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The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop‐transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export‐like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300 × 106 (n = 48 [27%]), 1.301 to 1.700 × 106 (n = 46 [26%]), 1.701 to 2.400 × 106 (n = 43 [24%]), and 2.401 to 5.100 × 106 (n = 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P = .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

PURPOSE: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival. METHODS: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range,

PurposeTisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.MethodsWe conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity.ResultsIntent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively.ConclusionCommercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.

Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range,

Chronic insomnia is the most common sleep disorder, occurring in ~32 million people in the United States per annum. Acute insomnia is even more prevalent, affecting nearly half of adults at some point each year. The prevalence of insomnia among primary care patients is even higher. The problem, however, is that most primary care providers do not feel adequately knowledgeable or equipped to treat sleep-related concerns. Many providers have never heard of or have not been trained in cognitive behavioral therapy for insomnia or CBT-I (the first line treatment for insomnia). The focus of the current review is to summarize the factors contributing to why sleep health and insomnia treatment have been mostly neglected, identify how this has contributed to disparities in sleep health among certain groups, particularly racial and ethnic minorities and discuss considerations or potential areas of exploration that may improve access to behavioral sleep health interventions, particularly in primary care.

The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop‐transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export‐like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins. [ABSTRACT FROM AUTHOR]

This article presents the international dataset of cases in which the association of Langerhans cell Histiocytosis (LCH) with other malignancies (AM) was documented occurring at any age before, concurrently or after LCH. These data are mostly derived from previously published manuscripts or from completed case report forms (CRFs) by Histiocyte Society (HS) members or colleagues. In particular, for each case of LCH-AM, the database reports all the available data about clinical and biologic characteristics of the two tumors, as well about treatment and status at follow-up. The AM were categorized as: i) leukemias [acute lymphoblastic or myeloid leukemia (ALL and AML, respectively), other leukemias] and myeloproliferative disorders; ii) lymphomas [Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL)] and iii) solid tumors.A total of 270 LCH-AM cases were documented, of which 116 (43%) occurred among children. After stratification by age at LCH diagnosis, using 18 years as cut-off between children and adults, we here provide details on the clinical characteristics in terms of LCH system involvement and affected organs, as well on the temporal relationship between the LCH and AM diagnoses, including details on the AM malignancy types. In 19 cases the LCH and the corresponding AM occurred in a different age group.The data set is available for future studies in view of new insights of the genetic or environmental determinants of LCH and/or of treatment related subsequent neoplasms.

ABSTRACT: The article presents a case study within the recent renaissance of folkloristic approaches to Old Norse-Icelandic religious history and saga literature. It undertakes a comparative analysis of medieval literary and recent local traditions about the burial of Ǫnundr Wooden-Foot, who was the great-grandfather of Grettir the Strong and an important character in the introductory chapters of Grettis saga. First, the article lays out the different accounts of Ǫnundr’s burial in medieval literature. Second, it contrasts the literary accounts with a broad range of more recent local traditions. Furthermore, it brings the physical topography of Ǫnundr’s alleged burial site into the discussion. The article then uses this ensemble of data to problematise issues such as the relative importance of chronological vs. geographical distance between a narrative and its alleged object, throwing new light on the relevance of recent local traditions for understanding medieval saga accounts. RESUME: Denne artikel præsenterer en case study inden for den folkloristiske tilgang til studiet af oldnordisk og oldislandsk religionshistorie og sagalitteratur. Den byder på en komparativ analyse af litterære middelalderkilder samt nyere, lokale traditioner om begravelsen af Ǫnundr Træfod, som var oldefar til Grettir den Stærke og en vigtig figur i de indledende kapitler af Grettis saga. Først fremstiller artiklen forskellige beretninger om Ǫnundrs begravelse ifølge middelalderlitteraturen. Derpå kontrasteres disse beretninger med en bred vifte af nyere, lokale traditioner. I tillæg diskuteres den konkrete topografi omkring Ǫnundrs påståede gravsted. Derpå bruger artiklen denne samling af data til at problematisere aspekter såsom den kronologiske kontra den geografiske afstand mellem fortællingen og dens genstand. Herved kastes der nyt lys på lokale traditioners relevans i forhold til vores forståelse af sagaberetninger fra middelalderen.

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.

Objective: Between the ages of 12 and 25 the onset of mental disorders typically occurs, and the burden of mental health problems is greatest for this group. Indicated preventive interventions to target individuals with subclinical symptoms to prevent the transition to clinical levels of disorders have gained considerable traction. However, the threshold to seek help appears to be high even when help is needed. Online interventions could offer a solution, especially during the COVID-19 pandemic. This scoping review will present an overview of the recent research of indicated online preventive interventions for youth (12–25 years) experiencing the early stages of mental health complaints with the aim of identifying the nature and extent of the research evidence.Methods: The 5-stage framework by Arksey and O'Malley was used. Academic literature published from 2013 onwards in printed or electronic format was included from Scopus, PsychINFO, and Ovid MEDLINE(R) ALL.Results: The search yielded 11,122 results, with the final selection resulting in inclusion of 30 articles for this review. In total, the articles included 4,950 participants. 26.7% of the selected articles focused on youth between 12 and 25 years. Of the articles 60% did not screen for, nor exclude participants with clinical levels of symptoms. Most studies used a common evidence-based therapy for the disorder-category targeted. More than half of the online interventions included some form of human support. Adherence levels ranged between 27.9 and 98%. The results indicate general effectiveness, usability and acceptability of online indicated preventive interventions. The most commonly used approach was CBT (n = 12 studies). Studies varied in their size, rigor of study, effectiveness and outcome measures. Online interventions with a combination of clinical and peer moderation (n = 3 studies) appear to result in the most stable and highest effect sizes.Conclusion: Online indicated preventive mental health interventions for youth with emerging mental health issues show promise in reducing various mental health complaints, and increasing positive mental health indicators such as well-being and resilience. Additionally, high levels of usability and acceptability were found. However, the included studies show important methodological shortcomings. Also, the research has mainly focused on specific diagnostic categories, meaning there is a lack of transdiagnostic approaches. Finally, clear definitions of- as well as instruments to measure- emerging or subclinical mental health symptoms in youth remain are missing.

More than 20% of allogeneic hematopoietic cell transplantations (HCTs) are performed in children and adolescents at a large number of relatively small centers. Unlike adults, at least one-third of HCTs in children are performed for rare, nonmalignant indications. Clinical trials to improve HCT outcomes in children have been limited by small numbers and these pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has led to the involvement of international collaborative groups. Representatives of the Pediatric Blood and Marrow Transplant Consortium, European Group for Blood and Marrow Transplantation's Pediatric Working Group, International Berlin-Frankfurt-Munster (iBFm) Stem Cell Transplantation Committee, and Children's Oncology Group's Hematopoietic Stem Cell Transplantation Discipline Committee met on October 3, 2012, in Frankfurt, Germany to develop a consensus on the highest priorities in pediatric HCT. In addition, it explored the creation of an international consortium to develop studies focused on HCT in children and adolescents. This meeting led to the creation of an international HCT network, dubbed the Westhafen Intercontinental Group, to develop worldwide priorities and strategies to address pediatric HCT issues. This review outlines the priorities of need as identified by this consensus group.

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAFV600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAFV600E protein are not presented by HLA class I molecules. Given that the BRAFV600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

The contribution analyses how the late medieval Harðar saga uses place-names as literary devices. It proposes that toponyms are employed not only to locate plot elements, but also for purposes of subversion, the dropping of keywords then taken up by the narrative in an often grotesque and ironic fashion, the creation of an (again, typically ironic) subtext, and the evocation of physical topographies and their visual appearance in the context of accounts of travels. Thus, the contribution argues that place-names are a central part of the storyteller’s toolkit which can provide important pointers for how to read the saga. Der Beitrag analysiert, wie die spätmittelalterliche Harðar saga Ortsnamen als literarische Ausdrucksmittel verwendet. Dabei wird vorgeschlagen, dass Toponyme nicht nur herangezogen werden, um die Schauplätze von Elementen der Sagahandlung zu lokalisieren, sondern auch zu Zwecken der Subversion, als insbesondere in ironischer und grotesker Weise verwendete Stichwortgeber für die Entwicklung von einzelnen Episoden der Saga, zur Schaffung eines (erneut typischerweise ironischen) Subtexts, und zur Evozierung des visuellen Erscheinungsbilds der physischen Topographie im Rahmen von Reisebeschreibungen. Damit erweisen sich Ortsnamen als ein zentraler Teil des »Werkzeugkastens« des Erzählers, der für eine Interpretation der Saga wichtige Anhaltspunkte geben kann.

Background:. The integration of oncological surgery with reconstructive techniques has gained popularity in the treatment of breast cancer. oncoplastic reconstruction after partial mastectomy can be performed by the breast surgeon or in cooperation with a consulted plastic surgeon. This study aims to objectively assess the differences in outcomes for partial mastectomy and subsequent oncoplastic reconstruction performed by either general surgery alone or in combination with a plastic and reconstructive surgery team. Methods:. Unilateral oncoplastic breast reconstruction cases were extracted from the National Surgical Quality Improvement Program databases from 2005 to 2017. Outcomes of cases performed by the general surgery team alone were compared with those in which the partial mastectomy was performed by the general surgeon with subsequent reconstruction performed by plastic surgeons. To account for cohort baseline differences, propensity score-matched analysis was performed. Results:. In total, 4,350 patients were included in this study; 3,759 procedures were performed by general surgery alone versus 591 combined with plastic surgery. The analysis of propensity score-matched cohorts, comprising 490 patients each, showed no statistical difference in the risk for postoperative complications when surgery was performed by either of the 2 specialty services. A longer operative time and length of stay were found in the group reconstructed by plastic surgeons. Conclusions:. This study found no significant differences in adverse postoperative outcomes for oncoplastic reconstructions after partial mastectomy between the 2 groups. The data may indicate collaboration between both surgical specialties in oncoplastic breast care was not associated with increased morbidity in these patients.

Background:. Brachial plexus injuries have devastating effects on upper extremity function, with significant pain, psychosocial stress, and reduced quality of life. The aim of this study is to identify socioeconomic disparities in the receipt of brachial plexus repair in the emergent versus elective setting, and in the use of supported services on discharge. Methods:. Analysis of the Healthcare Cost and Utilization Project National Inpatient Sample Database was performed for the years 2009–2014. Adults with brachial plexus injury with or without nerve repair were identified; patient and hospital specific factors were analyzed. Results:. Overall, 6,618 cases of emergent brachial plexus injury were retrieved. Six hundred sixty cases of brachial plexus repair were identified in the emergency and elective settings over the study period. Of the 6,618 injured, 153 (2.3%) underwent nerve surgery during the admission. Patients undergoing repair in the elective setting were more likely to be white males with private insurance. Patients treated in the emergency setting were more likely to be African American and in the lowest income quartile. Significant differences were also seen in supported discharge: more likely males (P < 0.001), >55 years of age (P < 0.001), white (P < 0.001), with government-based insurance (P < 0.001). Conclusions:. There are significant disparities in the timing of brachial plexus surgery. These relate to timing rather than receipt of nerve repair; socioeconomically advantaged individuals with private insurance in the higher income quartiles are more likely to undergo surgery in the elective setting and have a supported discharge.

Abstract Background This study analyzes the surgical outcomes for single setting surgeries involving en-bloc solitary calvarial tumor resection in combination with three-layered reconstruction, presenting a novel planning algorithm. Methods Data were retrieved for all patients undergoing single-stage tumor excision, using our novel three-layered reconstructive approach (duraplasty, cranioplasty, and soft tissue reconstruction) between 2005 and 2017 at a single tertiary hospital center. Patients ≥18 years with a Karnofsky Performance score (KPS) >70 and a life expectancy of > 2 months were included. Patient characteristics, surgical specifics, histological diagnoses, outcomes, and complications were reviewed. Results Eighteen single-staged excisions and three-layered reconstructions were performed. Seven patients presented with primary tumors and 11 patients with metastases. Mean age was 62 years. Mean follow-up time was 39 months. Primary closure was used in 12 of 18 patients, microvascular free flap with skin grafting in 4 of 18, and local advancement or rotational flap in 2 of 18. Two compromised free flaps were revised. There was no flap necrosis, skin graft failure, or wound infection observed in this series. Neurosurgical complications included two cases with seizures, one sublesional intraparenchymal hematoma, one adjacent parenchymal infarct, one case of delayed postradiation cerebrospinal fluid leakage, and one case of subdural hemorrhage. Conclusion En-bloc excision followed by three-layered reconstruction is a feasible and often suitable single-stage technique for complex solitary metastasis or primary calvarial tumors, which historically have been challenging to treat. It can offer an alternative approach to primary and metastatic calvarial tumors other than palliative treatment or hospice care.

Background:. Implicit gender bias may result in lower wages for women, fewer leadership positions, and lower perceived competence. Understanding public and patient gender preferences for plastic surgeons may enable opportunities to address public perceptions. This investigation evaluates public preferences for a plastic surgeon’s gender or demeanor. Methods:. Members of the Amazon Mechanical Turk crowdsourcing platform read 1 of the 8 randomly assigned scenarios describing a hypothetical situation requiring a plastic surgeon to operate on their mother. The scenarios differed only by surgeon gender, surgeon demeanor (“agentic,” traditionally more masculine versus “communal,” traditionally more feminine), or type of surgery. Using a Likert scale, respondents indicated their agreement with 7 statements on surgeon competence, skills, leadership qualities, likeability, respect, trustworthiness, and, ultimately, preference as a surgeon. Independent t tests were used to compare scores. Lower scores indicated a more negative response. Results:. Overall, 341 responses were received: 55.7% were male and 45.5% white. There were no significant differences in any of the 7 characteristics assessed when examining by surgeon gender, only. However, female surgeons with a communal demeanor were perceived as less competent (4.32 versus 4.51, P = 0.018) and less skilled (4.36 versus 4.56, P = 0.019) than agentic female surgeons. Male respondents rated female surgeons lower than male surgeons in terms of competence (P = 0.018), skills (P = 0.034), likeability (P = 0.042), and preferred choice as a surgeon (P = 0.033). Conclusions:. Women plastic surgeons’ demeanor and respondent gender affected perception of certain characteristics. Women plastic surgeons may consider ways to engage with the public to address possible gender role stereotypes.

Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n = 10 and advanced MDS: n = 7) and pediatric controls (n = 10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets.

Background: Bone is the most common organ of involvement in patients with Langerhans cell histiocytosis (LCH), which is often painful and associated with significant morbidity from pathological fractures. Current first-line treatments include chemotherapy and steroids that are effective but often associated with adverse effects, whereas the disease may reactivate despite an initial response to first-line agents. Bisphosphonates are osteoclast inhibitors that have shown to be helpful in treating bone lesions of LCH. To date, there are no large international studies to describe their role in treating bone lesions of LCH. Method: We conducted a multicenter retrospective review of 13 patients with histologically proven LCH, who had received bisphosphonates either at diagnosis or at disease reactivation. Results: Ten patients (77%) had a single system bone disease, and 3 (23%) had bone lesions as part of multisystem disease. Median follow-up time post-bisphosphonate therapy was 4.6 years (range, 0.8 to 8.2 years). Treatment with bisphosphonates was associated with significant pain relief in almost all patients. Twelve (92%) achieved resolution of active bone lesions, and 10 out of them had no active disease for a median of 3.5 years (range, 0.8 to 5 years). One patient did not respond. No major adverse effects were reported in this series. Conclusion: Bisphosphonates are well-tolerated drugs that can significantly improve bone pain and induce remission in active bone LCH. Future prospective studies evaluating the role of bisphosphonates in LCH are warranted.

An aberrant interaction between hematopoietic stem cells and mesenchymal stromal cells has been linked to disease and shown to contribute to the pathophysiology of hematologic malignancies in murine models. Juvenile myelomonocytic leukemia is an aggressive malignant disease affecting young infants. Here we investigated the impact of juvenile myelomonocytic leukemia on mesenchymal stromal cells. Mesenchymal stromal cells were expanded from bone marrow samples of patients at diagnosis (n=9) and after hematopoietic stem cell transplantation (n=7; from 5 patients) and from healthy children (n=10). Cells were characterized by phenotyping, differentiation, gene expression analysis (of controls and samples obtained at diagnosis) and in vitro functional studies assessing immunomodulation and hematopoietic support. Mesenchymal stromal cells from patients did not differ from controls in differentiation capacity nor did they differ in their capacity to support in vitro hematopoiesis. Deep-SAGE sequencing revealed differential mRNA expression in patient-derived samples, including genes encoding proteins involved in immunomodulation and cell-cell interaction. Selected gene expression normalized during remission after successful hematopoietic stem cell transplantation. Whereas natural killer cell activation and peripheral blood mononuclear cell proliferation were not differentially affected, the suppressive effect on monocyte to dendritic cell differentiation was increased by mesenchymal stromal cells obtained at diagnosis, but not at time of remission. This study shows that active juvenile myelomonocytic leukemia affects the immune response-related gene expression and function of mesenchymal stromal cells. In contrast, the differential gene expression of hematopoiesis-related genes could not be supported by functional data. Decreased immune surveillance might contribute to the therapy resistance and progression in juvenile myelomonocytic leukemia.

Chronic graft-versus-host disease (cGvHD) is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD) in vivo models using NOD-SCID il2rγ-/- (NSG) mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs) would lead to cGvHD following cyclophosphamide (CTX) administration and total body irradiation (TBI) in NSG mice. Engraftment was assessed in peripheral blood (PB) and in specific target organs by either flow cytometry or immunohistochemistry (IHC). Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%). The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106) leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.