Peripheral Inflammation Links with the Severity of Clinical Phenotype in Spinocerebellar Ataxia 2.

BACKGROUND: The role of peripheral inflammation in spinocerebellar ataxia type 2 (SCA2) is unknown. OBJECTIVE: The objective of this study was to identify peripheral inflammation biomarkers and their relationship with the clinical and molecular features. METHODS: Blood cell count-derived inflammatory indices were measured in 39 SCA2 subjects and their matched controls. Clinical scores of ataxia, nonataxia, and cognitive dysfunction were assessed. RESULTS: The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the Systemic Inflammation Index (SII), and the Aggregate Index of Systemic Inflammation (AISI) were significantly increased in SCA2 subjects compared with controls. The increases in PLR, SII, and AISI were even observed in preclinical carriers. NLR, PLR, and SII were correlated with the Scale for the Assessment and Rating of Ataxia speech item score rather than with the total score. The NLR and SII were correlated with the nonataxia and the cognitive scores. CONCLUSIONS: Peripheral inflammatory indices are biomarkers in SCA2, which may help to design future immunomodulatory trials and advance our understanding of the disease. © 2023 International Parkinson and Movement Disorder Society.

Lung Transplantation After Ex Vivo Lung Perfusion Early Outcomes From a US National Registry.

OBJECTIVE: The objective of this study was to examine early lung transplant outcomes following EVLP using a large national transplant registry. SUMMARY OF BACKGROUND DATA: Lung transplantation in the United States continues to be constrained by a limited supply of donor organs. EVLP has the potential to significantly increase the available pool of donor lung allografts through the reconditioning of "marginal" organs. METHODS: The united network for organ sharing registry was queried for all adults (age ≥18) who underwent first-time lung transplantation between March 2018 (when united network for organ sharing began collecting confirmed donor EVLP status) and June 2019. Transplants were stratified by EVLP use. The primary outcome was short-term survival and secondary outcomes included acute rejection before discharge and need for extracorpo-real membrane oxygenation support post-transplant. RESULTS: A total of 3334 recipients met inclusion criteria including 155 (5%) and 3179 (95%) who did and did not receive allografts that had undergone EVLP, respectively. On unadjusted descriptive analysis, EVLP and non-EVLP cohorts had similar 180-day survival (92% vs 92%, P = 0.9). EVLP use was associated with a similar rate of acute rejection (13% vs 9%, P = 0.08) but increased rate of early extracorporeal membrane oxygenation use (12% vs 7%, P = 0.04). After adjustment, EVLP use was not associated with significantly increased mortality (adjusted hazard ratio 0.99, 95% confidence interval 0.62-1.58) or acute rejection (adjusted odds ratio 0.89, 95% confidence interval 0.40-1.97) compared to non-EVLP use. CONCLUSIONS: In the largest national series of EVLP lung transplant recipients, EVLP is associated with early recipient outcomes comparable to that of non-EVLP recipients with similar baseline characteristics. Longer term follow-up data is needed to further assess the impact of EVLP on post-lung transplant outcomes.

Fast and flexible coarse-grained prediction of protein folding routes using ensemble modeling and evolutionary sequence variation.

MOTIVATION: Protein folding is a dynamic process through which polypeptide chains reach their native 3D structures. Although the importance of this mechanism is widely acknowledged, very few high-throughput computational methods have been developed to study it. RESULTS: In this paper, we report a computational platform named P3Fold that combines statistical and evolutionary information for predicting and analyzing protein folding routes. P3Fold uses coarse-grained modeling and efficient combinatorial schemes to predict residue contacts and evaluate the folding routes of a protein sequence within minutes or hours. To facilitate access to this technology, we devise graphical representations and implement an interactive web interface that allows end-users to leverage P3Fold predictions. Finally, we use P3Fold to conduct large and short scale experiments on the human proteome that reveal the broad conservation and variations of structural intermediates within protein families. AVAILABILITY AND IMPLEMENTATION: A Web server of P3Fold is freely available at http://csb.cs.mcgill.ca/P3Fold. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A Method to Calculate the Relative Binding Free Energy Differences of α-Helical Stapled Peptides.

Hydrocarbon-stapled peptides are a class of bioactive α-helical ligands developed to target protein-protein interactions. Peptide stapling has benefited from the development of several chemical reactions to modulate their membrane permeability and binding affinity. However, in most current programs, choosing the best stapling positions is usually a trial-and-error process. Here, we develop a protocol to obtain optimal stapling positions computationally. Our method is based on molecular dynamics simulations and free energy calculations with nonequilibrium approaches; here, we predict the binding poses, hot-spot residues, and binding affinity differences of a set of perfluoroarene stapled α-helical peptides of the BIM BH3 peptide to the BCLXL receptor. The prediction of the hot-spot residues within the target peptide through computational alanine scanning anticipates not only the key residues for the receptor-peptide complex formation but also which positions should be avoided when applying the stapling groups. The staple moieties introduce local conformational changes not only in the replaced positions but also on their neighbor residues of the template peptide further affecting their binding behavior. Our approach is successful at rank-ordering the binding affinities of these stapled peptides with respect to the BIM BH3 peptide.

Laparoscopic distal pancreatectomy for pancreatic cancer is safe and effective.

PURPOSE: To compare the short-term and oncologic outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) undergoing laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP). METHODS: Consecutive cases of distal pancreatectomy (DP) (n = 422) were reviewed at a single high-volume institution over a 10-year period (2005-2014). Inclusion criteria consisted of any patient with PDAC by surgical pathology. Ninety-day outcomes were monitored through a prospectively maintained pancreatic resection database. The Social Security Death Index was used for 5-year survival. Two-way statistical analyses were used to compare categories; variance was reported with standard error of the mean; * indicates P value <0.05. RESULTS: Seventy-nine patients underwent DP for PDAC. Thirty-three underwent LDP and 46 ODP. There were no statistical differences in demographics, BMI, and ASA classification. Intraoperative and surgical pathology variables were comparable for LDP versus ODP: operative time (3.9 ± 0.2 vs. 4.2 ± 0.2 h), duct size, gland texture, stump closure, tumor size (3.3 ± 0.3 vs. 4.0 ± 0.4 cm), lymph node harvest (14.5 ± 1.1 vs. 17.5 ± 1.2), tumor stage (see table), and negative surgical margins (77 vs. 87%). Patients who underwent LDP experienced lower blood loss (310 ± 68 vs. 597 ± 95 ml; P = 0.016*) and required fewer transfusions (0 vs. 13; P = 0.0008*). Patients who underwent LDP had fewer positive lymph nodes (0.8 ± 0.2 vs. 1.6 ± 0.3; P = 0.04*) and a lower incidence of type C pancreatic fistula (0 vs. 13%; P = 0.03*). Median follow-up for all patients was 11.4 months. Long-term oncologic outcomes revealed similar outcomes including distant or local recurrence (30 vs. 52%; P = 0.05) and median survival (18 vs. 15 months), as well as 1-year (73 vs. 59%), 3-year (22 vs. 21%), and 5-year (20 vs. 15%) survival for LDP and ODP, respectively. CONCLUSIONS: The results of this series suggest that LDP is a safe surgical approach that is comparable from an oncologic standpoint to ODP for the management of pancreatic adenocarcinoma.

Congenital Pulmonary Vein Stenosis: Encouraging Mid-term Outcome.

Congenital pulmonary vein stenosis (PVS) is a rare entity with limited outcome literature. Multiple interventional approaches have evolved including surgical and catheterization techniques. Our objective is to report our center experience and to compare short-term and mid-term outcomes among these therapeutic modalities. Retrospective study on 23 patients (n = 23) with PVS that required intervention over the last 13 years (2000-2013). Patients were divided into three groups based on type of initial intervention. Of these, 10 (43.5%) had balloon angioplasty, 3 (13.0 %) had surgical dilation, and 10 (43.5%) had surgical marsupialization. Mortality and number of re-interventions were our primary outcomes. Mean age at diagnosis was 10.9 ± 18.4 months. Mean age at initial intervention was 14.5 ± 18.0 months. Mean pre- and post-initial intervention PVS gradients were 9.2 ± 3.4 and 3.4 ± 2.2 mmHg, respectively. Mean survival time and re-intervention-free survival time were 4.8 ± 4.0 and 2.8 ± 3.4 years. No statistical significance was found between the interventions with respect to survival time (p = 0.52) and re-intervention free time (p = 0.78). High initial pre- and post-intervention gradients were significantly associated with re-intervention-free survival (p = 0.01 and p = 0.03, respectively). Patients with bilateral disease have increased mortality (p = 0.01) and decreased 5-year survival (p = 0.009) compared to patients with unilateral disease irrespective of type of intervention. No statistically significant difference in mortality or re-intervention rate was present among these different therapeutic modalities. This study has the longest follow-up so far reported in the current literature (58 months) with overall survival of 78%.

Drug-Resistance Strategies of Early Adolescents in Mexico: Gender Differences in the Influence of Drug Offers and Relationship to the Offeror.

To address increases in substance use among Mexican adolescents, particularly females, US prevention programs are being adapted to the Mexican cultural context. Understanding how responses to substance offers by Mexican adolescents are shaped by gender and relationships to those making offers is an important step in the adaptation process. Using data from Guadalajara, Mexico middle schools (N = 431), this pilot study tested for gender differences in the use of several drug resistance strategies commonly taught in US substance abuse prevention interventions. Results indicated that the drug-resistance strategies of Mexican early adolescents differ by gender, type of substance offered, and the youth's relationship to the offeror. Contrary to previous research on older Mexican adolescents, in this sample, females received more substance offers from age peers than males did, and employed a wider repertoire of drug-resistance strategies, including active strategies such as direct refusals. Gender differences in use of the strategies persisted after controlling for number of offers received. There were gender differences in the conditional effects of greater exposure to offers. A larger volume of alcohol and cigarette offers predicted females' use of direct strategies more strongly than for males, but less strongly than males for marijuana offers. Females' use of drug resistance strategies was more strongly associated with offers from family adults, siblings, and cousins, while males' use of strategies was predicted more strongly by offers from nonfamily adults. Interpretations and prevention implications are discussed in light of changing gender norms in Mexico and gendered patterns of substance use.

Linguistic acculturation and perceptions of quality, access, and discrimination in health care among Latinos in the United States.

This study examined the relationship between acculturation and Latinos' perceptions of health care treatment quality, discrimination, and access to health information. The results of this study indicated that participants who had lower levels of acculturation perceived: 1) greater discrimination in health care treatment; 2) a lower quality of health care treatment; 3) less confidence filling out health related forms; and 4) greater challenges understanding written information about their medical conditions. Participants who identified as immigrants also perceived that their poor quality of medical care was due to their inability to pay and to their race/ethnicity.

TIROSEC: Molecular, Clinical and Histopathological Profile of Papillary Thyroid Carcinoma in a Colombian Cohort.

INTRODUCTION: In Colombia, thyroid cancer ranks among the highest incidences, yet our population lacks studies on its molecular profile. This study aims to characterize clinical, histopathologic and molecular data in a Colombian cohort with papillary thyroid carcinoma (PTC). METHODS: A retrospective review of clinical history, clinicopathologic characteristics, treatment and 5-10-year follow-up for all patients was done. DNA and RNA were extracted from formalin-fixed paraffin-embedded (FFPE) tissue using the Quick-DNA & RNA FFPE Min iPrep kit (Zymo Research). Next-generation sequencing (NGS) analysis was performed with SOPHiA Solid Tumor Solutions kit (SOPHiA GENETICS). Tumor mutation genomic analysis used SOPHiA DDM™ platform, with descriptive analysis reporting frequencies, means and associations via chi-square analysis. RESULTS: Among 231 sequenced patients, mean age at diagnosis was 46 (± 12.35) years, with higher frequency in women (81.82%). Two cases were reclassified as non-invasive follicular thyroid neoplasm (NIFT-P); an NRAS mutation was found in one of them. Predominant histologic subtype was classic PTC (57.64%) followed by tall cell (28.82%). Of the 229 sequenced carcinomas, mutations were identified in 186 cases, including BRAF, IDH1, RAS and PIK3CA. Notable copy number variations (CNVs) were PDGFRA, CDK4 and KIT, with RET being the most frequent gene fusion, including CCDC6-RET in two classic subtype cases. CONCLUSION: This is the first study in Colombia (TIROSEC) to our knowledge that integrates molecular and histopathologic profiles enriching our local comprehension and knowledge of PTC. The identification of target mutations such as BRAF, RET and NTRK fusions holds the potential to guide targeted therapies for tumor recurrence and predict aggressive behavior.

Factors associated with short- versus long-term survival after lung transplant.

OBJECTIVE: A small but growing proportion of lung transplant recipients survive longer than a decade post-transplant. The aim of this study was to identify factors associated with survival beyond a decade after lung transplant. METHODS: We queried the United Network for Organ Sharing registry for adult (age ≥18 years) recipients undergoing first-time isolated lung transplantation between the introduction of the Lung Allocation Score in 2005 and 2009. Recipients were stratified into 3 cohorts: those who survived less than 1 year, 1 to 10 years, and greater than 10 years. Multivariable logistic regression was used to identify factors independently associated with early mortality (<1 year) and long-term (>10 years) survival. RESULTS: A total of 5171 lung transplant recipients and their associated donors met inclusion criteria, including 964 (18.6%) with early mortality, 2843 (55.0%) with intermediate survival, and 1364 (26.3%) long-term survivors. Factors independently associated with early mortality included donor Black race, cigarette use, arterial oxygen partial pressure/fractional inspired oxygen ratio, diabetes, recipient Lung Allocation Score, total bilirubin, extracorporeal membrane oxygenation bridge requirement, single lung transplantation, and annual lung transplant center volume. The only factors independently associated with long-term survival among those who survived at least 1 year was donor age and single lung transplantation. CONCLUSIONS: Of patients undergoing lung transplantation after the implementation of the Lung Allocation Score, approximately one-quarter survived 10 years post-transplant. There was minimal overlap between the factors associated with 1-year and 10-year survival. Of note, the Lung Allocation Score was not associated with long-term survival. Further research is needed to better refine patient selection and optimize management strategies to increase the number of long-term survivors.