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Background: Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans., Case Series: The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation., Results: All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis., Conclusions: This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene ( ACTA2 ) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9 enzymes, deaminases, and gRNAs) to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We then created a murine model of MSMDS that exhibits phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this base editing strategy. Delivery of the customized base editor via an engineered SMC-tropic adeno-associated virus (AAV-PR) vector substantially prolonged survival and rescued systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta, and brain. Together, our optimization of a customized base editor highlights how bespoke CRISPR-Cas enzymes can enhance on-target correction while minimizing bystander edits, culminating in a precise editing approach that may enable a long-lasting treatment for patients with MSMDS., Competing Interests: Competing interests C.L.C., R.M., C.A.M., D.Y.C., B.P.K., M.E.L., and P.L.M. are inventors on a patent application filed by Mass General Brigham (MGB) that describes the development of genome editing technologies to treat MSMDS. C.R.R.A, R.A.S., J.F.dS., and B.P.K. are inventors on additional patents or patent applications filed by MGB that describe genome engineering technologies. S.Q.T. is an inventor on a patent covering CHANGE-seq. S.Q.T. is a member of the scientific advisory board of Prime Medicine and Ensoma. R.M., D.Y.C., C.A.M., B.P.K., M.E.L., and P.M.M received sponsored research support from Angea Biotherapeutics, a company developing gene therapies for vasculopathies. R.M. receives research funding from Amgen and serves as a consultant for Pharmacosmos, Myokardia/BMS, Renovacor, Epizon Pharma, and Third Pole and performs speaker bureaus through Vox Media, all of which are unrelated to the current work. C.A.M. has financial interests in Chameleon Biosciences, Skylark Bio, and Sphere Gene Therapeutics, companies developing Adeno Associated Virus (AAV) vector technologies for gene therapy applications. C.A.M. performs paid consulting work for all three companies. C.A.M.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. B.P.K. is a consultant for EcoR1 capital, Novartis Venture Fund, and Jumble Therapeutics, and is on the scientific advisory boards of Acrigen Biosciences, Life Edit Therapeutics, and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, Inc., a company developing therapeutic CRISPR-Cas technologies for gene editing. B.P.K.’s interests were reviewed and are managed by MGH and MGB in accordance with their conflict-of-interest policies. The other authors declare no competing interests.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34 + hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders., Competing Interests: Declaration of interests A.S. has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine. He is a medical monitor for RCI BMT CSIDE clinical trials, for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. A.S. is the St. Jude Children’s Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to A.S.’s institution. A.S. has no direct financial interest in these therapies. J.S.Y. is an equity owner of Beam Therapeutics. M.J.W. is on advisory boards for Cellarity Inc., Novartis, and Forma Therapeutics. S.Q.T. is a co-inventor on licensed patents for CHANGE-seq and other genome engineering technologies. S.Q.T. is a member of the scientific advisory boards of Prime Medicine and Ensoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastroesophageal reflux disease (GERD) is common in patients who have undergone lung transplantation and is associated with poorer outcomes, but guidelines are lacking to direct management strategies in this population. We assessed the diagnostic yield of impedance metrics compared to pH-metry alone for detecting GERD among lung transplant recipients and evaluated their association with clinical outcomes. We performed a retrospective cohort study of consecutive patients who underwent lung transplantation. Demographic data, acid exposure time (AET), number of reflux episodes, mean nocturnal baseline impedance (MNBI), post-reflux swallowing-induced peristaltic wave index (PSPWI), and clinical outcomes including mortality were collected. The relationship between GERD metrics and clinical outcomes was assessed using Wilcoxon signed-rank test and Fisher's exact test as appropriate. Of the 76 patients studied, 29 (38%) had GERD based on abnormal AET after lung transplantation. One (1.3%) patient had GERD based on elevated number of reflux episodes and abnormal distal MNBI detected GERD in 19 (26%) patients, resulting in 62% sensitivity and 94% specificity. Two (2.6%) patients had normal PSPWI. Patients with low distal MNBI had significantly decreased forced expiratory volume in 1 second (FEV1) at 3-year posttransplant compared to those without low distal MNBI (P = 0.03). Three-year survival was significantly worse among patients with elevated AET (66.7% vs. 89.1%, P = 0.03) but not with low distal MNBI (68.4% vs. 84.3%, P = 0.18). Abnormal AET is more sensitive for detecting GERD than other reflux metrics studied and is associated with survival, suggesting pH-metry alone may be sufficient to guide GERD management after lung transplant., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We describe utilization trends and center volume-outcomes relationship of ER of early stage esophageal cancer using a large hospitalbased registry., Summary of Background Data: ER is increasingly accepted as the preferred treatment for early stage esophageal cancer, however its utilization and the center volume-outcomes relationship in the United States is unknown., Methods: The National Cancer Database was used to identify patients with cT1N0M0 esophageal cancer treated with ER or esophagectomy between 2004 and 2015. Relative frequencies were plotted over time. Restricted cubic splines and maximally selected rank statistics were used to identify an inflection point of center volume and survival., Results: A total of 1136 patients underwent ER and 2829 patients underwent esophagectomy during the study period. Overall utilization of ER, and relative use compared to esophagectomy, increased throughout the study period. Median annualized center ER volume was 1.9 cases per year (interquartile range 0.5-5.8). Multivariable Cox regression showed increasing annualized center volume by 1 case per year was associated with improved survival. Postoperative 30- or 90-day mortality, 30-day readmission, and pathologic T upstaging rates were similar irrespective of center volume., Conclusions: Utilization of ER compared to esophagectomy for stage I esophageal cancer has increased over the past decade, though many individual centers perform fewer than 1 case annually. increasing annualized center volume by one procedure per year was associated with improved survival. increased volume beyond this was not associated with survival benefit. Referral to higher volume centers for treatment of superficial esophageal cancer should be considered., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pediatric osteosarcomas (OS) exhibit extensive genomic instability that has complicated the identification of new targeted therapies. We found the vast majority of 108 patient tumor samples and patient-derived xenografts (PDXs), which display an unusually dilated endoplasmic reticulum (ER), have reduced expression of four COPII vesicle components that trigger aberrant accumulation of procollagen-I protein within the ER. CRISPR activation technology was used to increase the expression of two of these, SAR1A and SEC24D , to physiological levels. This was sufficient to resolve the dilated ER morphology, restore collagen-I secretion, and enhance secretion of some extracellular matrix (ECM) proteins. However, orthotopic xenograft growth was not adversely affected by restoration of only SAR1A and SEC24D . Our studies reveal the mechanism responsible for the dilated ER that is a hallmark characteristic of OS and identify a highly conserved molecular signature for this genetically unstable tumor. Possible relationships of this phenotype to tumorigenesis are discussed., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background: Variability in colon polyp detection impacts patient outcomes. However, the relative influence of physician, patient, and procedure-specific factors on polyp detection is unclear. Therefore, determining how these factors contribute to adenoma and sessile serrated polyp (SSP) detection is important to contextualize measures of colonoscopy quality such as adenoma detection rate and patient outcomes., Aims: To determine the relative contribution of physician, patient, and procedure-specific factors in total polyp, adenoma, and SSP detection rates., Methods: We performed a retrospective study of patients undergoing screening colonoscopy and used a two-level generalized linear mixed regression model to identify factors associated with polyp detection., Results: 7799 average risk screening colonoscopies were performed between July 2016 and October 2017. The patient factor most strongly associated with increased risk of adenoma and sessile serrated polyp detection was white race (OR 1.21, 95% CI 1.05-1.39 and OR 3.17, 95% CI 2.34-4.30, respectively). Adenomatous (OR 1.92, 95% CI 1.04-3.57) and sessile serrated polyps (OR 5.56, 95% CI 1.37-20.0) were more likely to be found during procedures performed with anesthesia care as compared to those with moderate sedation. Physician with a luminal gastrointestinal focus had increased odds of adenoma detection (OR 1.61, 95% CI 1.02-2.50)., Conclusions: In a multi-level model accounting for clustering effects, we identified patient, provider and procedural factors independently influence adenoma and sessile serrated polyp detection. Our findings suggest that to compare polyp detection rates between endoscopists, even at the same institution, risk adjustment by characteristics of the patient population and practice is necessary., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aim: Intubation of the terminal ileum (TI) demonstrates a complete colonoscopy, but its clinical value during screening exams is unknown. We aimed to determine whether TI intubation during screening colonoscopy is associated with colonoscopy quality measures or identifies subclinical pathology., Methods: We performed a retrospective cohort study examining average-risk screening colonoscopies performed at an academic health system between July 2016 and October 2017. Data were extracted from an internal colonoscopy quality registry and the electronic health record. Appropriate statistical tests were used for group comparisons, to correlate TI intubation rate (TIIR) with measures of colonoscopy quality and to examine factors associated with the likelihood of TI intubation., Results: There were 7799 colonoscopies performed with adequate prep quality by 28 gastroenterologists. Most patients were female (56.4%) with a median age of 58. The median TIIR was 37.0%, with significant variability among physicians (2-93%). The detection rates for all polyps, adenomas, and sessile serrated polyps were 62.1%, 45.5%, and 7.2%, respectively, and none correlated with TIIR. Intubation of the TI was associated with significantly longer withdrawal times. In a random 10% sample of cases with TI intubation, no clinically significant pathology was found., Conclusions: There is wide variability in TIIR among endoscopists. Except to provide photodocumentation of exam extent when other images may be difficult to obtain, the lack of correlation between TI intubation and meaningful clinical outcomes together with the associated time costs suggest routine TI intubation during screening colonoscopy may not be warranted., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Gastroesophageal reflux and esophageal dysmotility are common in patients with advanced lung disease and are associated with allograft dysfunction after lung transplantation. The effect of transplantation on reflux and esophageal motility is unclear. The aim of this study was to describe the changes in esophageal function occurring after lung transplantation. A retrospective cohort study was performed on lung transplant candidates evaluated at a tertiary care center between 2015 and 2016. A total of 76 patients who underwent lung transplantation had high-resolution manometry and ambulatory pH-metry before and after transplant. Demographic data, esophageal function testing results, and clinical outcomes such as pulmonary function testing were collected and analyzed using appropriate statistical tests and multivariable regression. Of the 76 patients, 59 (78%) received a bilateral transplant. There was a significant increase in esophageal contractility posttransplant, with an increase in median distal contractile integral from 1470 to 2549 mmHg cm s (P < 0.01). There were 19 patients with Jackhammer esophagus posttransplant, including 15 patients with normal motility pretransplant. Nine patients with ineffective or fragmented peristalsis pretransplant had normal manometry posttransplant. Abnormal pH-metry was observed in 35 (46%) patients pretransplant and 29 (38%) patients posttransplant (P = 0.33). Patients with gastroesophageal reflux disease posttransplant had less improvement in pulmonary function at one year, as measured by forced expiratory volume (P = 0.04). These results demonstrate that esophageal contractility increases significantly after lung transplantation, with an associated change in motility classification. In comparison, gastroesophageal reflux does not worsen, but is associated with worse pulmonary function, posttransplant., (© The Author(s) 2019. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gastroesophageal reflux disease and esophageal dysmotility are prevalent in patients with advanced lung disease and are associated with graft dysfunction following lung transplantation. As a result, many transplant centers perform esophageal function testing as part of the wait-listing process but guidelines for testing in this population are lacking. The aim of this study is to describe whether symptoms of gastroesophageal reflux correlate with abnormal results on pH-metry and high-resolution manometry and can be used to identify those who require testing. We performed a retrospective cohort study of 226 lung transplant candidates referred for high-resolution manometry and pH-metry over a 12-month period in 2015. Demographic data, results of a standard symptom questionnaire and details of esophageal function testing were obtained. Associations between the presence of symptoms and test results were analyzed using Fisher's exact tests and multivariable logistic regression. The most common lung disease diagnosis was interstitial lung disease (N = 131, 58%). Abnormal pH-metry was seen in 116 (51%) patients and the presence of symptoms was significantly associated with an abnormal study (p < 0.01). Dysmotility was found in 98 (43%) patients, with major peristaltic or esophageal outflow disorders in 45 (20%) patients. Symptoms were not correlated with findings on esophageal high-resolution manometry. Fifteen of 25 (60%) asymptomatic patients had an abnormal manometry or pH-metry. These results demonstrate that in patients with advanced lung disease, symptoms of gastroesophageal reflux increase the likelihood of elevated acid exposure on pH-metry but were not associated with dysmotility. Given the proportion of asymptomatic patients with abnormal studies and associated post-transplant risks, a practice of universal high-resolution manometry and pH-metry testing in this population is justifiable.

DNA methylation is an epigenetic regulator of gene expression, and this process has been shown to be disrupted by environmental contaminants. Di-2-(ethylhexyl) phthalate (DEHP) and related phthalate esters have been shown to affect development in early life stages of fish and can alter genomic methylation patterns in vertebrates. The objectives of this study were the following: (1) Describe the expression patterns of the DNA methyltransferase (dnmt) genes during early fathead minnow (FHM) development. These genes are critical for methylation and imprinting during development. (2) Determine the effects of DEHP on the development of FHM larvae [1 and 14 days post-hatch (dph)]. (3) Determine the effect of DEHP on dnmt expression and global methylation status in larval FHM. FHMs were first collected over a developmental time course [1, 3, 5, 6, and 14 days post-fertilization (dpf)] to investigate the expression patterns of five dnmt isoforms. The expression of dnmt1 and dnmt7 was relatively high in embryos at 1 dpf but was variable in expression, and these transcripts were later expressed at a lower level (>3 dpf); dnmt3 was significantly higher in embryos at 1 dpf compared to those at 3 dpf. Dnmt6 showed more of a constitutive pattern of expression during the first 2 weeks of development, and the mRNA levels of dnmt8 were higher in embryos at 5 and 6 dpf compared to those at 1 and 3 dpf, corresponding to the hatching period of the embryos. A waterborne exposure to three concentrations of DEHP (1, 10 and 100 µg/L) was conducted on 1-day FHM embryos for 24 h and on larval fish for 2 weeks, ending at 14 dpf. DEHP did not negatively affect survival, hatch rate, or the expression of dnmt isoforms in FHMs. There were no differences in global cytosine methylation following DEHP treatments in 14 dpf larvae, suggesting that environmentally relevant levels of DEHP may not affect global methylation at this stage of FHM development. However, additional targeted methylome studies are required to determine whether specific gene promoters are differently methylated following exposure to DEHP. This study offers new insight into the roles of the dnmt enzymes during FHM development.

Lung transplantation is an effective and life-prolonging therapy for patients with advanced lung disease (ALD). However, long-term patient survival following lung transplantation is primarily limited by development of an inflammatory and fibrotic process involving the lung allograft known as bronchiolitis obliterans syndrome (BOS). Although the precise cause of BOS remains uncertain and is likely multifactorial, chronic aspiration of gastro-duodenal contents is one possible contributing factor. Multiple small, cross-sectional studies performed over the past two decades have reported a high prevalence of gastro-esophageal reflux disease (GERD) and esophageal dysmotility in the ALD population and several investigations suggest the prevalence may increase following lung transplantation. More recent studies evaluating the direct effect of gastro-duodenal contents on airways have demonstrated a possible biologic link between GERD and BOS. Despite the recent advances in our understanding of BOS, further investigations are needed to establish GERD as a causative factor in its development. This review will discuss the existing literature that has identified an association of GERD with ALD and post-transplant populations, with a focus on recent advances in the field.

Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 μM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Fundamental studies characterizing transcript variability in teleost tissues are needed if molecular endpoints are to be useful for regulatory ecotoxicology. The objectives of this study were to (1) measure transcript variability of steroidogenic enzymes and steroid receptors in the fathead minnow (FHM; Pimephales promelas) ovary to better determine normal variability and the sample sizes needed to detect specific effect sizes and to (2) determine how expression patterns related to higher level endpoints used in some regulatory ecotoxicology programs (e.g. relative gonad size). Estrogen receptor 2b (esr2b) and 5α-reductase a3 (srd5a3) showed high variability in the ovary (CV>1.0) while progesterone receptor (pgr), androgen receptor (ar), and esr2a showed comparatively low variability (CV=~0.5--0.7). Using these estimates, a power analysis revealed that sample sizes for real-time PCR experiments would need to be>20 to detect a 2-fold change for 7 of the transcripts examined; thus many molecular studies conducted in the fish ovary may have insufficient power to detect smaller effects. Two transcripts were correlated to steroid production in the ovary; cyp19a1 levels were positively correlated to in vitro E2 production, while ar levels were negatively correlated to in vitro T production. Thus, these transcripts may be informative molecular surrogates for ovarian steroid production. No transcript investigated showed any correlation to GSI, condition, or body weight/length. Molecular approaches in fish are increasingly used to assess biological impacts of chemical stressors; however additional studies are required that determine how molecular variability relates to higher level biological endpoints., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sex differentiation in organisms is correlated to sex steroid production and receptor signaling pathways involving androgens and estrogens. Timing of expression is critical, and characterization of sensitive windows is needed to determine how environmental stressors may perturb sex differentiation. The objectives of this study were to determine whether genes related to steroid biosynthesis, steroid receptor signaling, and those related to sex differentiation were expressed in pre-differentiated fathead minnow (FHM) embryos, an ecotoxicological model. Transcripts were measured over two weeks (1 day post fertilization (dpf) to 14 days), prior to sex differentiation. The first three time points investigated (1, 3, and 5 dpf) corresponded to the neurula stage, dorsal swim bladder pigmentation, and pre-hatch. The fourth time point (6 dpf) was collected immediately post-hatch and the fifth time point investigated was after 8 days of larval growth (14 dpf). The majority of transcripts investigated, for example estrogen, androgen, and thyroid receptors as well as steroid biosynthesis transcripts, were expressed within the first 72 hours of development; exceptions were star (steroidogenic acute regulatory protein) and cyp19a, which did not have detectable expression until 5 dpf (pre-hatch). Transcripts that increased in relative mRNA abundance over the first two weeks of development included ar, dax1, hsd11b2, hsd17b, cyp19a and thra. This study demonstrates that there is early expression of transcripts related to steroid biosynthesis, steroid receptor signaling, and sex differentiation in pre-hatch FHM embryos. Additional studies are required to determine their relative roles in male and female differentiation during these early developmental periods., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Lung transplantation has become an effective therapeutic option for selected patients with end stage lung disease. Long-term survival is limited by chronic rejection manifest as bronchiolitis obliterans syndrome (BOS). The aspiration of gastric contents has been implicated as a causative or additive factor leading to BOS. Gastroesophageal reflux (GER) and altered foregut motility are common both before and after lung transplantation. Further, the normal defense mechanisms against reflux are impaired in the allograft. Recent studies using biomarkers of aspiration have added to previous association studies to provide a growing body of evidence supporting the link between rejection and GER. Further, the addition of high-resolution manometry (HRM) and impedance technology to characterize bolus transit and the presence and extent of reflux regardless of pH might better identify at-risk patients. Although additional prospective studies are needed, fundoplication appears useful in the prevention or treatment of post-transplant BOS., Purpose: This review will highlight the existing literature on the relationship of gastroesophageal reflux and altered motility to lung transplant rejection, particularly BOS. The article will conclude with a discussion of the evaluation and management of patients undergoing lung transplantation at our center.

With the rising incidence and overall poor prognosis of esophageal adenocarcinoma (EA) there is great interest in furthering our understanding of Barrett's esophagus, the precursor lesion for most cases of EA. The best available evidence from true population-based analysis suggests that the prevalence of Barrett's is 1.6%. In addition, nearly half of the patients with Barrett's are asymptomatic. Several risk factors for development of Barrett's have been identified including gastro-esophageal reflux disease (GERD), central obesity, H. pylori eradication, and male gender. The precise incidence of progression from Barrett's to esophageal adenocarcinoma is not known, but it probably is less than 0.5% per year, and our ability to predict who is at highest risk for progression remains poor. The degree of dysplasia is currently used as a marker for risk of progression to cancer though there is increasing evidence that biomarkers and level of genetic instability may provide better predictive measures. Intensive acid-suppression and COX-2 inhibition are potential strategies to reduce the risk of progression, though definitive studies are needed. Endoscopic surveillance remains the mainstay of management for non-dysplastic and low grade dysplasia Barrett's. The advent of various endoscopic ablative therapies has provided a promising alternative to surgery for Barrett's patients with high grade dysplasia (HGD).

Background: Various preoperative, surgical, and postoperative markers of impaired outcome after orthotopic liver transplantation have been reported, but the influence of intraoperative hemodynamic aberrations has not been thoroughly investigated., Setting: University Hospital.Study design Retrospective cohort analysis., Methods: The authors retrospectively reviewed computerized anesthesia records to determine associations between occurrences of abnormally low or high mean pulmonary artery pressure (MPAP), cardiac output, heart rate, systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure (MAP) with negative surgical outcome. Negative surgical outcome was defined as poor early graft function, primary graft nonfunction, or death attributable to hemodynamic causes., Results: Of 789 patients, 142 (18.0%) had negative surgical outcome. Controlling for the influence of United Network for Organ Sharing (UNOS) status > 1, long operation time, cold donor organ ischemia time, and donor age, the only hemodynamic parameters that were independently associated with negative surgical outcome were MAP < 40 mmHg at least once during the procedure (odds ratio [OR] 2.39, p = 0.0016) and MPAP > 40 mmHg at least 3 times during the procedure (OR 2.2, p = 0.035). The occurrence of MAP < 40 mmHg was temporally associated with donor graft reperfusion. Hepatic artery thromboses were not associated with hemodynamic aberrations., Conclusions: Hemodynamic events are independently associated with adverse outcomes after orthotopic liver transplantation.

The distribution of the enzyme tyrosine aminotransferase in tissues of mink, Mustela vison, was investigated. High levels of enzymatic activity were detected only in liver, documenting the hepatic-specific nature of this enzyme in this species. Further studies disclosed that tyrosine aminotransferase is not absent from non-hepatic tissues because of the lack of the use of a stabilized buffer, sensitivity to temperature, or due to the presence of an inhibitor. Collectively, these results suggest that the enzymatic assay of tyrosine aminotransferase will be unlikely to be an efficacious approach for identifying mink that are heterozygous for the autosomal recessive deficiency of this enzyme that is common in dark mink.

Unlabelled: Previous publications suggest that handwritten anesthesia records are less accurate when compared with computer-generated records, but these studies were limited by small sample size, unblinded study design, and unpaired statistical comparisons. Eighty-one pairs of handwritten and computer-generated neurosurgical anesthesia records were retrospectively compared by using a matched sample design. Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and heart rate (HR) data for each 5-min interval were transcribed from handwritten records. In computerized records, the median of up to 20 values was calculated for SAP, DAP, and HR for each consecutive 5-min epoch. The peak, trough, standard deviation, median, and absolute value of the fractional rate of change between adjacent 5-min epochs were calculated for each case. Pairwise comparisons were performed by using Wilcoxon tests. For SAP, DAP, and HR, the handwritten record peak, standard deviation, and fractional rate of change were less than, and the trough and median were larger than, those in corresponding computer records (all with P: < 0.05, except DAP median and HR peak). Considering together all the recorded measurements from all cases, extreme values were recorded more frequently in computerized records than in the handwritten records., Implications: The discrepancies between handwritten and computerized anesthesia records suggest that some of the data in handwritten records are inaccurate. The potential for inaccuracy should be considered when handwritten records are used as source material for research, quality assurance, and medicolegal purposes.