompeting risks methodology, we presented an example analysis of a pregnancy cohort from the electronic health record of an urban, academic medical center in Boston, Massachusetts (n=9161 pregnancies). We fit an illness-death model with proportional-hazards regression specifications describing 3 hazards for timings of preeclampsia, delivery in the absence of preeclampsia, and delivery following preeclampsia diagnosis. RESULTS: The results indicated nuanced relationships between a variety of risk factors and the timings of preeclampsia diagnosis and delivery, including maternal age, race/ethnicity, parity, body mass index, diabetes mellitus, chronic hypertension, cigarette use, and proteinuria at 20 weeks' gestation. Sample predictions for a diverse set of individuals highlighted differences in projected outcome trajectories with regard to preeclampsia risk and timing, and timing of delivery either before or after preeclampsia diagnosis. CONCLUSION: The semicompeting risks framework enables characterization of the joint risk and timing of preeclampsia and delivery, providing enhanced, meaningful information regarding clinical decision-making throughout the pregnancy.

Metabolic Surgery for Adult Obesity: Common Questions and Answers.

In 2019, approximately 256,000 metabolic surgery procedures were performed in the United States, a 32% increase since 2014. The most common procedures are the laparoscopic sleeve gastrectomy and the Roux-en-Y gastric bypass. Choice of procedure depends on concurrent medical conditions, patient preference, and expertise of the surgeon. These procedures have a mortality risk of 0.2% to 0.3%. On average, weight loss of 30 to 50 kg (66 to 110 lb), or a 20% to 30% reduction in total body weight, is achieved, although most patients will experience some weight regain three to 10 years after surgery. In patients who have had metabolic surgery, all-cause mortality is reduced by 30% to 45% at two to 15 years postsurgery compared with patients with obesity who did not have surgery. Remission of type 2 diabetes mellitus occurs in as many as 70% to 80% of patients within one to two years after surgery and is maintained at 10 years in about 30% of patients. Other obesity-related conditions are also greatly reduced, and quality of life improves. Postoperatively, patients require standardized nutritional supplementation and surveillance. Persistent changes in diet, such as consuming protein first at every meal, regular physical activity, and ongoing attention to behavior change are critical for the success of the patient after metabolic surgery. Common adverse outcomes include surgical complications, nutritional deficiencies, bone density loss, dumping syndrome, gastroesophageal reflux disease, and loose skin. The family physician is well positioned to counsel patients about metabolic surgical options and the risks and benefits of surgery and to provide long-term support and medical management for postsurgery patients.

Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene.

(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL/6J.Ldlr-/- background (Ldlr-/-VECadCre+Cc1fl/fl) were fed an atherogenic diet for 3-5 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2/Shc/NF-κB pathway with resultant transcriptional induction of NF-κB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr-/-VECadCre+Cc1fl/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis.

Can introducing a direct endocrine pathway reduce hyponatraemia in elective knee and hip replacements? A closed-loop audit and service evaluation study.

INTRODUCTION: Hyponatraemia has a prevalence of up to 30% after orthopaedic surgery and is associated with poor outcomes, including around 20% mortality and longer hospital stays. This study assessed the prevalence of hyponatraemia following total hip and knee replacement, the causes, further tests, management, effect on length of stay, intensive care admissions and the impact of an endocrinology hyponatraemia protocol. MATERIALS AND METHODS: Day one postoperative urea and electrolyte results for patients undergoing elective total hip and knee replacements were reviewed. Retrospective data was gathered through the web-based requesting and reporting system ICE. Parameters included demographics, procedure, sodium pre- and postoperatively, endocrine input, high-dependency admissions and length of hospital stay. Next, a hyponatraemia protocol based on NICE guidance was developed with the endocrinology department and a second audit cycle was initiated. SPSS software was used to analyse the data. RESULTS: Hyponatraemia occurred in 12% of patients, resulted in a significantly longer stay (7.7 days vs 4.6, t -4.6, p < 0.00001) and multiple critical care admissions (8 days). It was more common in total knee replacement (chi square 5.5194, p = 0.018807) and older age (t -2.81083, p = 0.002619). Prior to implementation of the endocrine pathway, hyponatraemia was under-investigated (38%). The precipitating factors such as age and use of diuretics corroborated with prior research. Implementation of the hyponatraemia protocol resulted in quicker endocrinology referrals (2.3 vs 3.6 days), reduced length of stay by 0.7 days (t -2.40973, p = 0.008144) and reduced intensive care days to 0 (chi square 4.6189, p = 0.031622). DISCUSSION: This study found a similar incidence of hyponatremia as earlier research with the same precipitating factors, the only exception being an increased incidence in patients undergoing knee compared with hip replacemenr The introduction of the direct endocrine pathway proved to be safe and effective without increasing local workload significantly. The main limitation in this project was the fact that it was carried out in a single unit, although this process could be easily replicated should other units wish to adopt it and compare results over a wider cohort. CONCLUSIONS: This endocrine pathway is easily reproducible for other departments. It may help reduce waiting times and improve outcomes for total hip and knee replacements within the NHS.

Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance.

The NAD-dependent deacetylase SIRT1 improves ß cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents ß cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on ß cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced ß cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased ß cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

Smartphone GPS signatures of patients undergoing spine surgery correlate with mobility and current gold standard outcome measures.

OBJECTIVE: Patient-reported outcome measures (PROMs) are currently the gold standard to evaluate patient physical performance and ability to recover after spine surgery. However, PROMs have significant limitations due to the qualitative and subjective nature of the information reported as well as the impossibility of using this method in a continuous manner. The smartphone global positioning system (GPS) can be used to provide continuous, quantitative, and objective information on patient mobility. The aim of this study was to use daily mobility features derived from the smartphone GPS to characterize the perioperative period of patients undergoing spine surgery and to compare these objective measurements to PROMs, the current gold standard. METHODS: Eight daily mobility features were derived from smartphone GPS data in a population of 39 patients undergoing spine surgery for a period of 2 months starting 3weeks before surgery. In parallel, three different PROMs for pain (visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]) and functional status (Patient-Reported Outcomes Measurement Information System [PROMIS]) were serially measured. Segmented linear regression analysis was used to assess trends before and after surgery. The Student paired t-test was used to compare pre- and postoperative PROM scores. Pearson's correlation was calculated between the daily average of each GPS-based mobility feature and the daily average of each PROM score during the recovery period. RESULTS: Smartphone GPS features provided data documenting a reduction in mobility during the immediate postoperative period, followed by a progressive and steady increase with a return to baseline mobility values 1 month after surgery. PROMs measuring pain, physical performance, and disability were significantly different 1 month after surgery compared to the 2 immediate preoperative weeks. The GPS-based features presented moderate to strong linear correlation with pain VAS and PROMIS physical score during the recovery period (Pearson r > 0.7), whereas the ODI and PROMIS mental scores presented a weak correlation (Pearson r approximately 0.4). CONCLUSIONS: Smartphone-derived GPS features were shown to accurately characterize perioperative mobility trends in patients undergoing surgery for spine-related diseases. Features related to time (rather than distance) were better at describing patient physical and performance status. Smartphone GPS has the potential to be used for the development of accurate, noninvasive and personalized tools for patient mobility monitoring after surgery.

Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1.

CEACAM1 regulates endothelial barrier integrity. Because insulin signaling in extrahepatic target tissues is regulated by insulin transport through the endothelium, we aimed at investigating the metabolic role of endothelial CEACAM1. To this end, we generated endothelial cell-specific Ceacam1 null mice (VECadCre+Cc1fl/fl) and carried out their metabolic phenotyping and mechanistic analysis by comparison to littermate controls. Hyperinsulinemic-euglycemic clamp analysis showed intact insulin sensitivity in VECadCre+Cc1fl/fl mice. This was associated with the absence of visceral obesity and lipolysis and normal levels of circulating non-esterified fatty acids, leptin, and adiponectin. Whereas the loss of endothelial Ceacam1 did not affect insulin-stimulated receptor phosphorylation, it reduced IRS-1/Akt/eNOS activation to lower nitric oxide production resulting from limited SHP2 sequestration. It also reduced Shc sequestration to activate NF-κB and increase the transcription of matrix metalloproteases, ultimately inducing plasma IL-6 and TNFα levels. Loss of endothelial Ceacam1 also induced the expression of the anti-inflammatory CEACAM1-4L variant in M2 macrophages in white adipose tissue. Together, this could cause endothelial barrier dysfunction and facilitate insulin transport, sustaining normal glucose homeostasis and retaining fat accumulation in adipocytes. The data assign a significant role for endothelial cell CEACAM1 in maintaining insulin sensitivity in peripheral extrahepatic target tissues.

Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.

OBJECTIVE: NAFLD is a complex disease marked by cellular abnormalities leading to NASH. NAFLD patients manifest low hepatic levels of CEACAM1, a promoter of insulin clearance. Consistently, Cc1-/- null mice displayed spontaneous hyperinsulinemia/insulin resistance and steatohepatitis. Liver-specific reconstitution of Ceacam1 reversed these metabolic anomalies in 8-month-old Cc1-/-xliver+ mice fed a regular chow diet. The current study examined whether it would also reverse progressive hepatic fibrosis in mice fed a high-fat (HF) diet. METHODS: 3-Month-old mice were fed a high-fat diet for 3-5 months, and metabolic and histopathological analysis were conducted to evaluate their NASH phenotype. RESULTS: Reconstituting CEACAM1 to Cc1-/- livers curbed diet-induced liver dysfunction and NASH, including macrovesicular steatosis, lobular inflammation, apoptosis, oxidative stress, and chicken-wire bridging fibrosis. Persistence of hepatic fibrosis in HF-fed Cc1-/- treated with nicotinic acid demonstrated a limited role for lipolysis and adipokine release in hepatic fibrosis caused by Ceacam1 deletion. CONCLUSIONS: Restored metabolic and histopathological phenotype of HF-fed Cc1-/-xliver+xliver+ assigned a critical role for hepatic CEACAM1 in preventing NAFLD/NASH including progressive hepatic fibrosis.

Making a business plan for starting a transitional pain service within the US healthcare system.

Chronic pain imposes a tremendous economic burden of up to US$635 billion per year in terms of direct costs (such as the costs of treatment) and indirect costs (such as lost productivity and time away from work). In addition, the initiation of opioids for pain is associated with a more than doubling of pharmacy and all-cause medical costs. The high costs of chronic pain are particularly relevant for anesthesiologists because surgery represents an inciting event that can lead to chronic pain and long-term opioid use. While the presence of risk factors and an individual patient's postoperative pain trajectory may predict who is at high risk for chronic pain and opioid use after surgery, to date, there are few interventions proven to reduce these risks. One promising approach is the transitional pain service. Programs like this attempt to bridge the gap between acute and chronic pain management, provide continuity of care for complicated acute pain patients after discharge from the hospital, and offer interventions for patients who are on abnormal trajectories of pain resolution and/or opioid use. Despite awareness of chronic pain after surgery and the ongoing opioid epidemic, there are few examples of successful transitional pain service implementation in the USA. Key issues and concerns include financial incentives and the required investment from the hospital or healthcare system. We present an economic analysis and discussion of important considerations when developing a business plan for a transitional pain service.

Financial analysis of revision knee surgery at a tertiary referral centre as classified according to the Revision Knee Complexity Classification (RKCC).

BACKGROUND: Revision total knee arthroplasty (rTKA) can be complex, with greater costs to the treating hospital than primary TKA. A rTKA regional network has been proposed in England. The aim of this work was to accurately quantify current costs and reimbursement for the rTKA service and to assess whether costs are proportional to case complexity at a tertiary referral centre within the National Health Service (NHS). METHODS: A review of all rTKA performed at our institution over two consecutive financial years (2017-2019) was performed. Cases were classified according to the Revision Knee Complexity Classification (RKCC) and by mode of failure; "infected" and "non-infected". Financial data was acquired through Patient-Level Information and Costing System (PLICS). The primary outcome was the financial difference between tariff and cost per episode. Comparisons between groups were analysed using analysis of variance and two-tailed unpaired t-test as appropriate. RESULTS: 159 patients underwent 188 rTKA procedures. Length of stay and cost significantly increased between complexity groups (p < 0.0001) and for infected revisions (p < 0.0001). All groups sustained a mean deficit but this significantly increased with revision complexity (from £1,903 to £5,269 per case) and for infected revisions. The total deficit to the Trust for the two-year rTKA service was £667,091. CONCLUSIONS: The current level of NHS reimbursement are inadequate for centres that offer rTKA and should be more closely aligned to case complexity. An increase in the most complex rTKA at major revision centres will undoubtedly place an even greater strain on the finances of these units.

Loss of Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis.

Patients with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin (Alb)Cre+ Cc1flox ( fl ) /fl mice with the liver-specific null deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1; alias Cc1) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated de novo lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD/NASH and atherosclerosis. To this end, mice were propagated on a low-density lipoprotein receptor (Ldlr) -/- background and at 4 months of age were fed a high-cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr-/-AlbCre+Cc1fl/fl mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin-1 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down-regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1-protein kinase B-endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc-transforming protein (Shc), activating the Shc-mitogen-activated protein kinase-nuclear factor kappa B pathway and stimulating endothelin-1 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver-specific deletion of Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. Conclusion: Altered CEACAM1-dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.