Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells.

OBJECTIVE: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or ß (TRα/ß). Here, we evaluated the influence of TH in hepatic fibrogenesis. DESIGN: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFß in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. RESULTS: TRα and TRß expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFß-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFß signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. CONCLUSION: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFß signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.

Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors.

Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

Linking Immigrants with Nutrition Knowledge (Project LINK): An Innovative Approach to Improve Cultural Competence in Dietetic Education.

Linking Immigrants with Nutrition Knowledge (Project LINK) was a service-learning cultural competence training programme completed by undergraduate dietetic students enrolled in the University of Saskatchewan's (USASK) nutrition and dietetic programme.This paper evaluates the impact of participation in the programme on students' cultural competence. We conducted a cross-sectional survey and qualitative analysis of reflective essays of 107 participants of Project LINK from 2011 to 2014. Cumulative logistic regression models assessed the impact of the intervention on students' cultural competencies. The Akaike information criterion compared models and Spearman correlation coefficient identified possible correlation among pre- and post-intervention data points. Student reflective essays were analyzed by inductive thematic analysis.All cultural competencies improved comparing pre- and post-participation in Project LINK. Odds of increasing one level of student knowledge were 110 times of that prior to Project LINK. Comparing student competencies before and after Project LINK, the odds of increasing one level of students' skills were six times greater, five times greater for increasing one level of students' ability to interact or encounter, and 2.8 times greater for increasing one level of students' attitude.The results of this study indicate Project LINK has successfully increased cultural competence and underscores the importance of combining opportunities for practical experience in addition to classroom-based training on cultural competence.

Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631.

We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.01%) was: TP1: 25% (±6%) versus 49% (±7%; p = .0009); TP2: 21% (±8%) versus 47% (±7%; p < .0001); and TP3: 22% (±14%) versus 51% (±6%; p = .0178). For KMT2A-germline patients, 3-year EFS was: TP1: 88% (±12%) versus 87% (±5%; p = .73); TP2: 100% versus 88% (±5%; p = .24); and TP3: 100% versus 87% (±5%; p = .53). MRD was a strong independent outcome predictor in KMT2A-rearranged, but not KMT2A-germline infant ALL.

AFX unibody stent graft: Effective and safe for the treatment of severe aorto-iliac occlusive disease.

OBJECTIVES: The primary objective of this study was to determine the primary, assisted primary and secondary patency rates of the Endologix AFX stent-graft in patients considered high risk for open surgery with complex aorto-iliac occlusive disease. The secondary objective was to determine 30-day major adverse cardiovascular and cerebrovascular events. METHODS: A retrospective review was undertaken of clinical records of 38 patients who underwent AFX stent-graft placement for aorto-iliac occlusive disease from 2016 to 2019. Patient data was de-identified and entered into a REDcap secure database. Descriptive statistical analysis (means and standard deviations) and Kaplan-Meier survival curves were created to determine the duration of patency of the AFX stent-graft system. RESULTS: Primary patency rates at 6, 12 and 24 months were 92%, 92% and 84%, respectively. Assisted primary patency rates at these times were 100%, 100% and 93% with secondary patency of 100% maintained throughout. The incidence of 30-day major adverse cardiovascular and cerebrovascular events was 8% and major adverse limb events was 3%. One death unrelated to the AFX device occurred during the study period though outside of the 30-day peri-operative period. CONCLUSIONS: Primary, assisted primary and secondary patency rates of AFX stent-grafts, when used to treat aorto-iliac occlusive disease, are high. This study supports the use of the AFX stent-graft for the endovascular treatment of complex aorto-iliac occlusive disease as an alternative to other endovascular options as well as a safe alternative to open aorto-iliac or aorto-femoral bypass in patients who are at high risk for open procedures.

National Needs Assessment of Utilization of Common Newborn Clinical Decision Support Tools.

OBJECTIVE: Clinical decision support tools (CDSTs) are common in neonatology, but utilization is rarely examined. We examined the utilization of four CDSTs in newborn care. STUDY DESIGN: A 72-field needs assessment was developed. It was distributed to listservs encompassing trainees, nurse practitioners, hospitalists, and attendings. At the conclusion of data collection, responses were downloaded and analyzed. RESULTS: We received 339 fully completed questionnaires. BiliTool and the Early-Onset Sepsis (EOS) tool were used by > 90% of respondents, the Bronchopulmonary Dysplasia tool by 39%, and the Extremely Preterm Birth tool by 72%. Common reasons CDSTs did not impact clinical care included lack of electronic health record integration, lack of confidence in prediction accuracy, and unhelpful predictions. CONCLUSION: From a national sample of neonatal care providers, there is frequent but variable use of four CDSTs. Understanding the factors that contribute to tool utility is vital prior to development and implementation. KEY POINTS: · Clinical decision support tools are common in medicine.. · There is a varied use of neonatal CDST.. · Understanding the use of CDST is vital for future development..

The Process Model of Stigmatized Loss: Identity-Threatened Experiences of Bereaved Mothers.

Despite almost one-third of women suffering from the loss of a baby through miscarriage, stillbirth, or infant loss, it is surprising how little research examines how such loss affects the identity and stigmas experienced by these individuals. Through in-depth, semi-structured interviews with bereaved mothers (in particular, mothers who lost a baby during pregnancy or within one year after birth), this research sheds light on the bereaved mother's experiences after loss. Specifically, this research applies the identity-threat model of stigma to showcase the process of stigmatized loss. Based on our findings, we also introduce the process model of stigmatized loss that can apply to all types of stigmatized loss. Key themes emerged as we explored stigmatized loss discourses. These include situational cues that trigger stigma, identity-based responses that aim to preserve both a baby's and mother's identity, as well as nonvolitional and volitional responses that help restore control and reconstruct identity. Additionally, other themes revolve around positive and negative outcomes stemming from avoiding stigmatized identity activation and identification of triggers that initiate a recursive process through stigmatized baby loss. Importantly, stigma can be perceived as both an identity threat (negative) and an identity confirmation (positive). Findings inform theory and practice alike.

Improving infectious adverse event reporting for children and adolescents enrolled in clinical trials for acute lymphoblastic leukemia: A report from the Children's Oncology Group.

Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.

Anatomical study of the internal carotid venous plexus: new findings with application to skull base surgery.

OBJECTIVE: The venous plexus (internal carotid venous plexus) surrounding the petrous part of the internal carotid artery (ICAp) is said to be one drainage pathway of the cavernous sinus. These veins have many potential clinical implications including iatrogenic hemorrhage during surgical approaches to the skull base and carotid-cavernous fistulas. Because there are few morphological data about this venous plexus at the skull base, this descriptive/quantitative study was performed to elucidate its anatomy. METHODS: Six latex-injected cadaveric heads (twelve sides) were dissected via a superior craniotomy approach in which the ICAp was exposed by drilling away the overlying bone. A venous plexus surrounding parts of the ICAp in all sides was documented along with the positions of its major tributaries and their connections. RESULTS: The veins were most concentrated near the junction of the ICAp and the cavernous part of the internal carotid artery, and usually along the medial and lateral sides of the ICAp. Tributaries included branches joining the basilar venous plexus posteriorly and branches joining the veins surrounding the foramen ovale anteriorly. CONCLUSION: Detailed knowledge of the anatomy of this venous plexus surrounding the ICAp is useful for interpreting imaging of the skull base and valuable for surgeons operating in this part of the cranium.

Advice from Bereaved Parents on Strategies to Heal After Baby Loss.

With close to one in three babies dying between conception and infancy, research examining how to assist bereaved parents after loss is critical. Prior research focuses primarily on a general understanding of the journey post-loss or on a specific strategy that can be pursued to assist in healing but does not adequately provide a holistic examination of post-loss strategies nor is it from firsthand recommendations of bereaved parents. Our research addresses this gap in the literature by identifying the post-loss healing strategies recommended by bereaved parents themselves, thereby informing coping post-loss. To do this, 30 semi-structured interviews were conducted with bereaved mothers. Four themes emerged from our findings: (1) honor the deceased baby, (2) engage in helpful practices, (3) pursue healing now, and (4) embrace the post-loss journey as unique.

Morphologic and molecular analysis of early-onset gastric cancer.

BACKGROUND: Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. METHODS: Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

Targeting myosin 1c inhibits murine hepatic fibrogenesis.

Myosin 1c (Myo1c) is an unconventional myosin that modulates signaling pathways involved in tissue injury and repair. In this study, we observed that Myo1c expression is significantly upregulated in human chronic liver disease such as nonalcoholic steatohepatitis (NASH) and in animal models of liver fibrosis. High throughput data from the GEO-database identified similar Myo1c upregulation in mice and human liver fibrosis. Notably, transforming growth factor-ß1 (TGF-ß1) stimulation to hepatic stellate cells (HSCs), the liver pericyte and key cell type responsible for the deposition of extracellular matrix, upregulates Myo1c expression, whereas genetic depletion or pharmacological inhibition of Myo1c blunted TGF-ß-induced fibrogenic responses, resulting in repression of α-smooth muscle actin (α-SMA) and collagen type I α 1 chain (Col1α1) mRNA. Myo1c deletion also decreased fibrogenic processes such as cell proliferation, wound healing response, and contractility when compared with vehicle-treated HSCs. Importantly, phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) and mothers against decapentaplegic homolog 3 (SMAD3) were significantly blunted upon Myo1c inhibition in GRX cells as well as Myo1c knockout (Myo1c-KO) mouse embryonic fibroblasts (MEFs) upon TGF-ß stimulation. Using the genetic Myo1c-KO mice, we confirmed that Myo1c is critical for fibrogenesis, as Myo1c-KO mice were resistant to carbon tetrachloride (CCl4)-induced liver fibrosis. Histological and immunostaining analysis of liver sections showed that deposition of collagen fibers and α-SMA expression were significantly reduced in Myo1c-KO mice upon liver injury. Collectively, these results demonstrate that Myo1c mediates hepatic fibrogenesis by modulating TGF-ß signaling and suggest that inhibiting this process may have clinical application in treating liver fibrosis.NEW & NOTEWORTHY The incidences of liver fibrosis are growing at a rapid pace and have become one of the leading causes of end-stage liver disease. Although TGF-ß1 is known to play a prominent role in transforming cells to produce excessive extracellular matrix that lead to hepatic fibrosis, the therapies targeting TGF-ß1 have achieved very limited clinical impact. This study highlights motor protein myosin-1c-mediated mechanisms that serve as novel regulators of TGF-ß1 signaling and fibrosis.

High-Fat Diet Drives an Aggressive Pancreatic Cancer Phenotype.

BACKGROUND: Emerging evidence indicates associations between high-fat diet (HFD), metabolic syndrome (MetS), and increased risk of pancreatic cancer. However, individual components of an HFD that increase cancer risk have not been isolated. In addition, a specific pattern of cytokine elevation by which MetS drives pancreatic tumor progression is not well described. We hypothesized that oleic acid (OA), a major component of HFD, would augment pancreatic neoplastic processes. METHODS: An orthotopic pancreatic cancer model with Panc02 cells was used to compare the effect of low-fat diet to OA-based HFD on cancer progression. Tumors were quantitated, analyzed by immunohistochemistry. In addition, serum cytokine levels were quantitated. Proliferation, migration assays, and expression of epithelial-to-mesenchymal transition factors were evaluated on Panc02 and MiaPaCa-2 pancreatic cancer cells cultured in high concentrations of OA. RESULTS: HFD tumor-bearing mice (n = 8) had an 18% weight increase (P < 0.001) and increased tumor burden (P < 0.05) compared with the low-fat diet tumor-bearing group (n = 6). HFD tumors had significantly increased angiogenesis (P < 0.001) and decreased apoptosis (P < 0.05). Serum of HFD mice demonstrated increased levels of glucagon and glucagon-like peptide-1. Two pancreatic cancer cell lines cultured in OA demonstrated significant increases in proliferation (P < 0.001) and a >2.5-fold increase in cell migration (P < 0.001) when treated with OA. Panc02 treated with OA had increased expression of epithelial-to-mesenchymal transition factors SNAI-1 (Snail) and Zeb-1(P < 0.01). CONCLUSIONS: High-fat conditions in vitro and in vivo resulted in an aggressive pancreatic cancer phenotype. Our data support further investigations elucidating molecular pathways augmented by MetS conditions to identify novel therapeutic strategies for pancreatic cancer.

Comprehensive review of the mastoid foramen.

Anatomical variations of the mastoid foramen have been observed to vary in a number of qualities including size, number, and location. These variants have the potential to become problematic during surgical approaches to the posterior cranial fossa and mastoid part of the temporal bone, and should thus be appreciated by the surgeon. Herein, we discuss the mastoid foramen in detail including issues with such foramina that should be known to the neurosurgeon.

Procalcitonin Differs in Children With Infection and Children With Disease Flares in Juvenile Idiopathic Arthritis.

BACKGROUND/OBJECTIVE: Patients with juvenile idiopathic arthritis (JIA) often present with signs and symptoms suggestive of serious bacterial infection (SBI). Procalcitonin (PCT) is a biomarker that is elevated in SBI. We conducted a comparative cohort study to test the hypothesis that PCT levels will differ between active JIA, quiescent JIA, and bacteremic patients and healthy controls. METHODS: From October 2016 to May2018, consecutive children 6 months to 18 years of age with (a) active untreated JIA, (b) quiescent JIA, and (c) healthy elective presurgical candidates were recruited from clinics at a musculoskeletal specialty hospital. Juvenile idiopathic arthritis was defined according to the International League of Associations for Rheumatology criteria. Clinical data and serum samples meeting the same criteria were included from a prior study. Consecutive bacteremic patients were identified over the same period. Procalcitonin and other common measures of inflammation were measured. Descriptive statistics and univariate logistic analyses were performed. RESULTS: Ninety-two study subjects were recruited. Erythrocyte sedimentation rate, C-reactive protein (CRP), and PCT levels were all elevated in bacteremic patients in comparison to the other groups. Erythrocyte sedimentation rate and CRP both had wide ranges that overlapped between groups; however, the PCT concentration was 0.15 µg/mL or greater in 1 of 59 patients with JIA, whereas it was 0.15 µg/mL or less in only 1 bacteremic patient. CONCLUSIONS: Our study indicates that serum erythrocyte sedimentation rate, CRP, and PCT levels are all biomarkers that can be used to distinguish SBI versus active JIA at presentation. However, PCT is the most accurate, with the least overlap between patients with infection and noninfectious inflammatory arthritis. This finding can help clinicians direct therapy.

PROMIS Computer Adaptive Tests and Their Correlation With Disease Activity in Juvenile Idiopathic Arthritis.

BACKGROUND/OBJECTIVE: The importance of patient-reported outcomes, like the Patient-Reported Outcomes Measurement Information System (PROMIS) measures, is increasingly recognized both in clinical care and in research. While "short forms" have been studied in juvenile idiopathic arthritis (JIA), study of PROMIS computer adaptive tests (CATs) in JIA is limited. This cross-sectional study evaluates whether PROMIS CATs correlate with disease activity in patients with JIA. METHODS: A convenience sample of patients with JIA (N = 44) was recruited from a single center. Patients and parents completed pediatric and parent proxy PROMIS CATs. Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) and the Childhood Health Assessment Questionnaire (CHAQ). Correlation of the CAT T scores with disease activity was assessed using Spearman correlation coefficients. RESULTS: Forty-four of 80 eligible subjects (29 patients and 15 parents) completed all or some PROMIS CATs. Pain interference and mobility CATs correlated moderately with JADAS-71. Nearly all correlations with the JADAS-71 were weakened when the patient global was removed. Pain interference, mobility, and fatigue were strongly correlated with the CHAQ. Among parent proxy CATs, only mobility and depressive symptoms correlated strongly with the CHAQ. CONCLUSIONS: Only pain interference and mobility PROMIS CATs showed strong correlation with standard disease activity measures in JIA, and nearly all correlations were weakened when the patient global was removed. Correlations of the CATs with the CHAQ were stronger than correlations with the JADAS-71, indicating that although the CHAQ is no longer routinely used it may be a better measure of health-related quality of life in routine clinical care.

Arthrofibrosis after total knee arthroplasty: patients with keloids at risk.

BACKGROUND: Arthrofibrosis remains one of the leading causes for revision in primary total knee arthroplasty (TKA). Similar in nature to arthrofibrosis, hypertrophic scars and keloid formation are a result of excessive collagen formation. There is paucity in the literature on whether there is an association between keloid formation and the development of arthrofibrosis following TKA. Therefore, the purpose of this study was to utilize a large nationwide database to identify and compare the rates of postoperative complications related to arthrofibrosis after primary TKA in patients with history of hypertrophic scar and keloid disorders versus those without. METHODS: Patient records from 2010 to the second quarter of 2016 were queried from an administrative claims database, comparing rates of arthrofibrosis, manipulation under anesthesia (MUA), lysis of adhesions (LOA), and revision TKA in patients with chart diagnosis of keloids versus those without in patients who underwent primary TKA. Data analysis was performed using R statistical software (R Project for Statistical Computing, Vienna, Austria) utilizing multivariate logistic regression, chi square analysis, or Welch's t- test where appropriate with p values < 0.05 being considered statistically significant. RESULTS: Of 545,875 primary TKAs, 11,461 (2.1%) had a keloid diagnosis at any time point in their record, while 534,414 (97.9%) had not. Patients in the keloid cohort had a significantly higher association with ankylosis within 30 days (OR, 1.7), 90 days (OR, 1.2), 6 months (OR, 1.2), and 1 year (OR, 1.3) following primary TKA. The keloid cohort also had a significantly greater risk of MUA (90-day OR, 1.1; 6-month OR, 1.1; 1-year OR, 1.2) and LOA (90-day OR, 2.2; 6-month OR, 2.0; 1-year OR, 1.9). CONCLUSION: Patients with keloids have increased odds risk of arthrofibrosis following primary TKA. These patients are subsequently at a higher odds risk of undergoing the procedures necessary to treat arthrofibrosis, such as MUA and LOA. Future studies investigating confounding factors such as race, prior surgery, range of motion, and postoperative recovery are needed to confirm the association of keloid diagnosis and arthrofibrosis following primary TKA demonstrated in this study. LEVEL OF EVIDENCE: Level III retrospective comparative study.

Modeling rectal cancer to advance neoadjuvant precision therapy.

Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.

Safety and Benefit of Transesophageal Echocardiography in Liver Transplant Surgery: A Position Paper From the Society for the Advancement of Transplant Anesthesia (SATA).

More anesthesiologists are routinely using transesophageal echocardiography (TEE) during liver transplant surgery, but the effects on patient outcome are unknown. Transplant anesthesiologists are therefore uncertain if they should undergo additional training and adopt TEE. In response to these clinical questions, the Society for the Advancement of Transplant Anesthesia appointed experts in liver transplantation and who are certified in TEE to evaluate all available published evidence on the topic. The aim was to produce a summary with greater explanatory power than individual reports to guide transplant anesthesiologists in their decision to use TEE. An exhaustive search recovered 51 articles of uncontrolled clinical observations. Topics chosen for this study were effectiveness and safety because they were a major or minor topic in all articles. The pattern of clinical use was a common topic and was included to provide contextual information. Summarized observations showed effectiveness as the ability to make a new and unexpected diagnosis and to direct the choice of clinical management. These were reported in each stage of liver transplant surgery. There were observations that TEE facilitated rapid diagnosis of life-threatening conditions difficult to identify with other types of monitoring commonly used in the operating room. Real-time diagnosis by TEE images made anesthesiologists confident in their choice of interventions, especially those with a high risk of complications such as use of anticoagulants for intracardiac thrombosis. The summarized observations in this systematic review suggest that TEE is an effective form of monitoring with a safety profile similar to that in cardiac surgery patients.

Burnout and resilience among Canadian palliative care physicians.

BACKGROUND: Physicians experience high rates of burnout, which may negatively impact patient care. Palliative care is an emotionally demanding specialty with high burnout rates reported in previous studies from other countries. We aimed to estimate the prevalence of burnout and degree of resilience among Canadian palliative care physicians and examine their associations with demographic and workplace factors in a national survey. METHODS: Physician members of the Canadian Society of Palliative Care Physicians and Société Québécoise des Médecins de Soins Palliatifs were invited to participate in an electronic survey about their demographic and practice arrangements and complete the Maslach Burnout Inventory for Medical Professionals (MBI-HSS (MP)), and Connor-Davidson Resilience Scale (CD-RISC). The association of categorical demographic and practice variables was examined in relation to burnout status, as defined by MBI-HSS (MP) score. In addition to bivariable analyses, a multivariable logistic regression analysis, reporting odds ratios (OR), was conducted. Mean CD-RISC score differences were examined in multivariable linear regression analysis. RESULTS: One hundred sixty five members (29%) completed the survey. On the MBI-HSS (MP), 36.4% of respondents reported high emotional exhaustion (EE), 15.1% reported high depersonalization (DP), and 7.9% reported low personal accomplishment (PA). Overall, 38.2% of respondents reported a high degree of burnout, based on having high EE or high DP. Median CD-RISC resilience score was 74, which falls in the 25th percentile of normative population. Age over 60 (OR = 0.05; CI, 0.01-0.38), compared to age ≤ 40, was independently associated with lower burnout. Mean CD-RISC resilience scores were lower in association with the presence of high burnout than when burnout was low (67.5 ± 11.8 vs 77.4 ± 11.2, respectively, p < 0.0001). Increased mean CD-RISC score differences (higher resilience) of 7.77 (95% CI, 1.97-13.57), 5.54 (CI, 0.81-10.28), and 8.26 (CI, 1.96-14.57) occurred in association with age > 60 as compared to ≤40, a predominantly palliative care focussed practice, and > 60 h worked per week as compared to ≤40 h worked, respectively. CONCLUSIONS: One in three Canadian palliative care physicians demonstrate a high degree of burnout. Burnout prevention may benefit from increasing resilience skills on an individual level while also implementing systematic workplace interventions across organizational levels.