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Background Individuals with a prior diagnosis of chronic lymphocytic leukaemia (CLL) have a higher risk of developing melanoma and exhibit poorer outcomes than patients without CLL. However, there are limited data reporting the clinicopathological features of melanoma diagnosed in patients with CLL. Aims To review clinicopathological characteristics of patients with coexisting diagnoses of melanoma and CLL. Methods A retrospective review was undertaken for patients with coexisting diagnoses of melanoma and CLL between 2005 and 2015 in 11 centres in the UK and Ireland. Results Overall, 46 cutaneous melanomas identified in 45 patients were included. In 28 (62.2%) patients, melanoma was diagnosed after an existing diagnosis of CLL. In this group, mean Breslow thickness was 2.7 mm (range 0.2–25 mm). Ten patients (35.7%) developed locoregional recurrence and 8 (28.6%) developed distant metastases. Melanoma-specific mortality was 5 of 28 (17.9%) and all-cause mortality was 13 of 28 (46.4%). In 17 patients, melanoma was diagnosed before CLL. In this group, mean BT was 2.9 mm (range 0.4–14 mm); five patients (29.4%) developed locoregional recurrence and three (17.6%) developed distant metastases. Melanoma-specific mortality was 1 of 17 (5.8%) and all-cause mortality was 5 of 17 (29.4%) in this group. Conclusions To our knowledge, this is the first and largest cohort study to report clinicopathological data of coexisting melanoma and CLL in the UK and Ireland. Although the thickness of primary melanoma was not different before or after a CLL diagnosis, melanoma recurrence and melanoma-specific mortality appear to be more common in patients with a prior diagnosis of CLL.

Profound natural killer (NK) cell suppression after cancer surgery is a main driver of metastases and recurrence, for which there is no clinically approved intervention available. Surgical stress is known to cause systemic postoperative changes that negatively modulate NK cell function including the expansion of surgery-induced myeloid-derived suppressor cells (Sx-MDSCs) and a marked reduction in arginine bioavailability. In this study, we determine that Sx-MDSCs regulate systemic arginine levels in the postoperative period and that restoring arginine imbalance after surgery by dietary intake alone was sufficient to significantly reduce surgery-induced metastases in our preclinical murine models. Importantly, the effects of perioperative arginine were dependent upon NK cells. Although perioperative arginine did not prevent immediate NK cell immunoparalysis after surgery, it did accelerate their return to preoperative cytotoxicity, interferon gamma secretion, and activating receptor expression. Finally, in a cohort of patients with colorectal cancer, postoperative arginine levels were shown to correlate with their Sx-MDSC levels. Therefore, this study lends further support for the use of perioperative arginine supplementation by improving NK cell recovery after surgery.

Acute myeloid leukemia (AML) often presents as an oligoclonal disease whereby multiple genetically distinct subclones can coexist within patients. Differences in signaling and drug sensitivity of such subclones complicate treatment and warrant tools to identify them and track disease progression. We previously identified >50 AML-specific plasma membrane (PM) proteins, and 7 of these (CD82, CD97, FLT3, IL1RAP, TIM3, CD25, and CD123) were implemented in routine diagnostics in patients with AML (n = 256) and myelodysplastic syndrome (n = 33). We developed a pipeline termed CombiFlow in which expression data of multiple PM markers is merged, allowing a principal component–based analysis to identify distinctive marker expression profiles and to generate single-cell t-distributed stochastic neighbor embedding landscapes to longitudinally track clonal evolution. Positivity for one or more of the markers after 2 courses of intensive chemotherapy predicted a shorter relapse-free survival, supporting a role for these markers in measurable residual disease (MRD) detection. CombiFlow also allowed the tracking of clonal evolution in paired diagnosis and relapse samples. Extending the panel to 36 AML-specific markers further refined the CombiFlow pipeline. In conclusion, CombiFlow provides a valuable tool in the diagnosis, MRD detection, clonal tracking, and understanding of clonal heterogeneity in AML.

The ObserVational survey of the Epidemiology, tReatment and Care of MigrainE (OVERCOME; United States) study is a multicohort, longitudinal web survey that assesses symptomatology, consulting, diagnosis, treatment, and impact of migraine in the United States.Regularly updating population-based views of migraine in the United States provides a method for assessing the quality of ongoing migraine care and identifying unmet needs.The OVERCOME (US) 2018 migraine cohort involved: (I) creating a demographically representative sample of US adults using quota sampling (n = 97,478), (II) identifying people with active migraine in the past year via a validated migraine diagnostic questionnaire and/or self-reported medical diagnosis of migraine (n = 24,272), and (III) assessing consultation, diagnosis, and treatment of migraine (n = 21,143). The current manuscript evaluated whether those with low frequency episodic migraine (LFEM; 0-3 monthly headache days) differed from other categories on outcomes of interest.Among the migraine cohort (n = 21,143), 19,888 (94.1%) met our International Classification of Headache Disorders, 3rd edition-based case definition of migraine and 12,905 (61.0%) self-reported a medical diagnosis of migraine. Respondents' mean (SD) age was 42.2 (15.0) years; 15,697 (74.2%) were women. Having at least moderate disability was common (n = 8965; 42.4%) and around half (n = 10,783; 51.0%) had consulted a medical professional for migraine care in the past year. Only 4792 (22.7%) of respondents were currently using a triptan. Overall, 8539 (40.4%) were eligible for migraine preventive medication and 3555 (16.8%) were currently using migraine preventive medication. Those with LFEM differed from moderate and high frequency episodic migraine and chronic migraine on nearly all measures of consulting, diagnosis, and treatment.The OVERCOME (US) 2018 cohort revealed slow but steady progress in diagnosis and preventive treatment of migraine. However, despite significant impact among the population, many with migraine have unmet needs related to consulting for migraine, migraine diagnosis, and getting potentially beneficial migraine treatment. Moreover, it demonstrated the heterogeneity and varying unmet needs within episodic migraine.

Background Patients with hematological malignancies (HMs) carry a wide range of chromosomal and molecular abnormalities that impact their prognosis and treatment. Since no current technique can detect all relevant abnormalities, technique(s) are chosen depending on the reason for referral, and abnormalities can be missed. We tested targeted transcriptome sequencing as a single platform to detect all relevant abnormalities and compared it to current techniques. Material and Methods We performed RNA-sequencing of 1385 genes (TruSight RNA Pan-Cancer, Illumina) in bone marrow from 136 patients with a primary diagnosis of HM. We then applied machine learning to expression profile data to perform leukemia classification, a method we named RANKING. Gene fusions for all the genes in the panel were detected, and overexpression of the genes EVI1, CCND1, and BCL2 was quantified. Single nucleotide variants/indels were analyzed in acute myeloid leukemia (AML), myelodysplastic syndrome and patients with acute lymphoblastic leukemia (ALL) using a virtual myeloid (54 genes) or lymphoid panel (72 genes). Results RANKING correctly predicted the leukemia classification of all AML and ALL samples and improved classification in 3 patients. Compared to current methods, only one variant was missed, c.2447A>T in KIT (RT-PCR at 10−4), and BCL2 overexpression was not seen due to a t(14; 18)(q32; q21) in 2% of the cells. Our RNA-sequencing method also identified 6 additional fusion genes and overexpression of CCND1 due to a t(11; 14)(q13; q32) in 2 samples. Conclusions Our combination of targeted RNA-sequencing and data analysis workflow can improve the detection of relevant variants, and expression patterns can assist in establishing HM classification.

The costs and consequences of intimate partner violence (IPV) and sexual violence (SV) are well-documented; however, little is known about how experiences of violence are connected to specific economic insecurities including food, healthcare, and housing insecurity among both men and women. This study investigates (1) the prevalence of food, healthcare, and housing insecurity across gender and racial groups exposed to IPV and SV and (2) associations between exposure to past-year IPV and SV and past-year food, healthcare, and housing insecurity controlling for confounding factors. A cross-sectional survey design was used in this study. Data from 2010 National Intimate Partner and Sexual Violence Survey (NISVS) were analyzed in a nationally representative sample of men ( N = 8079) and women ( N = 9970). Logistic regressions were used to model associations between past-year intimate partner and sexual violence and dependent variables of food, healthcare, and housing insecurity. Analyses were stratified by gender and included control variables of age, income, education, and race/ethnicity. Higher rates of food, housing, and healthcare insecurity were found among men and women of color exposed to violence, particularly among respondents who identified as Black/African American, Latinx, American Indian/Alaska Native, and other racial/ethnic minority groups. For men, IPV and SV was associated with higher odds for experiencing food ( AOR = 2.40, p

Surgery results in severe impairment of natural killer (NK) cell cytotoxicity (NKC) and activity (NKA, cytokine secretion), and a dramatic drop in arginine levels. Postoperative immunosuppression is associated with increased complications and recurrence. Perioperative arginine is reported to reduce postoperative complications. Because arginine modulates NK cell function, this study aimed to determine whether perioperative consumption of arginine-enriched supplements (AES) can improve NK cell function in colorectal cancer (CRC) surgery patients.This study randomized 24 CRC patients to receive the AES or isocaloric/isonitrogenous control supplement three times a day for five days before and after surgery. The AES contained 4.2 g of arginine per dose (12.6 g/day). The primary objective was to determine whether AES improved NKC by 50 % compared with the control group after surgery.On surgery day (SD) 1, NKC was significantly reduced postoperatively in the control group by 50 % (interquartile range [IQR], 36-55 %; p = 0.02) but not in the AES group (25 % reduction; IQR, 28-75 %; p = 0.3). Furthermore, AES had no benefit in terms of NKA or NK cell number. Compliance was much greater preoperatively (91 %) than postoperatively (46 %). However, despite excellent preoperative compliance, arginine was rapidly cleared from the blood within 4 h after consumption and therefore, did not prevent the postoperative drop in arginine.Oral consumption of arginine immunonutrition resulted in a modest improvement in NKC after surgery but was unable to prevent postoperative arginine depletion or the suppression of NKA (ClinicalTrials.gov NCT02987296).

Background: The objective of this work was to perform a critical review of the 2-dimensional and 3-dimensional anatomy of the adult brachial plexus divisions and cords. Methods: Twelve adult brachial plexuses from fresh cadavers were dissected. All were male and aged between 30 and 50 years. Only corpses without brachial plexus injuries were selected. The purpose of the dissections was to identify the origin of the anterior and posterior divisions of the adult brachial plexus in their respective trunks, as well as the positioning of the posterior, lateral, and medial cords. Results: The posterior division of all trunks had a cranial and dorsal origin, while the anterior division of all trunks had a caudal and ventral origin. The posterior cord was the most cranial of all, the lateral cord was central, and the medial cord was the most caudal of all cords. The posterior division of the superior trunk was always between the suprascapular nerve and the anterior division. Conclusions: Brachial plexus diagrams in most textbooks and papers are different from what was found in our dissections. Contrary to the known diagram, the posterior divisions always had a cranial origin in the superior, middle, and inferior trunks.

To create a nonsurgical animal model of osteoarthritis (OA) to evaluate the effects of embolotherapy during geniculate artery embolization (GAE).Fluoroscopy-guided injections of 700 mg of sodium monoiodoacetate were performed into the left stifle in 6 rams. Kinematic data were collected before and after induction. At 10 weeks after induction, Subjects 1 and 4-6 underwent magnetic resonance (MR) imaging with dynamic contrast enhancement (DCE) and Subjects 1, 3, and 4-6 underwent angiography with angiographic scoring to identify regions with greatest disease severity for superselective embolization (75-250-μm microspheres). Target vessel size was measured. At 24 weeks after angiography, DCE-MR imaging, angiography, and euthanasia were performed, and bilateral stifles were harvested. Medial/lateral tibial and femoral condylar, patellar, and synovial samples were cut, preserved, decalcified, and scored using the Osteoarthritis Research Society International criteria. The stifle and synovium Whole-Organ Magnetic Resonance Imaging Score and Multicenter Osteoarthritis Study score were determined. The volume transfer constant (KThe mean gross and microscopic pathological scores were elevated at 38 and 61, respectively. Mean synovitis score was elevated at 9.2. Mean pre-embolization and postembolization angiographic scores were 5 and 3.8, respectively. Mean superior, transverse, and inferior geniculate artery diameters were 3.1 mm ± 1.21, 2.0 mm ± 0.50, and 1.6 mm ± 0.41 mm, respectively. Mean pre-embolization and postembolization cartilage and synovitis scores were elevated at 35.13 and 73.3 and 5.5 and 9.2, respectively. The KA nonsurgical ovine animal knee OA model was created, which allowed the collection of angiographic, histopathological, MR imaging, and kinematic data to study the effects of GAE.

The aims of this study were to evaluate the effect of (1) the different surgical guide designs and (2) implant placement location on the accuracy of fully guided implant placement in single edentulous sites using an in vitro study model. Forty-five partially edentulous models were scanned and divided into 3 groups: group 1, tooth-supported full-arch surgical guide; group 2, 3 different tooth-supported shortened surgical guides (SSGs); and group 3, tooth-supported full-arch surgical guide with a crossbar. All surgical guides were printed and used for fully guided implant placement. A total of 180 implants (60 per group) were placed, and scan bodies were positioned on all models, and postoperative surface scan files (STL) files were obtained. Superimposition of preoperative and postoperative STL files was performed, and the accuracy of implant position was evaluated. The interaction between group and implant location was statistically significant for angle, 3D offset at the base, and at the tip (P < .001). The post-hoc tests showed a statistically significantly higher deviation for group 2 compared to group 3 for all outcomes for implants #4 (P < .05) and #7 (P < .05). There was also a statistically significant difference in all outcomes between groups 1 and 3 for implant #7 (P < .05). All surgical guide designs presented satisfactory performance with clinically acceptable levels of deviation. However, SSGs presented higher accuracy for guided implant placement in a single-edentulous site, whereas a full-arch surgical guide with a crossbar presented superior outcomes when 2 or more guided implants were placed simultaneously.

Therapeutic decision making is often challenging in older AML patients. We collected retrospective data of 355 consecutive AML patients (>= 60 years) who were treated with intensive chemotherapy (IC) (n=155), hypomethylating agents (HMA) (n=83), or best supportive care (BSC) (n=117) between 2002 and 2017. Overall survival (OS) and response rates after therapy were analyzed. Multivariate Cox regression was performed to analyze the impact of different treatment strategies on survival. The median OS was not significantly different between patients treated with IC or HMA (14.9 vs 10.9 months; HR=1.32, p=0.076)), despite a difference in complete remission rate (59% after IC vs 35% after HMA). Patients who received a allogeneic hematopoietic cell transplantation (allo HCT) after treatment with IC or HMA had a significant survival benefit compared to patient who didn't proceed to allo HCT (median OS 65 vs 8 months, respectively, p

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

OBJECTIVES The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base. SUMMARY OF BACKGROUND DATA RBC transfusions are common during surgery and there is evidence of wide variability in practice. METHODS Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines. RESULTS Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (

Measurement of BCR activator of RhoGEF and GTPase -ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL1) mRNA levels by reverse transcription quantitative polymerase chain reaction (RTqPCR) has been critical to treatment protocols and clinical trials in chronic myeloid leukaemia; however, interlaboratory variation remains a significant issue. Reverse transcriptase droplet digital PCR (RTddPCR) has shown potential to improve testing but a large-scale interlaboratory study is required to definitively establish this. In the present study, 10 BCR-ABL1-positive samples with levels ranging from molecular response (MR)(1 center dot 0)-MR5 center dot 0 were tested by 23 laboratories using RTddPCR with the QXDX BCR-ABL %IS kit. A subset of participants tested the samples using RTqPCR. All 23 participants using RTddPCR detected BCR-ABL1 in all samples to MR4 center dot 0. Detection rates for deep-response samples were 95 center dot 7% at MR4 center dot 5, 78 center dot 3% at MR4 center dot 7 and 87 center dot 0% at MR5 center dot 0. Interlaboratory coefficient of variation was indirectly proportional to BCR-ABL1 level ranging from 29 center dot 3% to 69 center dot 0%. Linearity ranged from 0 center dot 9330 to 1 center dot 000 (average 0 center dot 9936). When results were compared for the 11 participants who performed both RTddPCR and RTqPCR, RTddPCR showed a similar limit of detection to RTqPCR with reduced interlaboratory variation and better assay linearity. The ability to detect deep responses with RTddPCR, matched with an improved linearity and reduced interlaboratory variation will allow improved patient management, and is of particular importance for future clinical trials focussed on achieving and maintaining treatment-free remission.

The predictive value of measurable residual disease (MRD) for survival in acute myeloid leukemia (AML) has been firmly established in younger patients treated with intensive chemotherapy. The value of MRD after treatment with decitabine in older patients is unknown. This retrospective analysis included patients ≥60 years of age with AML who received an allogeneic hematopoietic cell transplantation (alloHCT) after treatment with decitabine or intensive chemotherapy. Of the 133 consecutively transplanted patients, 109 had available pretransplantation MRD analyses (by flowcytometry [threshold 0.1%]). Forty patients received decitabine treatment (10-day schedule), and 69 patients received intensive chemotherapy (7 + 3 regimen). Patients who received decitabine were older (median 67 versus 64 years) and more often had MRD (70% versus 38%). OS after alloHCT was comparable in both groups. In the chemotherapy group, MRD-positive patients had a significantly higher relapse probability (subdistribution hazard ratio [sHR] 4.81; P= .0031) and risk of death (HR 2.8; P= .02) compared to MRD-negative patients. In the decitabine group there was no significant association between the presence of MRD and relapse (sHR 0.85; P= .83) or death (HR 0.72; P= .60). Pretransplantation MRD in patients receiving decitabine treatment does not have similar predictive value for relapse or survival in older AML patients receiving an alloHCT, compared to patients receiving intensive chemotherapy.

Erythrocytosis is a common reason for referral to hematology services and is usually secondary in origin. The aim of this study was to assess clinical characteristics and clonal hematopoiesis (CH) in individuals with erythrocytosis in the population-based Lifelines cohort (n = 147 167). Erythrocytosis was defined using strict (World Health Organization [WHO] 2008/British Committee for Standards in Hematology) and wide (WHO 2016) criteria. Individuals with erythrocytosis (strict criteria) and concurrent leukocytosis and/or thrombocytosis were 1:2 matched with individuals with isolated erythrocytosis and analyzed for somatic mutations indicative of CH (≥5% variant allele frequency). One hundred eighty five males (0.3%) and 223 females (0.3%) met the strict criteria, whereas 4868 males (7.6%) and 309 females (0.4%) met the wide criteria. Erythrocytosis, only when defined using strict criteria, was associated with cardiovascular morbidity (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6), cardiovascular mortality (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6), and all-cause mortality (HR, 1.7; 95% CI, 1.2-2.6), independent of conventional risk factors. Mutations were detected in 51 of 133 (38%) evaluable individuals, with comparable frequencies between individuals with and without concurrent cytosis. The JAK2 V617F mutation was observed in 7 of 133 (5.3%) individuals, all having concurrent cytosis. The prevalence of mutations in BCOR/BCORL1 (16%) was high, suggesting aberrant epigenetic regulation. Erythrocytosis with CH was associated with cardiovascular morbidity (OR, 9.1; 95% CI, 1.2-68.4) in a multivariable model. Our data indicate that only when defined using strict criteria erythrocytosis is associated with cardiovascular morbidity (especially in the presence of CH), cardiovascular mortality, and all-cause mortality.

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

Upregulation of the plasma membrane receptor IL1RAP in acute myeloid leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMPlike state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1b resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFkB signaling pathways in IL1RAP-expressing AML cells, but IL1b-induced signaling was dispensable for AML cell proliferation and NFkB-driven survival. IL1RAP was also expressed in stromal cells where IL1b induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1b-induced inflammatory secretome of IL1RAP-expressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an Food and Drug Aministration-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy.

Radiological monitoring is fundamental for compliance with radiological protection policies in the aftermath of radiological events, such as nuclear accidents, terrorism, and out-of-commission uranium mines. An effective strategy for radiation monitoring is to use radiation detectors coupled with Unmanned Aerial Vehicles (UAVs), enabling for quicker surveillance of large areas without involving the need of human presence in the target area. The main aim of this study was to formulate the parameters for a UAV flight strategy in preparation for future field measurements using Geiger&ndash, Muller Counters (GMC) and Cadmium Zinc Telluride (CZT) spectrometers. As a proof of concept, the prepared flight strategy will be used to survey out-of-commission uranium mines in northern Portugal. Procedures to assure the calibration of the CZT and verification of the GMCs were conducted, as well as a sensitivity analysis of the sensors considering different acquisition times, distance to source, and detector response time. This article reports specific parameters, such as UAV distance to ground, time of exposition, speed, and the methodology to perform the identification and calculate the activity of possible radioactive sources. An effective flight strategy is also presented, aiming to use radiation detectors coupled with UAVs to undertake extensive monitoring of areas with enhanced levels of environmental radiation, which is of prime importance due to the lasting hazardous effects of enhanced environmental radiation in the nearby ecosystem and population.

BACKGROUND: Gender disparities in faculty rank have yet to be studied among Canadian physicians. The purpose of this study was to determine whether differences in region, training, research productivity and years in practice explain gender differences in academic promotion among Canadian general surgeons. METHODS: We developed a cross-sectional database of faculty-appointed general surgeons practising in the hospitals affiliated with the 17 universities within the Association of Faculties of Medicine of Canada in 2017 using publicly available directories, university and hospital websites, and direct communication. The data were collected between October and December 2018 and included gender, residency completion year, graduate education, fellowships, number of publications and Scopus h-index; faculty lists and professorship status were verified by program administrators or division heads of their respective divisions. The dependent variable was binary: full professor or not. A combined outcome of associate or full professor was also analyzed. We analyzed all variables in a multivariable logistic regression model. RESULTS: Of the 17 institutions contacted, all but 1 confirmed the faculty lists and professorship status. A total of 405 surgeons were included, of whom 111 (27.4%) were women. Sixty-eight women (61.3%) and 120 men (40.8%) were assistant professors, and 9 women (8.1%) and 75 men (25.5%) were full professors. Although on average women had completed residency more recently than men (15.2 yr v. 19.2 yr, p < 0.001), there was no difference between men and women in the mean number of publications as residents (2.98 v. 2.74, p = 0.7) or per year of practice (3.12 v. 2.09, p = 0.2), number of fellowships pursued (p = 0.7) or graduate education (p = 0.2). In the multivariable model (C-statistic = 0.88), gender remained significantly associated with full professorship (odds ratio 2.79, 95% confidence interval 1.13 to 6.92), along with years in practice (odds ratio 1.61, 95% confidence interval 1.13 to 2.30). INTERPRETATION: After controlling for years in practice, training and research productivity measures, we found that female surgeons with faculty appointments in Canada were less likely than their male counterparts to receive promotion to full professor. Pervasive inequities in systems of promotion must be addressed.

Osteoporosis is prevalent in the United States, with an increasing need for management. In this study, we evaluated the effectiveness of a private orthopaedic practice-based osteoporosis management service (OP MS) in reducing subsequent fracture risk and improving other aspects of osteoporosis management of patients who had sustained fractures.This was a retrospective cohort study using the 100% Medicare data set for Michigan residents with any vertebral; hip, pelvic or femoral; or other nonvertebral fracture during the period of April 1, 2010 to September 30, 2014. Patients who received OP MS care with a follow-up visit within 90 days of the first fracture, and those who did not seek OP MS care but had a physician visit within 90 days of the first fracture, were considered as exposed and unexposed, respectively (first follow-up visit = index date). Eligible patients with continuous enrollment in Medicare Parts A and B for the 90-day pre-index period were followed until the earliest of death, health-plan disenrollment, or study end (December 31, 2014) to evaluate rates of subsequent fracture, osteoporosis medication prescriptions filled, and bone mineral density (BMD) assessments. Health-care costs were evaluated among patients with 12 months of post-index continuous enrollment. Propensity-score matching was used to balance differences in baseline characteristics. Each exposed patient was matched to an unexposed patient within ± 0.01 units of the propensity score. After propensity-score matching, Cox regression examined the hazard ratio (HR) of clinical and economic outcomes in the exposed and unexposed cohorts.Two well-matched cohorts of 1,304 patients each were produced. The exposed cohort had a longer median time to subsequent fracture (998 compared with 743 days; log-rank p = 0.001), a lower risk of subsequent fracture (HR = 0.8; 95% confidence interval [CI] = 0.7 to 0.9), and a higher likelihood of having osteoporosis medication prescriptions filled (HR = 1.7; 95% CI = 1.4 to 2.0) and BMD assessments (HR = 4.3; 95% CI = 3.7 to 5.0). The total 12-month costs ($25,306 compared with $22,896 [USD]; p = 0.082) did not differ significantly between the cohorts.A private orthopaedic practice-based OP MS effectively reduced subsequent fracture risk, likely through coordinated and ongoing comprehensive patient care, without a significant overall higher cost.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Surgical stress results in a significant reduction in natural killer (NK) cell cytotoxicity (NKC), which has been linked to postoperative cancer metastases. However, few studies have measured the impact of surgical stress upon NK cell IFNγ secretion (NKA), a cytokine with essential roles in controlling infection and metastases. The objective of this study was to investigate the impact of surgical stress on NKA in colorectal cancer (CRC) surgery patients. Peripheral blood was collected from CRC surgery patients (n = 42) preoperatively and on postoperative day (POD) 1, 3, 5, 28, and 56. Healthy donor blood (n = 27) was collected for controls. We assessed NKA by production of IFNγ following whole blood cytokine stimulation, NKC by 51Cr-release assay, and immune cell profiling by flow cytometry. The mean reduction in NKA on POD1 compared with baseline was 83.1% (standard deviation 25.2%; confidence interval 75–91), and therefore the study met the primary endpoint of demonstrating a > 75% decrease in a cohort of CRC surgery patients (p

BACKGROUND Over 500 translocations have been identified in acute leukemia. To detect them, most diagnostic laboratories use karyotyping, fluorescent in situ hybridization, and reverse transcription PCR. Targeted locus amplification (TLA), a technique using next-generation sequencing, now allows detection of the translocation partner of a specific gene, regardless of its chromosomal origin. We present a TLA multiplex assay as a potential first-tier screening test for detecting translocations in leukemia diagnostics. METHODS The panel includes 17 genes involved in many translocations present in acute leukemias. Procedures were optimized by using a training set of cell line dilutions and 17 leukemia patient bone marrow samples and validated by using a test set of cell line dilutions and a further 19 patient bone marrow samples. Per gene, we determined if its region was involved in a translocation and, if so, the translocation partner. To balance sensitivity and specificity, we introduced a gray zone showing indeterminate translocation calls needing confirmation. We benchmarked our method against results from the 3 standard diagnostic tests. RESULTS In patient samples passing QC, we achieved a concordance with benchmarking tests of 81% in the training set and 100% in the test set, after confirmation of 4 and nullification of 3 gray zone calls (in total). In cell line dilutions, we detected translocations in 10% aberrant cells at several genetic loci. CONCLUSIONS Multiplex TLA shows promising results as an acute leukemia screening test. It can detect cryptic and other translocations in selected genes. Further optimization may make this assay suitable for diagnostic use.

In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENT Women with mild deficiencies of factor XI (FXI) ( 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

Little is known regarding the research and training expectations faced by modern general surgery graduates interested in pursuing academic surgical careers. In this study, we describe the changing face of the Canadian academic general surgeon by outlining the in-residency research productivity and postresidency clinical and academic training trends over time.Our cross-sectional cohort included Canadian academic general surgeons, defined as those with a university-affiliated appointment as assistant, associate or full professor. Academic surgeons were identified by the Royal College of Physicians and Surgeons of Canada online directory as well as directories of university and hospital websites. Data points included institution, faculty appointment and rank, graduation year, graduate education, fellowship training and research productivity.Our cohort included 417 surgeons from 17 Canadian academic institutions. The majority of surgeons were male (72.9%), had completed at least 1 fellowship (72.9%) and had had some form of supplementary research training (51.8%). Surgeons in the cohort had practised a median of 17 (10–27) years. The mean number of total and first-author publications for the participants in this study has increased consistently each decade before the 1980s (p0.001). The proportion of academic surgeons completing graduate degrees has increased steadily every decade, reaching a peak of 61.5% for surgeons graduating in the 2010s.The Canadian academic surgeon is becoming increasingly productive in research during residency and is pursuing higher levels of graduate education and more fellowships than ever before. These changes probably correspond to an evolving employment and research funding landscape that places tremendous academic pressure on surgical trainees.On en sait peu sur les attentes en matière de recherche et de formation auxquelles doivent aujourd’hui répondre les diplômés en chirurgie générale qui souhaitent poursuivre une carrière professorale dans le domaine. Nous décrivons ici l’évolution du parcours des professeurs de chirurgie générale canadiens à partir des tendances de productivité en recherche durant la résidence et de formation théorique et pratique après la résidence.Nous avons formé une cohorte transversale de professeurs de chirurgie générale adjoints, agrégés et titulaires affiliés à un établissement universitaire canadien à partir du répertoire en ligne du Collège royal des médecins et chirurgiens du Canada ainsi que des répertoires figurant sur les sites Web des universités et des hôpitaux. Les variables examinées comprenaient l’établissement, le poste et le rang occupés, l’année d’obtention du diplôme, les études supérieures, la formation postdoctorale et la productivité en recherche.La cohorte était constituée de 417 chirurgiens représentant 17 établissements universitaires canadiens. La majorité d’entre eux étaient des hommes (72,9 %), avaient effectué au moins 1 stage postdoctoral (72,9 %) et avaient reçu une formation supplémentaire en recherche (51,8 %). Le nombre d’années de pratique médian était de 17 (10 à 27) ans. Le nombre moyen de publications des membres de la cohorte à titre de coauteur et d’auteur principal a augmenté chaque décennie jusqu’aux années 1980 (p0,001). Le pourcentage des professeurs de chirurgie ayant un diplôme d’études supérieures a aussi augmenté de façon constante d’une décennie à l’autre, pour atteindre 61,5 % dans les années 2010.Les professeurs de chirurgie canadiens font de plus en plus de recherchedurant la résidence, sont plus nombreux à poursuivre des études à des niveaux supérieurs et effectuent plus de stages postdoctoraux que jamais. Ces changements s’expliquent probablement par l’évolution du marché de l’emploi et du financement en recherche, 2 facteurs qui exercent une pression énorme sur les chirurgiens en formation.

Ring sideroblasts (RS) emerge as result of aberrant erythroid differentiation leading to excessive mitochondrial iron accumulation, a characteristic feature for myelodysplastic syndromes (MDS) with mutations in the spliceosome gene SF3B1. However, RS can also be observed in patients diagnosed with acute myeloid leukemia (AML). The objective of this study was to characterize RS in patients with AML. Clinically, RS-AML is enriched for ELN adverse risk (55%). In line with this finding, 35% of all cases had complex cytogenetic aberrancies, and TP53 was most recurrently mutated in this cohort (37%), followed by DNMT3A (26%), RUNX1 (25%), TET2 (20%), and ASXL1 (19%). In contrast to RS-MDS, the incidence of SF3B1 mutations was low (8%). Whole-exome sequencing and SNP array analysis on a subset of patients did not uncover a single genetic defect underlying the RS phenotype. Shared genetic defects between erythroblasts and total mononuclear cell fraction indicate common ancestry for the erythroid lineage and the myeloid blast cells in patients with RS-AML. RNA sequencing analysis on CD34+ AML cells revealed differential gene expression between RS-AML and non RS-AML cases, including genes involved in megakaryocyte and erythroid differentiation. Furthermore, several heme metabolism-related genes were found to be upregulated in RS- CD34+ AML cells, as was observed in SF3B1mut MDS. These results demonstrate that although the genetic background of RS-AML differs from that of RS-MDS, they have certain downstream effector pathways in common.

On average 16%-53% of maternal deaths are from postpartum haemorrhage (PPH), with confidence intervals for Eastern Asia reaching beyond 60%. Success in preventing PPH mortality across many large low-resource populations has been fairly limited. Niger's government and an international non-governmental organization (NGO) have developed a model aiming to rapidly reduce primary postpartum haemorrhage mortality, combining relatively new technologies, misoprostol, condom tamponade, and non- inflatable anti-shock garment, with systematic measurement of blood loss and a set of traditional public health tools that constitute the Catalyst Approach to Public Health, with action steps for each phase if haemorrhage occurs. This paper describes each component and testing of the hypothesis that the model can effectively reduce PPH mortality on a national scale. The Niger model is a 'complex intervention' aiming to maximise impact from existing health system resources even in remote areas. The broad applicability of Niger's approach to address a serious global public health problem, and its innovative nature warrant describing the model itself, with results to be published separately. Combining this set of individually proven technologies and a set of organisational tools from disease eradication settings as a single 'complex intervention', has to our knowledge not been described before.

Introduction: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).Materials and methods: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, beta-antithrombin and anti-Xa activities were measured.Results: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R= 0.77) and LMWH (R= 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%.Conclusions: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.

Determine healthcare resource utilization (HCRU) in biologic-naïve initiators of TNF inhibitors (TNFis) associated with their disease activity from a national cohort of rheumatoid arthritis (RA) patients.RA patients were identified at their first TNFi initiation (index date) in the Corrona registry. Patients with age of RA onset18, comorbid psoriasis/psoriatic arthritis, fibromyalgia, or osteoarthritis were excluded. Patients were categorized into disease activity (DA) strata by the lowest level of DA (and sustaining low levels for at least two visits) using the Clinical Disease Activity Index (CDAI) across all visits in Corrona while on a TNFi during 1 year after initiation. Rates of all-cause and RA-related hospitalizations, rheumatologist visits, and joint surgeries while on TNFi therapy were reported and compared across DA levels along with the incidence rate ratio (IRR) adjusted for age, gender, and RA duration using Poisson mixed models.Of 1931 RA patients: 15% achieved sustained remission, 22% remission, 14% sustained low DA, 23% low DA and 27% moderate/high DA (M/HDA). Those in M/HDA had statistically higher rates of hospitalizations (37.3 per 100 patient years (py), 95% CI: 31.6-43.7 and joint surgeries (20.8 per 100 py, 95% CI: 16.6-25.8) compared to the sustained remission cohort, resulting in respective IRRs of 2.3 (p 0.001) and 1.7 (p = 0.046).Many biologic naïve RA patients initiating TNFi failed to achieve sustained remission during a 1 year period while remaining on TNFi therapy. Patients in higher DA levels had higher HCRU rates vs. patients in sustained remission, suggesting that achieving treat-to-target goals would reduce health care expenses.

Background: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, high-risk patients should be identified. The aim of this study was to assess BEP-chemotherapy induced vascular damage and to find risk factors for early vascular events.Patients and methods: A prospective cohort study was performed in (B) EP treated TC patients. Development of venous and arterial vascular events was assessed. Vascular damage markers (von Willebrand factor [vWF], coagulation factor VIII [FVIII], intima media thickness [IMT]) and cardiovascular risk factors were assessed before and until 1 year after chemotherapy. Before start of chemotherapy a vascular fingerprint was estimated. Presence of >= 3 risk factors was defined as high-risk vascular fingerprint: body mass index >25 kg/m(2), current smoking, blood pressure >140/90 mm Hg, total cholesterol >5.1 and/or low-density lipoprotein >2.5 mmol/L or glucose >= 7 mmol/L.Results: Seventy-three patients were included. Eight (11%) developed vascular events (four arterial events, four pulmonary embolisms). vWF and FVIII increased during chemotherapy, especially in patients with vascular events. Sixteen patients (22%) had a high-risk vascular fingerprint before start of chemotherapy. These patients had arterial events more often (3/16 [19%] versus 1/57 [2%]; p = 0.031) and higher vWF levels and IMT.Conclusions: Endothelial activation and upregulation of procoagulant activity seem important mechanisms involved in early (B) EP-chemotherapy-induced vascular events. Before chemotherapy, a quarter already had cardiovascular risk factors. A vascular fingerprint could identify patients at risk for arterial events. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies. (C) 2016 Elsevier Ltd. All rights reserved.

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes. Genes upregulated in H3.3 K27M tumors were enriched for those associated with neural development where H3K27me3 loss released the poised state of apparently bivalent promoters, whereas downregulated genes were enriched for those encoding homeodomain transcription factors.

Describe treatment patterns by disease severity among biologic-treated psoriasis patients.We selected our study cohort in the IQVIA PharMetrics Plus adjudicated claims database linked to Electronic Health Record data from Modernizing Medicine Data Services. Patients were classified as having mild, moderate, or severe psoriasis based on a hierarchy of available severity measures. Patients were followed for 360 days to assess combination therapy, therapy switching and restarting, adherence and persistence.The cohort comprised 2130 biologic-treated patients (mean age: 47.6 years; 45.4% female); 447 (21%) had available disease severity measures. Compared to patients with mild (N = 282) psoriasis, more patients with moderate (N = 116) or severe (N = 49) disease used combination therapy (21.3% vs. 34.5% and 32.7%, respectively), switched therapies (12.1% vs. 19.8% and 22.4%), and discontinued biologics (18.4% vs. 27.6% and 36.7%). Mean adherence was 75% by Medication Possession Ratio (MPR) (73.9%) and Proportion of Days Covered (PDC) (70.2%). Overall, 52.2% had a mean MPR 80%. Mean persistence to biologics was 297.6 days. Persistence and adherence decreased with increasing disease severity.Biologic-treated psoriasis patients had inadequate adherence (i.e., MPR 80%) and modest persistence to biologics, with moderate and severe patients demonstrating lower adherence and persistence than mild patients.

To describe healthcare resource utilization (HCRU) and costs among biologic-treated psoriasis patients in the US, overall and by disease severity.IQVIA PharMetrics Plus administrative claims data were linked with Modernizing Medicine Data Services Electronic Health Record data and used to select adult psoriasis patients between April 1, 2010 and December 31, 2014. Eligible patients were classified by disease severity (mild, moderate, severe) using a hierarchy of available clinical measures. One-year outcomes included all-cause and psoriasis-related outpatient, emergency department, inpatient, and pharmacy HCRU and costs.This study identified 2,130 biologic-treated psoriasis patients: 282 (13%) had mild, 116 (5%) moderate, and 49 (2%) severe disease; 1,683 (79%) could not be classified. The mean age was 47.6 years; 45.4% were female. Relative to mild psoriasis patients, patients with moderate or severe disease had more median all-cause outpatient encounters (28.0 [mild] vs 32.0 [moderate], 36.0 [severe]), more median psoriasis-related outpatient encounters (6.0 [mild] vs 7.5 [moderate], 8.0 [severe]), and a higher proportion of overall claims for medications that were psoriasis-related (28% [mild] vs 37% [moderate], 34% [severe]). Relative to mild psoriasis patients, patients with moderate or severe disease had higher median all-cause total costs ($37.7k [mild] vs $42.3k [moderate], $49.3k [severe]), higher median psoriasis-related total costs ($32.7k [mild] vs $34.9k [moderate], $40.5k [severe]), higher median all-cause pharmacy costs ($33.9k [mild] vs $36.5k [moderate], $36.4k [severe]), and higher median psoriasis-related pharmacy costs ($32.2k [mild] vs $33.9k [moderate], $35.6k [severe]).The assessment of psoriasis disease severity may not have necessarily coincided with the timing of biologic use. The definition of disease severity prevented the assessment of temporality, and may have introduced selection bias.Biologic-treated patients with moderate or severe psoriasis cost the healthcare system more than patients with mild psoriasis, primarily driven by higher pharmacy costs and more outpatient encounters.

High expression of VEGFC predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC-targeting efficacy as an AML therapy using a VEGFC mAb. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30% to 50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for patients with AML.Significance: These findings reveal VEGFC targeting as a promising new differentiation therapy in AML. Cancer Res; 78(20); 5940-8. ©2018 AACR. ispartof: CANCER RESEARCH vol:78 issue:20 pages:5940-5948 ispartof: location:United States status: published

Hereditary antithrombin deficiency is associated with a high incidence of venous thromboembolism (VTE), but VTE risk differs between families. Beta-antithrombin is reported to be the most active isoform of antithrombin in vivo. Whether beta-antithrombin activity and subtypes in antithrombin deficiency have impact on VTE risk has not been investigated outside the proband setting.We performed a retrospective family cohort study to investigate whether subtypes of antithrombin deficiency or beta-antithrombin levels are associated with the risk of first or recurrent VTE.Eighty-one subjects from 21 families were included, of which 52 were antithrombin deficient. Beta-antithrombin levels were decreased in most type I and type IIPE subjects, but normal levels were found in all subtypes of antithrombin deficiency.The annual incidence of VTE in antithrombin-deficient family members was 1.24%, 95%CI: 0.72-1.99%, in low beta-antithrombin 1.36% (95%CI: 0.76-2.25%) and in normal beta-antithrombin 0.79% (95%CI: 0.10-2.77). The annual incidence of recurrence in family members was 3.1% (95%CI: 0.9-7.1%). Duration of anticoagulation had an impact on recurrence risk: In family members annual recurrence with fixed duration was 10% (95%CI: 2.1-29.2%), with indefinite duration 1.5% (95%CI: 0.2-5.4%), p Conclusions: In this high-risk antithrombin-deficient population, both subjects with low and normal plasma beta-antithrombin activity had high risks of first and recurrent VTE. This puts the importance of beta-antithrombin into question. Long-term anticoagulation is warranted in antithrombin-deficient VTE patients.

Purpose To determine postintervention patency rates after endovascular interventions on intragraft stenosis within failing prosthetic arteriovenous (AV) grafts, as well as predictors of patency. Materials and Methods Retrospective review of percutaneous interventions on prosthetic AV grafts presenting with first-time intragraft stenoses over a 7-year period revealed 183 patients (81 male; mean age, 59.7 y). "Intragraft" was defined as 2 cm or more from the arterial or venous anastomosis. Procedural imaging was retrospectively reviewed. Patency rates were estimated by Kaplan–Meier test. Predictors of patency were calculated by Cox proportional-hazards model. Results Two-hundred twenty-nine intragraft stenoses were identified in 183 grafts. Intragraft stenoses were treated at a median of 20.7 months (interquartile range, 12.0–33.9 mo) after graft creation. Graft thrombosis was present in 62%. The anatomic success rate of angioplasty was 85%. Fifteen percent required stent or stent-graft deployment because of inadequate response to angioplasty. A concurrent nonintragraft stenosis within the access circuit was identified in 76% of grafts. At 3, 6, and 12 months, postintervention primary patency rates were 56%, 40%, and 23%, respectively. Secondary patency rates were 84%, 77%, and 67%, respectively. The lesion-specific patency rates were 89, 75%, and 63%, respectively. Graft thrombosis (hazard ratio [HR], 1.43; P = .048) and concurrent nonintragraft lesion (HR, 1.51; P = .047) were independent negative predictors of primary patency. Graft thrombosis (HR, 1.81; P = .029) was a negative predictor of lesion patency, and stent or stent-graft deployment (HR, 0.42; P = .045) was a positive predictor of lesion patency. Conclusions Endovascular interventions on intragraft stenoses resulted in primary, secondary, and lesion-specific patency rates of 40%, 77%, and 75%, respectively, at 6 months. Stent or stent-graft deployment may prolong lesion patency.

To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication.This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naïve, but treated ≥50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA.There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy.ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community-based setting.

Oxidative stress is considered a risk factor for physical function (PF) decline with aging. The objective of this study was to examine the relationship between antioxidant intake and change in PF over a 5-year period. The Boston Area Community Health (BACH) Survey is a population-based longitudinal study including 5,502 racially/ethnically diverse and randomly selected participants aged 30–79 years. In total, 2828 persons aged 30–79 years completed the validated Block Food Frequency Questionnaire (FFQ) and participated in the follow-up study. Change in PF from baseline (2002–2005) to follow-up (2006–2010) was assessed using the validated SF-12 questionnaire. Linear models were used to examine the association between energy-adjusted quartiles of vitamins C, E and carotenoids and change in PF. A low intake (first quartile) of vitamin E was associated with a greater decline in PF compared with the highest quartile, with a mean difference in change in PF of -1.73 (95%CI:-3.31,-0.15). Notably, this mean difference was clinically meaningful as it was equivalent to the effect estimate we found for participants who were approximately 15 years apart in age in our cohort, as 1 year increase in age was associated with a mean difference in change in PF of -0.11 (95%CI:-0.16,-0.06). PF decline was not significantly different in the lowest compared with the highest quartile of vitamin C (mean difference=-1.29, 95%CI:-2.61, 0.03) or carotenoids (mean difference=-0.62, 95%CI:-2.22,0.99). Low intake of vitamin E was significantly associated with decline in PF with aging. These results are clinically meaningful, extend previous findings that oxidative stress contributes to PF decline, and may inform the development of future prevention strategies aimed at reducing this clinical and public health problem.

Background: Currently, measurement of serum tryptase level is the most commonly used test to estimate the need for bone marrow biopsy in patients suspected to have indolent systemic mastocytosis (ISM). Yet tryptase levels do not solely reflect the mast cell load and can be elevated by overweight, older age, and impaired renal function. The influence of these factors on urinary methylhistamine (MH) and methylimidazole acetic acid (MIMA) is still unknown.Objective: We investigated the impact of age, body mass index (BMI), and kidney function on the diagnostic accuracy of tryptase, MH, and MIMA to select the most optimal test indicating the necessity of a bone marrow biopsy in ISM-suspected patients.Methods: Retrospective data analysis of all adults in whom bone marrow investigations were performed because of high clinical suspicion and/or elevated tryptase, MH, or MIMA.Results: 194 subjects were included. ISM was present in 112 and absent in 82 subjects (non-ISM). Tryptase was elevated by age and body weight in non-ISM subjects and by BMI in ISM subjects; however, these factors did not influence MH or MIMA. In the total study population, the diagnostic accuracy of tryptase, MH, and MIMA were comparable (area under the curve 0.80, 0.80, and 0.83). In subjects > 50 years with a BMI > 25 kg/m(2), the diagnostic accuracy of MIMA was higher compared with that of tryptase (area under the curve 0.93 vs 0.74; P = .011).Conclusion: In ISM-suspected patients > 50 years with a BMI of > 25 kg/m(2), MIMA has a greater value compared with tryptase in estimating the need for bone marrow biopsy.

Increasing evidence suggests a possible link between lower urinary tract symptoms and chronic illnesses. We determined whether lower urinary tract symptoms are associated with incident type 2 diabetes and heart disease in a population based study.BACH is a population based epidemiological survey of urological symptoms. A multistage, stratified, cluster sample design was used to obtain a random sample of 4,144 men and women 30 to 79 years old at baseline. Median followup was 4.8 years between baseline (2002 to 2005) and followup (2006 to 2010). Type 2 diabetes and heart disease were assessed by self-report. Lower urinary tract symptoms were assessed by the AUA-SI, and voiding and storage subscores. Logistic regression was used to estimate the OR and 95% CI, and adjust for potential confounders.In participants with a body mass index of 30 kg/m(2) or greater the adjusted ORs for incident heart disease were 1.89 (95% CI 1.05, 3.39) for AUA-SI 8 or greater and 2.32 (95% CI 1.33, 4.05) for a storage score of 4 or greater. In participants with abdominal obesity the adjusted ORs for incident type 2 diabetes were 2.06 (95% CI 1.19, 3.55) for AUA-SI 8 or greater and 1.81 (95% CI 1.04, 3.15) for a storage score of 4 or greater. Lower urinary tract symptoms (AUA-SI 8 or greater) were also predictive of type 2 diabetes in men and women younger than 50 years (adjusted OR 2.37, 95% CI 1.18, 4.80).Longitudinal results of BACH suggest that lower urinary tract symptoms are a marker of increased risk for type 2 diabetes and heart disease in obese men and women. The increased risk in younger men and women suggests that lower urinary tract symptoms may be an indicator of impending disease.

Increasing evidence of a link between erectile dysfunction and cardiovascular disease suggests a shared vascular etiology with endothelial dysfunction as a plausible underlying biological mechanism. To our knowledge whether this association is different for large arterial endothelium compared to microvascular endothelium has not yet been established. We investigated the association of erectile dysfunction with macrovascular and microvascular endothelial function.A sample of 390 men with a mean age of 55.5 years was recruited from the BACH survey, a population based survey of urological symptoms. Erectile dysfunction was assessed using IIEF-5. The percent of brachial artery flow mediated dilatation, a measure of macrovascular function, and hyperemic flow velocity in cm per second, a measure of microvascular function, were assessed by ultrasound. Linear regression was used to assess the association of erectile dysfunction and endothelial function, and adjust for potential confounders.Reactive hyperemia was lower in men with vs without erectile dysfunction (mean ± SE 97.1 ± 2.5 vs 106.0 ± 1.6 cm per second, p = 0.003). However, the difference in flow mediated dilatation between men with vs without erectile dysfunction was statistically nonsignificant (mean 6.6% ± 0.33% vs 7.2% ± 0.24%, p = 0.147). The association of erectile dysfunction with reactive hyperemia was attenuated but it remained statistically significant in men with moderate to severe erectile dysfunction (IIEF-5 less than 12) after adjusting for traditional cardiovascular risk factors (p = 0.038).These results provide evidence of greater microvascular than macrovascular endothelial dysfunction as a potential contributor to erectile dysfunction and an underlying mechanism linking erectile dysfunction and cardiovascular disease.

The prognostic significance of an incomplete esophageal cancer resection due to a positive microscopic radial margin remains unclear. The aim of this study is to examine the relationship between radial margin status and oncologic outcomes.We performed a retrospective review of esophageal cancer resections between 2004 and 2012. Radial margin status was defined according to the College of American Pathologists. Exclusion criteria were complete pathologic response (n = 12), positive proximal or distal margin (n = 11), R2 resection (n = 5), and carcinoma in situ (n = 2).Of 154 patients, 30 (19%) had a positive radial margin (RM+) and 124 (81%) had a complete resection (R0). The 2 groups were similar with respect to age, gender, proportion of squamous tumors, middle thoracic tumor location, rate of neoadjuvant chemoradiation and adjuvant radiation, transhiatal approach, number of examined lymph nodes, and length of proximal and distal margins. In patients with stage III, the locoregional recurrence-free interval was similar between groups; however, RM+ was associated with a 17-month decrease in the median time to distant recurrence (RM+ = 7 months [95% confidence interval, 4-14]; R0 = 24 months [median not reached]; P.01). The median survival was also significantly decreased by 12 months in the RM+ group (RM+ = 13 months [95% confidence interval, 7-26]; R0 = 25 months [95% confidence interval, 20-30]; P = .04).An isolated, positive microscopic radial margin was associated with a greater risk for distant recurrence. There was no impact on locoregional disease control. The role of adjuvant, systemic therapy in patients with an isolated, microscopically RM+ merits further evaluation.

Background The most commonly used definition of iron deficiency (ID; ferritin Methods and Results Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively ( P Conclusions A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of

Here we have explored whether inhibition of autophagy can be used as a treatment strategy for acute myeloid leukemia (AML). Steady-state autophagy was measured in leukemic cell lines and primary human CD34+ AML cells with a large variability in basal autophagy between AMLs observed. The autophagy flux was higher in AMLs classified as poor risk, which are frequently associated with TP53 mutations (TP53mut), compared with favorable- and intermediate-risk AMLs. In addition, the higher flux was associated with a higher expression level of several autophagy genes, but was not affected by alterations in p53 expression by knocking down p53 or overexpression of wild-type p53 or p53R273H. AML CD34+ cells were more sensitive to the autophagy inhibitor hydroxychloroquine (HCQ) than normal bone marrow CD34+ cells. Similar, inhibition of autophagy by knockdown of ATG5 or ATG7 triggered apoptosis, which coincided with increased expression of p53. In contrast to wild-type p53 AML (TP53wt), HCQ treatment did not trigger a BAX and PUMA-dependent apoptotic response in AMLs harboring TP53mut. To further characterize autophagy in the leukemic stem cell-enriched cell fraction AML CD34+ cells were separated into ROSlow and ROShigh subfractions. The immature AML CD34+-enriched ROSlow cells maintained higher basal autophagy and showed reduced survival upon HCQ treatment compared with ROShigh cells. Finally, knockdown of ATG5 inhibits in vivo maintenance of AML CD34+ cells in NSG mice. These results indicate that targeting autophagy might provide new therapeutic options for treatment of AML since it affects the immature AML subfraction.

Functionalizing medical devices with polypeptides to enhance their performance has become important for improved clinical success. The extracellular matrix (ECM) adhesion protein vitronectin (VN) is an effective coating, although the chemistry used to attach VN often reduces its bioactivity. In vivo, VN binds the ECM in a sequence-dependent manner with heparan sulfate (HS) glycosaminoglycans. We reasoned therefore that sequence-based affinity chromatography could be used to isolate a VN-binding HS fraction (HS9) for use as a coating material to capture VN onto implant surfaces. Binding avidity and specificity of HS9 were confirmed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR)-based assays. Plasma polymerization of allylamine (AA) to tissue culture-treated polystyrene (TCPS) was then used to capture and present HS9 as determined by radiolabeling and ELISA. HS9-coated TCPS avidly bound VN, and this layered surface supported the robust attachment, expansion, and maintenance of human pluripotent stem cells. Compositional analysis demonstrated that 6-O- and N-sulfation, as well as lengths greater than three disaccharide units (dp6) are critical for VN binding to HS-coated surfaces. Importantly, HS9 coating reduced the threshold concentration of VN required to create an optimally bioactive surface for pluripotent stem cells. We conclude that affinity-purified heparan sugars are able to coat materials to efficiently bind adhesive factors for biomedical applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1887-1896, 2018.