Outcomes of liver transplantation in non-alcoholic steatohepatitis (NASH) versus non-NASH associated hepatocellular carcinoma.

BACKGROUND: Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has potential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort. METHODS: Adults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria. RESULTS: 2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual proportional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87-1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89-1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34-0.98, p = 0.04). DISCUSSION: NASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.

The rapid anxiety screening study-pilot data.

Anxiety disorders are the most common mental health condition in the United States. Medical providers often have many active issues when treating a patient, and do not always have time for a thorough psychiatric evaluation. The Patient Health Questionnaire 2, a two-question binary (yes/no) screening tool, has been developed to address these issues in the identification of unipolar depression. No similar binary screening tool has been developed to comprehensively screen for anxiety disorders. Our study seeks to develop a three-question, comprehensive, binary screening tool for anxiety and related disorders such that these patients can be easily identified and connected to treatment. Our pilot data shows promising results for our three-question binary Rapid Anxiety Screen (the RAS). Future studies will look to confirm these preliminary data and determine the sensitivities and specificities of the RAS with a larger data set.

In silico approach identified benzoylguanidines as SARS-CoV-2 main protease (Mpro) potential inhibitors.

The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), became the highest public health crisis nowadays. Although the use of approved vaccines for emergency immunization and the reuse of FDA-approved drugs remains at the forefront, the search for new, more selective, and potent drug candidates from synthetic compounds is also a viable alternative to combat this viral disease. In this context, the present study employed a computational virtual screening approach based on molecular docking and molecular dynamics (MD) simulation to identify possible inhibitors for SARS-CoV-2 Mpro (main protease), an important molecular target required for the maturation of the various polyproteins involved in viral replication. The virtual screening approach selected four potential inhibitors against SARS-CoV-2 Mpro. In addition, MD simulation studies revealed changes in the positions of the ligands during the simulations compared to the complex obtained in the molecular docking studies, showing the benzoylguanidines LMed-110 and LMed-136 have a higher affinity for the active site compared to the other structures that tended to leave the active site. Besides, there was a better understanding of the formation and stability of the existing H-bonds in the formed complexes and the energetic contributions to the stability of the target-ligand molecular complexes. Finally, the in silico prediction of the ADME profile suggested that LMed-136 has drug-like characteristics and good pharmacokinetic properties. Therefore, from the present study, it can be suggested that these structures can inhibit SARS-CoV-2 Mpro. Nevertheless, further studies are needed in vitro assays to investigate the antiviral properties of these structures against SARS-CoV-2.

Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?

While the number of oncology-related nanotherapeutics and immunotherapies is constantly increasing, cancer patients still suffer from a lack of efficacy and treatment resistance. Among the investigated strategies, patient selection and combinations appear to be of great hope. This review will focus on combining nanotherapeutics and immunotherapies together, how they can dually optimize each other to face such limits, bringing us into a new field called nano-immunotherapy. While looking at current clinical trials, we will expose how passive immunotherapies, such as antibodies and ADCs, can boost nanoparticle tumor uptake and tumor cell internalization. Conversely, we will study how immunotherapies can benefit from nanotherapeutics which can optimize their lipophilicity, permeability, and distribution (e.g., greater tumor uptake, BBB crossing, etc.), tumor, tumor microenvironment, and immune system targeting properties.

Trends in liver transplantation for autoimmune liver diseases: a Canadian study.

BACKGROUND: To our knowledge, no analysis of data from liver transplantation registries exists in Canada. We aimed to describe temporal trends in the number of liver transplantation procedures, patient characteristics and posttransplantation outcomes for autoimmune liver diseases (AILDs) in Canada. METHODS: We used administrative data from the Canadian Organ Replacement Register, which contains liver transplantation information from 6 centres in Canada. This study included transplantation information from 5 of the centres, as liver transplantation procedures in children were not included. We included adult (age ≥ 18 yr) patients with a diagnosis of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) or overlap syndrome (PBC-AIH or PSC-AIH) who received a liver transplant from 2000 to 2018. RESULTS: Of 5722 primary liver transplantation procedures performed over the study period, 1070 (18.7%) were for an AILD: 489 (45.7%) for PSC, 341 (31.9%) for PBC, 220 (20.6%) for AIH and 20 (1.9%) for overlap syndrome. There was a significant increase in the absolute number of procedures for PSC, with a yearly increase of 0.6 (95% confidence interval 0.1 to 1.2), whereas the absolute number of procedures for PBC and AIH remained stable. The proportion of transplantation procedures decreased for PBC and AIH but remained stable for PSC. Recipient age at transplantation increased over time for males with PBC (median 53 yr in 2000-2005 to 57 yr in 2012-2018, p = 0.03); whereas the median age among patients with AIH decreased, from 53 years in 2000-2005 to 44 years in 2006-2011 (p = 0.03). The Model for Endstage Liver Disease score at the time of transplantation increased over time for all AILDs, particularly AIH (median 16 in 2000-2005 v. 24 in 2012-2018, p < 0.001). There was a trend toward improved survival in the PBC group, with a 5-year survival rate of 81% in 2000-2005 and 90% in 2012-2018 (p = 0.06). CONCLUSION: Between 2000 and 2018, the absolute number of liver transplantation procedures in Canada increased for PSC but remained stable for PBC and AIH; proportionally, PBC and AIH decreased as indications for transplantation. Posttransplantation survival improved only for the PBC group. An improved understanding of trends and outcomes on a national scale among patients with AILD undergoing liver transplantation can identify disparities and areas for potential health care improvement.

Characterization of novel papillomavirus from free-ranging Antillean manatee Trichechus manatus manatus with genital papillomatosis.

The Antillean manatee Trichechus manatus manatus is an Endangered species living along the Atlantic coasts of the Americas from Florida (USA), throughout the Caribbean, to Brazil. In July 2020, a manatee with multiple wounds due to boat-inflicted trauma was rescued from the coast east of Cayo Mata, Salinas, Puerto Rico. This manatee had neutropenia, leukopenia, and monocytosis associated with immunosuppression and nutritional deficiency anemia, as well as bacteria and fungi within the lesions. The manatee had genital lesions which included papules and linear plaques, microscopically characterized by mucosal hyperplasia with cytopathic changes typical of papillomavirus infection. Superficial epithelial cells had strong nuclear immunolabeling when examined using a monoclonal antibody specific to papillomavirus. The sequencing data of PCR products with papillomavirus-specific degenerative primers indicated that these lesions contained a novel manatee papillomavirus (Trichechus manatus papillomavirus, TmPV). The genomic DNA was amplified using a rolling circle amplification, and fully sequenced to be 7586 bp (GenBank accession no. OK073977). Other TmPVs were previously isolated from Florida manatees T. manatus latirostris. This novel virus was designated TmPV type 5 (TmPV5) based on its genomic characterization and sequence comparison. The TmPV5 genome shared 50.7, 48.9, 69.4, and 62.1% similarities with TmPV1, TmPV2, TmPV3, and TmPV4, respectively. TmPV5 is classified in the genus Rhopapillomavirus together with other manatee papillomaviruses. After 2.5 mo of veterinary treatment and rehabilitation, the manatee recovered and was released. This is the first report of papillomatosis in a free-ranging Antillean manatee.

Relationship between lymphedema after breast cancer treatment and biophysical characteristics of the affected tissue.

The treatment of breast cancer is often complicated by lymphedema of the upper limbs. Standard lymphedema evaluation methodologies are not able to measure tissue fibrosis. The ultrasound aspects related to tissue microstructures of lymphedema are neglected in clinical evaluations. The objective of this study was to identify and measure the degree of impairment, topography, and biophysical alterations of subcutaneous lymphedema tissue secondary to the treatment of breast cancer by ultrasonography. Forty-two women at a mean age of 58 (±9.7) years, with unilateral lymphedema due to breast cancer treatment, were evaluated. The upper limbs were divided into affected (affected by lymphedema) and control (contralateral limb). Each limb was subdivided into seven areas, defined by perimetry, evaluated in pairs. The biophysical characteristics thickness, entropy, and echogenicity were evaluated by ultrasonography. The results showed a significant difference in the echogenicity and thickness variables between the affected and unaffected upper limb, in all the extent of the upper limb, while entropy showed no significant difference. The findings indicate that the data presented were consistent both in identifying and measuring the degree of impairment and biophysical changes in the subcutaneous tissue of lymphedema secondary to the treatment of breast cancer.

Outcomes of Adult Liver Retransplantation: A Canadian National Database Analysis.

Background: Liver retransplantation remains as the only treatment for graft failure. This investigation aims to assess the incidence, post-transplant outcomes, and risk factors in liver retransplantation recipients in Canada. Materials and Methods: The Canadian Organ Replacement Register was used to obtain and analyse data on all adult liver retransplant recipients, matched donors, transplant-specific variables, and post-transplant outcomes from January 2000 to December 2018. Results: 377 (6.5%) patients underwent liver retransplantation. Autoimmune liver disease and hepatitis C virus (HCV) were the most common underlying diagnoses. Graft failure was 7.9% and 12.5%, and overall survival was 77.1% and 65.6% at 1 year and 5 years, respectively. In contrast to recipients receiving their first graft transplant, the retransplantation group had a significantly higher incidence of graft failure (p < 0.001) and lower overall survival (p < 0.001). The graft failure and patient survival rates were comparable between second transplant and repeat retransplant recipients. Furthermore, there were no differences in graft failure and patient survival when stratified according to time to retransplantation. Recipient and donor age (HR = 1.12, p=0.011; HR = 1.09, p=0.008), recipient HCV status (HR = 1.81, p=0.014), and donor cytomegalovirus status (HR = 4.10, p=0.006) were predictors of patient mortality. Conclusion: This analysis of liver retransplantation demonstrates that this is a safe treatment for early and late graft failure. Furthermore, even in patients requiring more than two grafts, similar outcomes to initial retransplantation can be achieved with careful selection.

Dynamic risk profiling of HCC recurrence after curative intent liver resection.

BACKGROUND AND AIMS: Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. APPROACH AND RESULTS: Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. CONCLUSIONS: In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.

Long-term outcomes of laparoscopic liver resection for hepatocellular carcinoma: A propensity score matched analysis of a high-volume North American center.

BACKGROUND: Laparoscopic liver resections for malignancy are increasing worldwide, and yet data from North America are lacking. We aimed to assess the long-term outcomes of patients undergoing laparoscopic liver resection and open liver resection as a treatment for hepatocellular carcinoma. METHODS: Patients undergoing liver resection for hepatocellular carcinoma between January 2008 and December 2019 were retrospectively studied. A propensity score matching was performed using patient demographics, laboratory parameters, etiology of liver disease, liver function, and tumor characteristics. Primary outcomes included overall survival and cumulative incidence of recurrence. Kaplan-Meier and competing risk cumulative incidence were used for survival analyses. Multivariable Cox regression and Fine-Gray proportional hazard regression were performed to determine hazard for death and recurrence, respectively. RESULTS: Three hundred and ninety-one patients were identified (laparoscopic liver resection: 110; open liver resection: 281). After propensity score matching, 149 patients remained (laparoscopic liver resection: 57; open liver resection: 92). There were no significant differences between groups with regard to extent of hepatectomy performed and tumor characteristics. The laparoscopic liver resection group experienced a lower proportion of ≥Clavien-Dindo grade III complications (14% vs 29%; P = .01). In the matched cohort, the 1-, 3-, and 5-year overall survival rate in the laparoscopic liver resection versus open liver resection group was 90.9%, 79.3%, 70.5% vs 91.3%, 88.5%, 83.1% (P = .26), and the cumulative incidence of recurrence 31.1%, 59.7%, 62.9% vs 18.9%, 40.6%, 49.2% (P = .06), respectively. CONCLUSION: This study represents the largest single institutional study from North America comparing long-term oncologic outcomes of laparoscopic liver resection and open liver resection as a treatment for primary hepatocellular carcinoma. The combination of reduced short-term complications and equivalent long-term oncologic outcomes favor the laparoscopic approach when feasible.

Enhancing the Therapeutic Potential of Extracellular Vesicles Using Peptide Technology.

Extracellular vesicles are lipid-bilayer-enclosed nanoparticles present in the majority of biological fluids that mediate intercellular communication. EVs are able to transfer their contents (including nucleic acids, proteins, lipids, and small molecules) to recipient cells, and thus hold great promise as drug delivery vehicles. However, their therapeutic application is limited by lack of efficient cargo loading strategies, a need to improve EV tissue-targeting capabilities and a requirement to improve escape from the endolysosomal system. These challenges can be effectively addressed by modifying EVs with peptides which confer specific advantageous properties, thus enhancing their therapeutic potential. Here we provide an overview of the applications of peptide technology with respect to EV therapeutics. We focus on the utility of EV-modifying peptides for the purposes of promoting cargo loading, tissue-targeting and endosomal escape, leading to enhanced delivery of the EV cargo to desired cells/tissues and subcellular target locations. Both endogenous and exogenous methods for modifying EVs with peptides are considered.

Influence of age and lymphedema on the postural balance of women undergoing breast cancer treatment.

INTRODUCTION: Breast cancer affects women of different ages, and comorbidities resulting from treatment can affect postural stability. The study aimed to evaluate the influence of age and lymphedema on the postural balance of women undergoing breast cancer treatment. METHODS: The study included 77 women undergoing breast cancer treatment, divided into different groups: 37 young adult women divided into 17 with lymphedema (GYL) and 20 young adults without lymphedema (GY); 40 elderly women, 20 elderly women with lymphedema (GEL) and 20 elderly women without lymphedema (GE). Mini Balance Evaluation Systems Test (Mini BESTest) and Falls Efficacy Scale - International (FES-I) were used. RESULTS: Mini BESTest and FES-I between the groups showed that GE and GEL had a significant difference to GY. Mini BESTest Total and Time Up and Go TUG-Double Task showed that GE has a significant difference to GYL, with GE and GEL having lower scores. Moderate negative correlation in the GEL between FES-I and Mini BESTest. In the age correlation between the Mini BESTest, FES-I, TUG, and double task TUG, a moderate positive correlation was observed for TUG. GEL showed a moderate positive correlation for FES-I and double-task TUG, strong for TUG, and moderate negative correlation with Mini BESTest. Correlation of the volume difference between the limb affected and not affected by lymphedema and the FES-I, Mini BESTest, TUG, and TUG double task, GYL showed moderate negative correlation for TUG. CONCLUSION: Age and lymphedema influenced the dynamic postural balance of women undergoing breast cancer treatment.

Trends in indications and outcomes of liver transplantation in Canada: A multicenter retrospective study.

The liver transplantation (LT) landscape is continuously evolving. We sought to evaluate trends in indications for LT in Canada and the impact of primary liver disease on post-LT outcomes using a national transplant registry. Adult patients who underwent a primary LT between 2000 and 2018 were retrospectively identified in the Canadian Organ Replacement Registry. Outcomes included post-LT patient and graft survival. A total of 5,722 LTs were identified. The number of LT per year increased from 251 in 2000 to 349 in 2018. The proportion of patients transplanted for HCV decreased from 31.5% in 2000 to 3.4% in 2018. In contrast, the percentage of transplants for HCC increased from 2.3% in 2000 to 32.4% in 2018, and those performed for NASH increased from 0.4% in 2005 to 12.6% in 2018. Year of transplant (per 1 year) was protective for both patient (HR:0.96,95%CI:0.94-0.97; P < 0.001) and graft survival (HR:0.97, 95%CI: 0.96-0.99; P = 0.001). Post-LT outcomes have improved over time in this nationwide analysis spanning 18 years. Moreover, trends in the indications for LT have changed, with HCC becoming the leading etiology. The decrease in the proportion of HCV patients and increase in those with NASH has implications on the evolving management of LT patients.

Body postural realignment in the first 2 months after orthognathic surgery.

INTRODUCTION: This study aimed to assess the static posture in patients with Angle Class II and III malocclusions in the first 2 months after orthognathic surgery. METHODS: This was a longitudinal observational study. Eligible participants were adult patients who had an indication of orthognathic surgery (bilateral sagittal split osteotomy of the maxilla and/or mandible, can be associated or not with genioplasty). Thirty-five patients were evaluated from the orthognathic surgery group (OSG) and control group (CG). Measurements in OSG were performed at 3 time points: preoperative orthognathic surgery (P0), first postoperative month (P1), and second postoperative month (P2). Static posture was evaluated using the PostureScreen Mobile (PostureCo Inc, Trinity, Fla) application in 4 views. RESULTS: Patients with Angle Class II malocclusion in the OSG evidenced a tendency to a left hip translation at P1 with a significant difference at P2 in the anterior view (P = 0.052). In the right lateral view, patients with Angle Class II malocclusion in the OSG at P1 presented an accentuated anterior shoulder translation when compared with CG (P <0.001). At P1, patients with Angle Class II malocclusion in the OSG showed a significant anterior knee translation compared with the CG and OSG at P0 and P2 (P <0.001 for all). Patients in the OSG with Angle Class III malocclusion presented an average posterior head translation in the right lateral view at P1 when compared with those in the CG and OSG at P0, who presented an anterior translation (P = 0.0008). CONCLUSIONS: These findings suggest a realignment of static posture in the first 2 months after orthognathic surgery.

Anterior Pedicled Lateral Nasal Wall Flap for Endonasal Lining: A Radiologic and Anatomical Study.

OBJECTIVES/HYPOTHESIS: The objective of this radiological/anatomical study was to evaluate the feasibility of a new endoscopic technique that uses the anterior pedicled lateral nasal flap (APLNW) for the endonasal lining in complex nasal reconstructions. STUDY DESIGN: An anatomical study was performed on 20 nasal fossae of cadaverous specimens to measure the area and lengths of the anterior pedicled nasal lateral wall flap. In addition, a radiological analysis with computed tomography was performed in 150 nostrils to determine the potential donor of the simple and extended flap in the nasal fossa floor. Complex nasal reconstruction with nasofrontal flap and internal lining using the lateral wall pedicled flap was performed in 3 patients. RESULTS: Complete reconstruction for the inner lining of the nasal tip and lateral nasal wall was achieved in the cadaveric study (10 specimens). The surface areas of the simple and extended APLNW flaps were 7.53 (standard deviation [SD] 1.25) cm2 and 24.6 (SD 3.14) cm2 , respectively. Using computed tomography scans, we determined that to reconstruct defects secondary to full-thickness nasal defects, the APLNW flap surface for the simple and extended versions was 7.90 (SD 1.68) cm2 and 23.64 (SD 4.7) cm2 . We present one case were the APLNW flap was used. CONCLUSIONS: The simple or expanded APLNW flap represents a feasible option to reconstruct the internal lining in complex nasal reconstruction. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E1462-E1467, 2021.

Significados en torno a la experiencia de someterse a una segunda intervención quirúrgica para bajar de peso / MEANING ABOUT THE EXPERIENCE OF SUBMITTING A SECOND SURGICAL INTERVENTION TO LOSE WEIGHT

Diversos motivos inciden en que los pacientes se sometan a cirugía bariátrica para hacer frente a la obesidad. Pese a ser el procedimiento más eficaz contra el exceso de peso, existe una alta tasa de pacientes que después de la cirugía, recuperan un porcentaje importante del peso perdido. Esta re-ganancia de peso genera consecuencias médicas, físicas y psicológico-emocionales; y en muchos casos lleva a que los pacientes vuelvan a someterse a intervenciones quirúrgicas con el objetivo de reactivar la pérdida de peso. No obstante, las re-operaciones no suelen tener la misma eficacia en términos de la pérdida de peso y su mantención. Esta investigación se centra en los significados psicológicos de la experiencia de someterse a más de una intervención quirúrgica para perder peso, con el objetivo de comprender lo que implica este proceso para los pacientes, así como también las repercusiones que trae consigo someterse a más de una intervención de este tipo. La metodología que se utilizó fue cualitativa con un enfoque desde la Teoría Fundamentada y con un alcance descriptivo para comprender lo que deben vivir estos pacientes. Para llevar a cabo esta investigación, se realizaron entrevistas semi-estructuradas a cuatro mujeres y un hombre, quienes previamente se habían sometido a una intervención quirúrgica para perder peso, y luego de unos años y de haber recuperado el peso perdido se sometieron a una cirugía bariátrica. La elección de la segunda intervención se asoció a la creencia que la recuperación de peso se debió principalmente a la técnica de la primera intervención, evaluación que cambia hacia una percepción de bajo control en la alimentación, tras la re-ganancia de peso post-segunda intervención. Se observa niveles importantes de frustración tras esta segunda re-ganancia.

There are several reasons why patients choose to undergo bariatric surgery to cope with obesity. Despite being the most effective procedure against excess weight, there is a high rate of patients who, after surgery, recover a significant percentage of the weight lost. This regain of weight generates medical, physical and psychological-emotional consequences; and in many cases it leads to patients re-undergo surgery with the aim of reactivating weight loss. However, re-operations are usually not as effective in terms of weight loss and weight maintenance. This research focuses on the psychological meanings of a patient's experience of more than one surgical intervention to lose weight, with the aim of understanding what this process implies for patients, as well as the repercussions of obtaining more than one intervention of this type. The specified methodology was qualitative with an approach from the Grounded Theory and with a descriptive scope to understand what these patients must live. To carry out this research, semi-structured interviews were conducted with four women and one man, who had previously undergone surgery to lose weight, and after a few years and having recovered the lost weight, underwent surgery. bariatric The choice of the second intervention was associated with the belief that weight recovery was mainly due to the technique of the first intervention, an evaluation that changes towards a perception of low control in the diet, after the post-weight gain second intervention. Significant levels of frustration are seen after this second regain

Computationally Modeling Electrostatic Binding Energetics in a Crowded, Dynamic Environment: Physical Insights from a Peptide-DNA System.

The cell is a crowded place, and it may be crucial at times to account for the local environment when studying determinants of molecular recognition. In this work, we use continuum electrostatics calculations on snapshots extracted from molecular dynamics simulations to understand how various aspects of a crowded environment affect electrostatic binding energies between the antimicrobial peptide buforin II and DNA. By comparing multiple models for representing crowding, sequentially introducing layers of model complexity for maximum control, we explore how electrostatic binding energetics depend on crowder physical properties, the sampling of the binding partners and crowder molecules, and the treatment of bulk solvent. We show that physical characteristics can combine to create an interplay of competing effects in this highly charged system. For example, increased ionic strength screening due to crowding partially cancels out the reduced solvent screening due to water depletion. We also quantify the effect of crowders' charge distributions on binding energetics. While we focus on electrostatic effects of crowding on binding, we begin to consider nonpolar components as well, and we implement a thermodynamic cycle accounting for both bound and unbound states to show the necessity of adequate crowder sampling in future studies. The insights developed here provide a rich starting point for experiments to further explore these competing effects and, ultimately, to rationally modulate molecular recognition in the complex cellular environment.

Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response.

BACKGROUND: Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined. AIM: To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models. RESULTS: There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage. CONCLUSION: Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.

A simple test to assess the emotional status of smokers.

BACKGROUND AND AIMS: Smokers exhibit a high prevalence of psychological abnormalities, and these factors may contribute to smoking initiation, its maintenance, and quitting difficulties. This study reports the development of a scale aiming at evaluating the emotional status of smokers in face of tobacco. METHODS: Levels of Anxiety, Depression, Perceived Stress, Self-esteem, and Loneliness of 120 smokers (age: 54.6 years; 74 women) were compared with those of 76 nonsmokers (age: 45.5 years; 47 women). Correlations between psychological scores, plus the feature Attachment to Cigarettes, and Fagerström test of nicotine dependence (FTND) counts were explored. Features showing the best correlations with FTND were selected to be part of a 6-item scale called Smoker's Emotional Test (SET). SET scores of this group and of an additional sample of smokers (n = 102; age = 52.6; women = 63) were submitted to psychometric analyses and validation tests. RESULTS: SET showed a structure of two factors, Anxiety/Depression and Attachment to Cigarettes. SET showed significant correlations with FTND (r = 0.418), number of smoked cigarettes (r = 0.299), time to urge for a new cigarette (r = -0.441), and pleasure of smoking (r = 0.346). The internal consistency of SET was higher than that of FTND scores (Cronbach's alpha: respectively .712 and .542). The test-retest reliability of SET was excellent (ICC = 0.944). SET scores higher than four distinguished smokers from nonsmokers with sensitivity of 87.3% and specificity of 92.7%. CONCLUSIONS: SET is a simple instrument that gives an estimative of smoking-related emotional status and may define a new valuable construct of tobacco addiction.

[Escherichia vulneris etiologic agent of septic arthritis in a child]. / Escherichia vulneris como agente etiológico de artritis séptica en una niña.

Escherichia vulneris is a gram-negative bacillus that belongs to the family Enterobacteriaceae, with a questioned pathogenic role. However, it has been confirmed as the cause of wound infections. We report the case of a 12-year-old girl, previously healthy, with a diagnosis of septic arthritis of the right knee, secondary to a spinal lesion. Escherichia vulneris, an unusual etiology of septic arthritis in children, was isolated in the joint fluid. This case is one of the first cases of septic arthritis due to E. vulneris, secondary to a plant-derived foreign body in a child, described in the medical literature. The importance of performing the microbiological study of joint fluid in patients with septic arthritis caused by a foreign body of plant-derived origin is emphasized.