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.

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.

Liquid Ventilation Reconditions Isolated Rat Lungs Following Ischemia-Reperfusion Injury.

Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Lung ischemia-reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate lungs before transplant but has failed to provide significant improvements after IRI. We hypothesized that liquid ventilation (LV) could be utilized for ex vivo lung reconditioning in a rat IRI model. We compared EVLP with LV in an isolated ex vivo rat lung with an aqueous ventilant using quantitative physiological and immunological parameters. We observed improved physiological parameters and mechanical clearance of alveolar macrophages and cytokines halting the propagation of the inflammatory response in IRI. While the wide applicability to large animal or human transplantation have yet to be explored, these findings represent a method for lung reconditioning in the setting of significant IRI that could widen the lung organ donation pool and limit morbidity and mortality associated with ischemia-induced primary graft dysfunction.

Protease inhibitor Camostat Mesyalte blocks wild type SARS-CoV-2 and D614G viral entry in human engineered miniature lungs.

The catastrophic global effects of the SARS-CoV-2 pandemic highlight the need to develop novel therapeutics strategies to prevent and treat viral infections of the respiratory tract. To enable this work, we need scalable, affordable, and physiologically relevant models of the human lung, the primary organ involved in the pathogenesis of COVID-19. To date, most COVID-19 in vitro models rely on platforms such as cell lines and organoids. While 2D and 3D models have provided important insights, human distal lung models that can model epithelial viral uptake have yet to be established. We hypothesized that by leveraging techniques of whole organ engineering and directed differentiation of induced pluripotent stem cells (iPSC) we could model human distal lung epithelium, examine viral infection at the tissue level in real time, and establish a platform for COVID-19 related research ex vivo. In the present study, we used type 2 alveolar epithelial cells (AT2) derived from human iPSCs to repopulate whole rat lung acellular scaffolds and maintained them in extended biomimetic organ culture for 30 days to induce the maturation of distal lung epithelium. We observed emergence of a mixed type 1 and type 2 alveolar epithelial phenotype during tissue formation. When exposing our system to a pseudotyped lentivirus containing the spike of wildtype SARS-CoV-2 and the more virulent D614G, we observed progression of the infection in real time. We then found that the protease inhibitor Camostat Mesyalte significantly reduced viral transfection in distal lung epithelium. In summary, our data show that a mature human distal lung epithelium can serve as a novel moderate throughput research platform to examine viral infection and to evaluate novel therapeutics ex vivo.

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.

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.

Orthotopic Transplantation of Human Bioartificial Lung Grafts in a Porcine Model: A Feasibility Study.

Lung transplantation is the only treatment for end-stage lung disease; however, donor organ shortage and intense immunosuppression limit its broad clinical impact. Bioengineering of lungs with patient-derived cells could overcome these problems. We created bioartificial lungs by seeding human-derived cells onto porcine lung matrices and performed orthotopic transplantation to assess feasibility and in vivo function. Porcine decellularized lung scaffolds were seeded with human airway epithelial cells and human umbilical vein endothelial cells. Following in vitro culture, the bioartificial lungs were orthotopically transplanted into porcine recipients with planned 1-day survival (n = 3). Lungs were assessed with histology and in vivo function. Orthotopic transplantation of cadaveric lungs was performed as control. Engraftment of endothelial and epithelial cells in the grafts were histologically demonstrated. Technically successful orthotopic anastomoses of the vasculatures and airway were achieved in all animals. Perfusion and ventilation of the lung grafts were confirmed intraoperatively. The gas exchange function was evident immediately after transplantation; PO2 gradient between pulmonary artery and vein were 178 ± 153 mm Hg in the bioartificial lung group and 183 ± 117 mm Hg in the control group. At time of evaluation 24 hours after reperfusion, the pulmonary arteries were found to be occluded with thrombus in all bioartificial lungs. Engineering and orthotopic transplantation of bioartificial lungs with human cells were technically feasible in a porcine model. Early gas exchange function was evident. Further progress in optimizing recellularization and maturation of the grafts will be necessary for sustained perfusability and function.

High-Throughput Culture Method of Induced Pluripotent Stem Cell-Derived Alveolar Epithelial Cells.

Lung regeneration is dependent on the availability of progenitor lung cells. Large numbers of self-renewing, patient-specific induced pluripotent stem cell-derived alveolar epithelial cells (iPSC-AECs) are needed to adequately recellularize whole-organ constructs. Prior methods to generate functional iPSC-AECs are not feasible for large-scale cell production. We present a novel protocol to produce iPSC-AECs, which is scalable for whole-organ regeneration. Differentiation of iPSCs was performed with genetically modified iPSCs with fluorescent reporters, which underwent differentiation in a stepwise protocol mimicking lung development. Cells were purified, sorted, and embedded in a liquid Matrigel precursor either to form adherent droplets or to form cell-laden Matrigel spheroids, which were subsequently transferred to spinner flasks with media as floating droplets. After culture, monolayer spheres of iPSC-AECs were isolated to form single cell suspensions. Equal numbers of iPSC-AECs from the two culture conditions were seeded into decellularized lung scaffolds. IPSC-AECs cultured in floating droplets were significantly more proliferative than those in adherent droplets, with significantly higher total cell counts and Ki67 expression. Equivalent expression of the distal lung markers was observed for both culture conditions. Lungs recellularized from both culture groups had similar histological appearance. Media changes took significantly less time with the floating droplet method and was more cost effective. The floating droplet culture method demonstrated enhanced proliferative capacity, stable distal lung epithelial phenotype, and reduced resources compared with prior culture methods. In this study, we provide a means for iPSC-AEC production for regeneration of whole-lung constructs. Impact statement We describe a novel culture method for induced pluripotent stem cell-derived alveolar epithelial cell (AEC) expansion with enhanced proliferative capacity and reduced resource requirements compared with previously described methods. This method is scalable for human whole-lung regeneration bioengineering or could be automated for commercial cell production. This culture method may have implications for the differentiation of type I AECs from type II AECs.

Computational generation of proteins with predetermined three-dimensional shapes using ProteinSolver.

Computational generation of new proteins with a predetermined three-dimensional shape and computational optimization of existing proteins while maintaining their shape are challenging problems in structural biology. Here, we present a protocol that uses ProteinSolver, a pre-trained graph convolutional neural network, to quickly generate thousands of sequences matching a specific protein topology. We describe computational approaches that can be used to evaluate the generated sequences, and we show how select sequences can be validated experimentally. For complete details on the use and execution of this protocol, please refer to Strokach et al. (2020).

Characterization of an elastase-induced emphysema model in immune-deficient rats.

OBJECTIVES: Emphysema affects millions of patients worldwide. Cell transplantation and tissue engineering are promising approaches for the regeneration of gas exchange tissue in vivo. A reproducible and resource-efficient animal model with relevant pathological and physiological features is critical to assess efficacy of novel therapies. Here, we share a method for rapid development of emphysema in an adaptive immune-deficient rat with <5% mortality, which is ideal for high-throughput human cell-based experimentation. METHODS: Porcine pancreatic elastase (PPE) was intratracheally administered to male RNU rats. Rats were monitored for 21 days after which subjects underwent lung computed tomography (CT) scans. Rats were then weighed, intubated and mechanically ventilated to measure dynamic compliance. After sacrifice, lungs were fixed, and histological sections were quantitatively assessed for emphysematous changes. RESULTS: A single instillation of elastase was enough to produce anatomic and physiological evidence of emphysema. Weight change for doses of 16 and 32 units PPE/100 g were significantly lower than controls (P = 0.028 and P = 0.043, respectively). Compliance values for doses of 16 and 32 units PPE/100 g were significantly higher than controls (P = 0.037 and P = 0.006, respectively). Lung hyperlucency was confirmed by CT with mean Hounsfield units for a dose of 32 units PPE/100 g being significantly lower than controls (P < 0.001). The mean linear intersect for doses of 16 and 32 units PPE/100 g were significantly higher than controls (both P < 0.001). All reported P-values are one-sided. CONCLUSIONS: We present an efficient method for emphysema development in immune-deficient rats as a tool to evaluate human biological therapeutics. Changes in dynamic compliance, histology and cross-sectional imaging recapitulate human emphysema.

Fast and Flexible Protein Design Using Deep Graph Neural Networks.

Protein structure and function is determined by the arrangement of the linear sequence of amino acids in 3D space. We show that a deep graph neural network, ProteinSolver, can precisely design sequences that fold into a predetermined shape by phrasing this challenge as a constraint satisfaction problem (CSP), akin to Sudoku puzzles. We trained ProteinSolver on over 70,000,000 real protein sequences corresponding to over 80,000 structures. We show that our method rapidly designs new protein sequences and benchmark them in silico using energy-based scores, molecular dynamics, and structure prediction methods. As a proof-of-principle validation, we use ProteinSolver to generate sequences that match the structure of serum albumin, then synthesize the top-scoring design and validate it in vitro using circular dichroism. ProteinSolver is freely available at http://design.proteinsolver.org and https://gitlab.com/ostrokach/proteinsolver. A record of this paper's transparent peer review process is included in the Supplemental Information.

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.

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.

Long-Term Personalization of an In-Home Socially Assistive Robot for Children With Autism Spectrum Disorders.

Socially assistive robots (SAR) have shown great potential to augment the social and educational development of children with autism spectrum disorders (ASD). As SAR continues to substantiate itself as an effective enhancement to human intervention, researchers have sought to study its longitudinal impacts in real-world environments, including the home. Computational personalization stands out as a central computational challenge as it is necessary to enable SAR systems to adapt to each child's unique and changing needs. Toward that end, we formalized personalization as a hierarchical human robot learning framework (hHRL) consisting of five controllers (disclosure, promise, instruction, feedback, and inquiry) mediated by a meta-controller that utilized reinforcement learning to personalize instruction challenge levels and robot feedback based on each user's unique learning patterns. We instantiated and evaluated the approach in a study with 17 children with ASD, aged 3-7 years old, over month-long interventions in their homes. Our findings demonstrate that the fully autonomous SAR system was able to personalize its instruction and feedback over time to each child's proficiency. As a result, every child participant showed improvements in targeted skills and long-term retention of intervention content. Moreover, all child users were engaged for a majority of the intervention, and their families reported the SAR system to be useful and adaptable. In summary, our results show that autonomous, personalized SAR interventions are both feasible and effective in providing long-term in-home developmental support for children with diverse learning needs.

Trauma, Post-Migration Stress, and Mental Health: A Comparative Analysis of Refugees and Immigrants in the United States.

Numerous studies describe mental health effects of pre-migration trauma and post-resettlement stress among refugees, yet less research examines these associations with non-refugee immigrants. Additionally, few studies assess the prevalence and impact of traumatic experiences after settlement in a new country. Using a U.S.-based representative sample of Asian (n = 1637) and Latino (n = 1620) refugees and immigrants, we investigated how traumatic events prior to and after migration, and post-migration stressors, are associated with mental illness and distress. Pre-migration trauma posed risk across a broad range of psychological outcomes for Asian refugees and Latino immigrants. Deleterious effects of post-migration trauma were notable for both groups of refugees and immigrants. Discrimination, acculturative stress, and family conflict increased risk for disorder and distress across groups in complex ways. Findings highlight the importance of examining trauma and stress at pre- and post-migration phases across migrant populations, including those not labeled as refugees.

Higher Use of Surgery Confers Superior Survival in Stage I Non-Small Cell Lung Cancer.

BACKGROUND: Lobar resection is the gold standard therapy for medically fit patients with stage I non-small cell lung cancer (NSCLC). However, considerable variability exists in the use of surgical therapy. This study tested the hypothesis that center-based variation in the use of surgical therapy affects survival in NSCLC. METHODS: We queried the National Cancer Database for patients with stage I NSCLC. Mixed-effects multivariable models were developed to establish the per-center adjusted rate of surgical therapy. Patients were stratified into quartiles based on the treating center's adjusted rate of surgical therapy. Survival was estimated and then tested by using Kaplan-Meier and the log-rank test. Multivariable Cox proportional hazard models were developed to estimate the effect of rate of surgical therapy on overall survival. RESULTS: A total of 139,802 patients met the criteria. There was wide variation in the per-center rate of surgical resection in the highest (80.8%) versus lowest (41.4%, p < 0.001) quartile. Across cohorts, patients were similar in age (mean 68.8 years in the highest quartile versus 69.7 in the lowest quartile) and Charlson-Deyo Score of 2 or greater (15.1% in the highest quartile versus 14.4% in the lowest quartile). Five-year survival was higher for patients treated at high-use centers (52.7% versus 36.7%, p < 0.001). After adjustment, an adjusted rate of surgical therapy in the lowest 25th percentile was associated with lower survival (adjusted hazard ratio 1.40, 95% confidence interval: 1.37 to 1.40, p < 0.001). CONCLUSIONS: Treatment at a center with a higher rate of surgical therapy confers a considerable survival advantage, even after adjustment for hospital volume, surgical approach, and other confounders. Targeted efforts to improve adherence to guidelines about provision of surgical therapy in early-stage NSCLC may represent a meaningful opportunity to improve outcomes.

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.

On Stable States in a Topologically Driven Protein Folding Model.

Theoretical models of protein folding often make simplifying assumptions that allow analysis, yielding interesting theoretical results. In this article, we study models where folding dynamics is primarily driven by local topological features in an iterative manner. We illustrate the merit of the proposed approach through its ability to simulate realistic protein folding processes even when the sequence content information is reduced to just hydrophobic and polar. We then analyze our models and show that under our simple assumptions, certain structures are inherently unstable, and that determining whether structures can be stable is an [Formula: see text]-hard problem. Interestingly, we find that when our model has only two amino acids, the problem becomes solvable in polynomial time.

The Impact of Hepaticojejunostomy Leaks After Pancreatoduodenectomy: a Devastating Source of Morbidity and Mortality.

INTRODUCTION: Hepaticojejunostomy leaks are less frequent than pancreatic leaks after pancreatoduodenectomy, and the current literature suggests comparable outcomes. The purpose of this study was to determine if the hepaticojejunostomy leak adversely affected patient outcomes. METHODS: Consecutive cases of pancreatoduodenectomy (n = 924) were reviewed at a single high-volume institution over an 8-year period (2006-2014). RESULTS: Pancreaticojejunostomy leaks were identified in 217 (23%) patients and hepaticojejunostomy leaks were identified in 24 patients (3%); combined hepaticojejunostomy/pancreaticojejunostomy leaks were identified in 31 patients (3%). Those with hepaticojejunostomy leaks or combined leaks had a significantly increased risk of morbidity when compared to pancreaticojejunostomy leaks or no leak (54 and 58 vs. 34 and 24%, respectively, p < 0.05). The median length of stay was significantly greater for hepaticojejunostomy leaks or combined leaks when compared to pancreatojejunostomy leaks (17 or 14 vs. 9 days, p = 0.001) and those with no leak (17 or 14 vs. 7 days, p = 0.001). Ninety-day mortality for all patients was 3.6%. Hepaticojejunostomy leaks and combined leaks significantly increased 90-day mortality rate (17 and 32%, respectively, p < 0.05). CONCLUSIONS: Hepaticojejunostomy and combined leaks after pancreatoduodenectomy are rarer than pancreaticojejunostomy leaks; these patients are at a significantly increased risk of major morbidity and mortality.

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.