Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheeze. There are few mechanistic data linking chromosome 17q12-q21 to wheezing illness. OBJECTIVE: We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. METHODS: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells with rhinovirus A1 (RV-A1) and rhinovirus A16 (RV-A16) and measured IFN and IFN-induced C-X-C motif chemokine ligand 10 (aka IP10) responses in supernatants. We investigated associations between virus-induced cytokines and 6 SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. RESULTS: Five SNPs (in high linkage disequilibrium, r2 ≥ 0.8) were significantly associated with RV-A1-induced IFN-ß (rs9303277, P = .010; rs11557467, P = .012; rs2290400, P = .006; rs7216389, P = .008; rs8079416, P = .005). A reduction in RV-A1-induced IFN-ß was observed among individuals with asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified 3 clusters that differed in IFN-ß induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-ß responses was characterized by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3 times more likely to be in clusters with reduced/average RV-A1-induced IFN-ß responses than in the high immune response cluster. CONCLUSIONS: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-ß, suggesting a novel mechanism-impaired IFN-ß induction-links 17q12-q21 risk alleles with asthma/wheeze.

Out-of-Pocket Costs among Commercially Insured Individuals with type 2 Diabetes and Obesity: Comparison between Ozempic and Sleeve Gastrectomy.

OBJECTIVE: Determine out-of-pocket (OOP) costs two years after sleeve gastrectomy (SG) or initiating Ozempic for patients with type 2 diabetes (T2D) and obesity. SUMMARY BACKGROUND DATA: Individuals with obesity and T2D have a variety of treatment options. Risks and benefits of these treatment options are becoming more well documented; however, the real-world patient costs of these options are not known. METHODS: Adults with body mass index (BMI) 35 kg/m2 or higher, and T2D who had an SG or used Ozempic were identified in the employer-based retrospective claims database Merative™ (previously Truven IBM Marketscan) from 2017 to 2021. SG cohort was defined as having a SG (without filling a prescription for Ozempic) and Ozempic cohort was defined as continuously filling a prescription for Ozempic for at least 2 years (and not having any bariatric surgery). Individuals in each cohort were 1:1 propensity matched on demographics, obesity-related comorbidities, and baseline OOP costs. in the year before treatment. OOP costs were compared in the two years after treatment using paired t-tests. RESULTS: 302 SG were matched to 302 Ozempic patients (mean age 50, mean baseline BMI 40, 41% male). OOP healthcare costs were similar for the SG ($2,267) and Ozempic ($2,131) cohorts 1-year after index date (difference=$136, P=0.19). OOP healthcare costs were significantly lower in the SG cohort ($1,155 vs. $2,084, P<0.01) 2-years after index date. CONCLUSIONS: Within 2 years of starting treatment, OOP healthcare costs were significantly lower among individuals who had a SG versus those treated with Ozempic.

Room for Improvement: The Impact of Guideline-Recommended Extended Thromboprophylaxis in Patients Undergoing Abdominal Surgery for Colorectal and Anal Cancer at a Tertiary Referral Center.

BACKGROUND: Venous thromboembolism occurs in approximately 2% of patients undergoing abdominal and pelvic surgery for cancers of the colon, rectum, and anus and is considered preventable. The American Society of Colon and Rectal Surgeons recommends extended prophylaxis in high-risk patients, but there is low adherence to the guidelines. OBJECTIVE: This study aims to analyze the impact of venous thromboembolism risk-guided prophylaxis in patients undergoing elective abdominal and pelvic surgeries for colorectal and anal cancers from 2016 to 2021. DESIGN: This was a retrospective analysis. SETTING: The study was conducted at a multisite tertiary referral academic health care system. PATIENTS: Patients who underwent elective abdominal or pelvic surgery for colon, rectal, or anal cancer. MAIN OUTCOME MEASURES: Receipt of Caprini-guided venous thromboembolism prophylaxis, 90-day postoperative rate of deep vein thrombosis, pulmonary embolism, venous thromboembolism, and bleeding events. RESULTS: A total of 3504 patients underwent elective operations, of whom 2224 (63%) received appropriate thromboprophylaxis in the inpatient setting. In the postdischarged cohort of 2769 patients, only 2% received appropriate thromboprophylaxis and no thromboembolic events were observed. In the group receiving inappropriate thromboprophylaxis, at 90 days postdischarge, the deep vein thrombosis, pulmonary embolism, and venous thromboembolism rates were 0.60%, 0.40%, and 0.88%, respectively. Postoperative bleeding was not different between the 2 groups. LIMITATIONS: Limitations to our study include its retrospective nature, use of aggregated electronic medical records, and single health care system experience. CONCLUSION: Most patients in our health care system undergoing abdominal or pelvic surgery for cancers of the colon, rectum, and anus were discharged without appropriate Caprini-guided venous thromboembolism prophylaxis. Risk-guided prophylaxis was associated with decreased rates of inhospital and postdischarge venous thromboembolism without increased bleeding complications. See Video Abstract . MARGEN DE MEJORA EL IMPACTO DE LA TROMBOPROFILAXIS RECOMENDADA POR LAS DIRECTRICES EN PACIENTES SOMETIDOS A CIRUGA ABDOMINAL POR CNCER COLORRECTAL Y ANAL EN UN CENTRO DE REFERENCIA TERCIARIO: ANTECEDENTES:El tromboembolismo venoso ocurre en aproximadamente el 2% de los pacientes sometidos a cirugía abdominal y pélvica por cánceres de colon, recto y ano, y se considera prevenible. La Sociedad Estadounidense de Cirujanos de Colon y Recto recomienda una profilaxis prolongada en pacientes de alto riesgo, pero el cumplimiento de las directrices es bajo.OBJETIVO:Este estudio tiene como objetivo analizar el impacto de la profilaxis guiada por el riesgo de tromboembolismo venoso (TEV) en pacientes sometidos a cirugías abdominales y pélvicas electivas por cáncer colorrectal y anal entre 2016 y 2021.DISEÑO:Este fue un análisis retrospectivo.AJUSTE:El estudio se llevó a cabo en un sistema de salud académico de referencia terciaria de múltiples sitios.PACIENTES:Pacientes sometidos a cirugía abdominal o pélvica electiva por cáncer de colon, recto o ano.PRINCIPALES MEDIDAS DE RESULTADO:Recepción de profilaxis de tromboembolismo venoso guiada por Caprini, tasa postoperatoria de 90 días de trombosis venosa profunda, embolia pulmonar, tromboembolismo venoso y eventos de sangrado.RESULTADOS:Un total de 3.504 pacientes se sometieron a operaciones electivas, de los cuales 2.224 (63%) recibieron tromboprofilaxis adecuada en el ámbito hospitalario. En el cohorte de 2.769 pacientes después del alta, solo el 2% recibió tromboprofilaxis adecuada en la que no se observaron eventos tromboembólicos. En el grupo que recibió tromboprofilaxis inadecuada, a los 90 días después del alta, las tasas de trombosis venosa profunda, embolia pulmonar y tromboembolia venosa fueron del 0,60%, 0,40% y 0,88%, respectivamente. El sangrado posoperatorio no fue diferente entre los dos grupos.LIMITACIONES:Las limitaciones de nuestro estudio incluyen su naturaleza retrospectiva, el uso de registros médicos electrónicos agregados y la experiencia de un solo sistema de atención médica.CONCLUSIÓN:La mayoría de los pacientes en nuestro sistema de salud sometidos a cirugía abdominal o pélvica por cánceres de colon, recto y ano fueron dados de alta sin una profilaxis adecuada de TEV guiada por Caprini. La profilaxis guiada por el riesgo se asoció con menores tasas de tromboembolismo venoso hospitalario y dado de alta sin un aumento de las complicaciones de sangrado. (Traducción-Dr. Aurian Garcia Gonzalez ).

Regulation of neonatal IgA production by the maternal microbiota.

Infants are prone to enteric infections due to an underdeveloped immune system. The maternal microbiota, through shaping the neonatal microbiota, helps establish a strong immune system in infants. We and others have observed the phenomenon of enhanced early neonatal immunoglobulin A (IgA) production in preweaning immunocompetent mice nursed by immunodeficient dams. Here, we show that this enhancement of IgA in neonates results from maternally derived microbiota. In addition, we have found that the neonatal IgA production can be induced by Lactobacillus reuteri, which is enriched in the milk of immunodeficient dams. Moreover, we show that while the production of neonatal IgA is dependent on neonatal T cells, the immunodeficient maternal microbiota-mediated enhancement of neonatal IgA has a T cell-independent component. Indeed, this enhancement may be dependent on type 3 innate lymphoid cells in the neonatal small intestinal lamina propria. Interestingly, maternal microbiota-induced neonatal IgA does not cross-react with common enteric pathogens. Future investigations will determine the functional consequences of having this extra IgA.

Countering 'the moral science of biopolitics': Understanding hepatitis C treatment 'non-compliance' in the antiviral era.

Although new hepatitis C treatments are a vast improvement on older, interferon-based regimens, there are those who have not taken up treatment, as well as those who have begun but not completed treatment. In this article, we analyse 50 interviews conducted for an Australian research project on treatment uptake. We draw on Berlant's (2007, Critical Inquiry, 33) work on 'slow death' to analyse so-called 'non-compliant' cases, that is, those who begin but do not complete treatment or who do not take antiviral treatment as directed. Approached from a biomedical perspective, such activity does not align with the neoliberal values of progress, self-improvement and rational accumulation that pervade health discourses. However, we argue that it is more illuminating to understand them as cases in which sovereignty and agency are neither simplistically individualised nor denied, and where 'modes of incoherence, distractedness, and habituation' are understood to co-exist alongside 'deliberate and deliberative activity […] in the reproduction of predictable life' (Berlant, 2007, p. 754). The analysed accounts highlight multiple direct and indirect forces of attrition and powerfully demonstrate the socially produced character of agency, a capacity that takes shape through the constraining and exhausting dynamics of life in conditions of significant disadvantage.

Troubling complaint: Addressing hepatitis C-related stigma and discrimination through complaint mechanisms.

The need to grapple with hepatitis C-related stigma and discrimination in Australian health-care settings has been recognised in public policy, and work is underway to address it. But how likely are people to raise a complaint when they experience stigma or discrimination? And how effective and accessible are complaints mechanisms? Given complaint procedures are considered important parts of the delivery of safe and ethical health care, these are important questions that have yet to be substantially explored. Drawing on interviews with people with lived experience of hepatitis C (n = 30), this article considers how affected people feel about complaints processes and the act of complaining. Alongside these perspectives, we discuss complaint mechanisms, and the views of stakeholders who work with hepatitis C-affected communities in policy, health, legal and advocacy roles (n = 30) on the institutional and cultural dynamics of complaint. We draw on Sara Ahmed's Complaint! and Fraser et al.'s work on drug-related stigma to analyse these concerns that have yet to be researched, and argue that the (unlikely) prospect of successful complaint is a key part of the network of forces that perpetuate stigma, discrimination and disadvantage among people who have (lived with) hepatitis C. Although people with lived experience are often powerful advocates and acutely aware of the deficiencies in the quality of their treatment, our interviews suggest that the obstacles they face to accessing health care are seen as commonplace, intractable and insurmountable; and, that mechanisms for addressing them-where they exist at all-treat complaints in narrowly individualising terms and expose complainants to dismissal. Following Ahmed, we call for a 'troubling' of complaints-responding to them not as individual problems but rather as collective, structural concerns, necessitating new approaches.

Sphingosine Prevents Rhinoviral Infections.

Rhinoviral infections cause approximately 50% of upper respiratory tract infections and novel treatment options are urgently required. We tested the effects of 10 µM to 20 µM sphingosine on the infection of cultured and freshly isolated human cells with minor and major group rhinovirus in vitro. We also performed in vivo studies on mice that were treated with an intranasal application of 10 µL of either a 10 µM or a 100 µM sphingosine prior and after infection with rhinovirus strains 1 and 2 and determined the infection of nasal epithelial cells in the presence or absence of sphingosine. Finally, we determined and characterized a direct binding of sphingosine to rhinovirus. Our data show that treating freshly isolated human nasal epithelial cells with sphingosine prevents infections with rhinovirus strains 2 (minor group) and 14 (major group). Nasal infection of mice with rhinovirus 1b and 2 is prevented by the intranasal application of sphingosine before or as long as 8 h after infection with rhinovirus. Nasal application of the same doses of sphingosine exerts no adverse effects on epithelial cells as determined by hemalaun and TUNEL stainings. The solvent, octylglucopyranoside, was without any effect in vitro and in vivo. Mechanistically, we demonstrate that the positively charged lipid sphingosine binds to negatively charged molecules in the virus, which seems to prevent the infection of epithelial cells. These findings indicate that exogenous sphingosine prevents infections with rhinoviruses, a finding that could be therapeutically exploited. In addition, we demonstrated that sphingosine has no obvious adverse effects on the nasal mucosa. Sphingosine prevents rhinoviral infections by a biophysical mode of action, suggesting that sphingosine could serve to prevent many viral infections of airways and epithelial cells in general. Future studies need to determine the molecular mechanisms of how sphingosine prevents rhinoviral infections and whether sphingosine also prevents infections with other viruses inducing respiratory tract infections. Furthermore, our studies do not provide detailed pharmacokinetics that are definitely required before the further development of sphingosine.

Are the non-weight bearing guidelines for the after treatment of calcaneal fractures still decisive? A Dutch survey among orthopaedic and trauma surgeons.

PURPOSE: The current rehabilitation for patients with surgically treated displaced intra-articular calcaneal fractures (DIACFs) consists of non-weightbearing for 8-12 weeks. The purpose of the present survey was to investigate the current pre-, peri- and post-operative practices among Dutch foot and ankle surgeons. Moreover, it aims to analyze whether surgeons comply to the Arbeitsgemeinschaft für Osteosynthesefragen (AO) guidelines and which decision criteria were used in the determination of the start of weightbearing. METHODS: A survey was distributed among Dutch trauma and orthopaedic surgeons to determine the most common practices in postoperative weightbearing in patients with DIACFs. RESULTS: 75 surgeons responded to the survey. 33% of the respondents adhered to the AO guidelines. 4% of the respondents strictly followed non-weightbearing guidelines, while 96% interpret the AO guidelines or their local protocol freely, in any frequency. When respondents tended to deviate from the AO guidelines or local protocol, a good patients' compliance to therapy was expected. 83% of the respondents started weightbearing on the fracture, based on reported patient complaints. 87% of the respondents did not see any relation between early weightbearing and the occurrence of complications, including loosening of osteosynthesis materials. CONCLUSION: This study demonstrates that there is limited consensus on the rehabilitation for DIACFs. Moreover, it shows that most surgeons are inclined to interpret the current (AO) guideline or their own local protocol freely. New guidelines, supported with well-founded literature, could help surgeons in a more appropriate daily practice in weightbearing for the rehabilitation of calcaneal fractures.

Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice.

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.

Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model.

Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wk hypoxia develop severe PH and unlike rodents, hypoxia-induced PH in this species can lead to right heart failure. We, therefore, sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14 days of environmental hypoxia (equivalent to 4,570 m/15,000 ft elevation, n = 29) or ambient normoxia (1,525 m/5,000 ft, n = 25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics, and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling as seen in advanced disease. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with 1) hypertrophic gene expression and prosurvival mechanotransduction through YAP-TAZ signaling, 2) extracellular matrix (ECM) remodeling, 3) inflammatory cell activation, and 4) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected, enriched in functions related to cell movement, tissue differentiation, and angiogenesis. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.NEW & NOTEWORTHY Using a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.

A systematic review and meta-analysis of the accuracy and methodology of the 13C mixed triglyceride breath test for the evaluation of pancreatic function.

INTRODUCTION: The diagnosis of pancreatic exocrine insufficiency (PEI) is challenging. The 13C mixed triglyceride breath test (13C MTGT) has emerged as a promising diagnostic method. However, there is need to assimilate high quality evidence to understand its accuracy and address variation in the conduct of the test. This systematic review aims to appraise the existing literature on the methodology and accuracy of the 13C MTGT. METHODS: A systematic literature search of PUBMED, MEDLINE, and EMBASE databases identified articles describing the use of the 13C MTGT in the analysis of pancreatic function in adults. Data extraction addressed each methodological step in detail. These were combined in a narrative synthesis. For quantitative analysis, those studies within this search that assessed the accuracy of the 13C MTGT were selected. RESULTS: 37 studies were included for qualitative review, 6 assessed sensitivity and specificity of the 13C MTGT against another measure of PEI and were included in quantitative synthesis. Areas with a majority consensus were pre-test overnight fasting, a test meal with a lipid load of at least 10 g, within-test control of exercise and dietary intake, breath sampling every 30 min and the preference of isotope ratio mass spectrometry (IRMS) for analysis. Good evidence suggests there is no benefit to extend the total timeframe of breath sampling beyond 6 h. Areas of uncertainty are a) Duration of PERT cessation b) the addition of metoclopramide, c) the ideal test meal and d) if the time frame can be shortened. Quantitative analysis among 6 studies demonstrated a pooled sensitivity and specificity of the 13C MTGT for diagnosing PEI of 0.84 (95% CI: 0.73-0.91) and 0.87 (95% CI: 0.79-0.93) respectively. CONCLUSION: There is yet to emerge a clear standard of breath test methodology that is validated for all causes of PEI and suitable for routine use. The accuracy of the 13C MTGT for diagnosing PEI is encouraging when compared to other measures. We present a suggested set protocol based on the current literature and identify areas that need further, high quality evidence. With refinement, the 13C MTGT could become a valuable, non-invasive PEI diagnostic tool that could be used outside of specialist centres.

Untargeted Metabolomics Analyses and Contaminant Chemistry of Dreissenid Mussels at the Maumee River Area of Concern in the Great Lakes.

Bivalves serve as an ideal ecological indicator; hence, their use by the NOAA Mussel Watch Program to monitor environmental health. This study aimed to expand the baseline knowledge of using metabolic end points in environmental monitoring by investigating the dreissenid mussel metabolome in the field. Dreissenids were caged at four locations along the Maumee River for 30 days. The mussel metabolome was measured using nuclear magnetic resonance spectroscopy, and mussel tissue chemical contaminants were analyzed using gas or liquid chromatography coupled with mass spectrometry. All Maumee River sites had a distinct mussel metabolome compared to the reference site and revealed changes in the energy metabolism and amino acids. Data also highlighted the importance of considering seasonality or handling effects on the metabolome at the time of sampling. The furthest upstream site presented a specific mussel tissue chemical signature of pesticides (atrazine and metolachlor), while a downstream site, located at Toledo's wastewater treatment plant, was characterized by polycyclic aromatic hydrocarbons and other organic contaminants. Further research into the dreissenid mussel's natural metabolic cycle and metabolic response to specific anthropogenic stressors is necessary before successful implementation of metabolomics in a biomonitoring program.

Ultrasound-guided noninvasive pancreas ablation using histotripsy: feasibility study in an in vivo porcine model.

Pancreatic cancer is a malignant disease associated with poor survival and nearly 80% present with unresectable tumors. Treatments such as chemotherapy and radiation therapy have shown overall improved survival benefits, albeit limited. Histotripsy is a noninvasive, non-ionizing, and non-thermal focused ultrasound ablation modality that has shown efficacy in treating hepatic tumors and other malignancies. In this novel study, we investigate histotripsy for noninvasive pancreas ablation in a pig model. In two studies, histotripsy was applied to the healthy pancreas in 11 pigs using a custom 32-element, 500 kHz histotripsy transducer attached to a clinical histotripsy system, with treatments guided by real-time ultrasound imaging. A pilot study was conducted in 3 fasted pigs with histotripsy applied at a pulse repetition frequency (PRF) of 500 Hz. Results showed no pancreas visualization on coaxial ultrasound imaging due to overlying intestinal gas, resulting in off-target injury and no pancreas damage. To minimize gas, a second group of pigs (n = 8) were fed a custard diet containing simethicone and bisacodyl. Pigs were euthanized immediately (n = 4) or survived for 1 week (n = 4) post-treatment. Damage to the pancreas and surrounding tissue was characterized using gross morphology, histological analysis, and CT imaging. Results showed histotripsy bubble clouds were generated inside pancreases that were visually maintained on coaxial ultrasound (n = 4), with 2 pigs exhibiting off-target damage. For chronic animals, results showed the treatments were well-tolerated with no complication signs or changes in blood markers. This study provides initial evidence suggesting histotripsy's potential for noninvasive pancreas ablation and warrants further evaluation in more comprehensive studies.

Venous thromboembolism and bleeding after hepatectomy: role and impact of risk adjusted prophylaxis.

Venous thromboembolism (VTE) occurs in 2-6% of post-hepatectomy patients and is associated with increased mortality and morbidity. The use of VTE risk assessment models in hepatectomy cases remains unclear. Our study aimed to determine the use and impact of Caprini guideline indicated VTE prophylaxis following hepatectomy. Hepatectomy cases performed during 2016-2021 were included. Caprini score and VTE prophylaxis were determined retroactively, and VTE prophylaxis was categorized as appropriate or inappropriate. The primary outcome was the receipt of appropriate prophylaxis, and secondary outcomes were postoperative VTE and bleeding. Statistical analyses included Fisher Exact test, Kruskal-Wallis, Pearson Chi-Square test, and multivariate regression models. R Statistical software was used for analysis. A p-value < 0.05 or 95% Confidence Interval (CI) excluding 1 was considered significant. A total of 1955 hepatectomy cases were analyzed. Patient demographics were similar between study cohorts. Inpatient, 30- and 90-day VTE rates were 1.28%, 0.56%, and 1.24%, respectively. By Caprini guidelines, 59% and 4.3% received appropriate in-hospital and discharged VTE prophylaxis, respectively. Inpatient VTE (4.5-fold) and mortality (9.5-fold) were lower in patients receiving appropriate prophylaxis. All discharged VTE and mortality occurred in patients not receiving appropriate prophylaxis. Inpatient, 30- and 90-day bleeding rates were 8.4%, 0.62%, and 0.68%, respectively. Appropriate prophylaxis did not increase postoperative bleeding. Increasing Caprini score inversely correlated with receiving appropriate prophylaxis (OR 0.38, CI 0.31-0.46) at discharge, and appropriate prophylaxis did not correlate with bleeding risk (OR 0.79, CI 0.57-1.12). Caprini guideline indicated prophylaxis resulted in reduced VTE complications without increasing bleeding risk.

Risk adjusted venous thromboembolism prophylaxis following pancreatic surgery.

This study analyzes pancreatectomy cases performed between 2016 and 2021 to determine the impact of using Caprini guideline indicated VTE prophylaxis on VTE and bleeding complications. This is a retrospective study of cases performed in a single academic health care system, in which Caprini score and VTE prevention measures were determined retroactively and prevention practices binarized as appropriate or not appropriate. Univariate and multivariate analyses were performed of 1,299 pancreatectomy case. Most patients were stratified as high risk for postoperative VTE. Receiving appropriate VTE prophylaxis during admission was associated with a 3-fold reduction in VTE complications (0.82% vs. 2.64%, p=0.01) without increasing bleeding complications. All VTE complications occurring with 30-day (1.2%) and 90-day (2.7%) from hospital discharged occurred in those not receiving appropriate prophylaxis, and discharged bleeding complications were also not associated with receivng appropriate discharged VTE prophylaxis. The findings our the study are significant as it highlights the ongoing need for standardization in VTE risk assessment and prevention measures to increase compliance to risk adjusted VTE prevention practice guidelines, thus reducing preventable VTE complications and potentially associated morbidity and mortality.

Trainee Effect on Procedural Efficiency is Limited in Vascular Surgery Operations.

BACKGROUND: Surgical residents prepare during their training for independent operating experience. However, there is a fine balance between supervised intraoperative teaching and the need to keep operations short since this is associated with improved patient safety. We aim to understand if the composition of the vascular surgical team-presence of anesthesia and surgical trainees as well as the number of circulating nurses-affects elective operative times at our institution. As a secondary aim, we analyzed how time of day affects overall operative time. METHODS: We performed a retrospective review of all vascular surgery elective operations occurring between January 1, 2019, and October 15, 2021. Our reference operation between procedures was the construction of an arteriovenous fistula (AVF). Reference teams included circulating staff (fewer than two nurses), anesthesia (anesthesiologist with certified registered nurse anesthetist [CRNA]), and surgery (surgeon with nurse practitioner). The primary dependent variable was the time interval in minutes from wheels-in to wheels-out of surgery, which was divided into three subintervals: wheels-in to cut, cut to close, and close to wheels-out. Univariate analysis was performed to examine each surgical procedure's distribution of wheels-in to wheels-out time interval. Linear regression was performed to determine the effect of team composition and time of day on operative durations. RESULTS: We included a total of 853 vascular operations. Regarding overall operative time, different procedures took various amounts of time compared with the reference operation (AVF creation). Amputations and arteriograms were shorter (-30 min, P = 0.03, and -12 min, P = 0.05, respectively). Other procedures were longer: endarterectomy (+48 min, P < 0.01), rib resection (+78 min, P < 0.01), endovascular aorta repair (+120 min, P < 0.01), lower extremity bypass (+170 min, P < 0.01), and open aortic repair (+410 min, P < 0.01). No significant difference was found in carotid artery stent placement. Overall, there was a significant reduction in the close to wheels-out interval for anesthesiologists with a trainee (mean: -2.4 min; 95%; CI: -4.7, -0.12; P = 0.04). AVF took significantly more time with a surgical resident: wheels-in to cut time (mean: +4.2 min; 95%; CI: 0.92, 7.4; P = 0.01) and cut to close time (mean: +13 min; 3.2, 23; P < 0.01). Arteriogram wheels-in to cut time took longer with a surgeon alone (mean: +5.6; 95%; CI: 0.29, 11; P = 0.04). There were no other statistically significant findings with change in composition of the surgical team or changes in start time. CONCLUSIONS: General surgery residents generally do not add time to vascular surgery cases but may do so in certain cases, perhaps when they are given more autonomy (i.e. AVF creation). Future studies should look at multiple centers, specific vascular procedures, and level of training to explore whether experience among residents (i.e., intern versus senior resident) and case complexity play a role in procedural length, as this may indirectly affect attending surgeon burnout and patient outcomes.

Caprini assessment utilization and impact on patient safety in gynecologic surgery.

PURPOSE: Postoperative venous thromboembolism (VTE) can potentially be associated with significant morbidity, mortality, and healthcare costs. The aim of this study was to determine the utilization of Caprini guideline indicated VTE in elective gynecologic surgery patients and its impact on postoperative VTE and bleeding complications. METHODS: This was a retrospective cohort study of elective gynecologic surgical procedures performed between January 1, 2016, and May 31, 2021. Two study cohorts were generated: (1) those who received and (2) those who did not receive VTE prophylaxis based on Caprini score risk stratification. Outcome measures were then compared between the study cohorts and included the development of a VTE up to 90-days postoperatively. Secondary outcome measures included postoperative bleeding events. RESULTS: A total of 5471 patients met inclusion criteria and the incidence of VTE up to 90 days postoperatively was 1.04%. Overall, 29.6% of gynecologic surgery patients received Caprini score-based guideline VTE prophylaxis. 39.2% of patients that met high-risk VTE criteria (Caprini > 5) received appropriate Caprini score-based prophylaxis. In multivariate regression analysis, the American Society of Anesthesiologists (ASA) score (OR 2.37, CI 1.27-4.45, p < 0.0001) and Caprini score (OR 1.13, CI 1.03-1.24, p = 0.008) predicted postoperatively VTE occurrence. Increasing Charlson comorbidity score (OR 1.39, CI 1.31-1.47, P < 0.001) ASA score (OR 1.36, CI 1.19-1.55, P < 0.001) and Caprini score (OR 1.10, CI 1.08-1.13, P < 0.001) were associated with increased odds of receiving appropriate inpatient VTE prophylaxis. CONCLUSION: While the overall incidence of VTE was low in this cohort, enhanced adherence to risk-based practice guidelines may provide more patient benefit than harm to postoperative gynecologic patients.

Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications.

Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO-), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD.

Between Public and Private: Electronic Health Record-sharing, Health Privacy Principles, and Hepatitis C.

People with (a history of) hepatitis C have concerns about privacy and the confidentiality of their health information. This is often due to the association between hepatitis C and injecting drug use and related stigma. In Australia, recent data breaches at a major private health insurer and legislative reforms to increase access to electronic health records have heightened these concerns. Drawing from interviews with people with lived experience of hepatitis C and stakeholders working in this area, this article explores the experiences and concerns of people with (a history of) hepatitis C in relation to the sharing of their health records. It considers the potential application of health privacy principles in the context of hepatitis C and argues for the development of guidelines concerning the privacy of health records held by health departments and public hospitals. Such principles might also inform reforms to legislation regarding access to health records.

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.