Search

Recent studies have shown that mutations of the developmental regulator Notch1 can be identified in most T-ALL patients (7). It is estimated that activation of the Notch1 signalling pathway occurs [...], T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents (1). T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse (2.3). For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment (3). Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance (4). Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.

The Antarctic environment has special characteristics that influence the local marine life. The benthic organisms, adapted to these extreme conditions of life, are subject nowadays to effects of climate change. Recently, the consequences of glacier retreat on these assemblages have been observed in many West Antarctic Peninsula (WAP) regions, including King George Island (KGI). This study described the spatial variation of the benthic macrofauna in different areas of the Martel Inlet (Admiralty Bay - KGI), at depths around 25-30 m. Sampling was done in January 2001 at ten stations classified in localities according to their proximity to ice-margin/coastline in marine-terminating glacier (MTG), terrestrial-terminating glacier (TTG) and ice-free area (IFA). The total density and the abundance of annelids, nematodes, peracarid crustaceans and bivalves were higher at IFA stations. The locality discrimination by taxa and species was independent of available environmental/sedimentary conditions or was the result of unmeasured variables or species life history processes not assessed herein. Considering that our findings were obtained 21 years ago, they will be especially useful for comparing future studies of benthic assemblage responses to the influence of climate change and continuous glacier retreats in the WAP region.

Mobile monitoring is a useful approach for measuring intra-urban variation of air pollution in urban environments. In this study, we used a mobile monitoring approach to study the spatial-temporal variability of air and noise pollution in urban neighborhoods of Philadelphia. During summer 2017, we used portable instruments to measure PM 2.5 , black carbon (BC), and noise levels along 5 km paths in four residential neighborhoods (Tioga, Mill Creek, Chestnut Hill, and Northern Liberties) and one commercial district (Center City) in Philadelphia, Pennsylvania, USA. A total of 62 sets of measurements were made at three different times of day (during morning rush hour, mid-afternoon, and during afternoon rush hour) from June 5 to July 7, 2017. Spatially, there was a significant difference in PM 2.5 concentrations among the four residential neighborhoods. Overall, the Chestnut Hill neighborhood had the highest PM 2.5 concentrations (13.25 ± 6.89 μg/m 3 ), followed by Tioga (9.58 ± 4.83 μg/m 3 ), Northern Liberties (7.02 ± 4.17 μg/m 3 ), and Mill Creek (3.9 ± 4.5 μg/m 3 ). There was temporal variability of pollutants depending on the neighborhood; Northern Liberties demonstrated the highest temporal variability in these data. The highest PM 2.5 (18.86 ± 3.17 mg/m 3 ) was measured in the Chestnut Hill neighborhood during mid-afternoon. Mean PM 2.5 , BC, and noise levels based on mobile measurements at Philadelphia during summer 2017 were 8.41 ± 4.31 μg/m 3 , 0.99 ± 0.44 μg C/m 3 , and 62.01 ± 3.20 dBA, respectively. Environmental noise showed the highest temporal variation of the monitored components for 3 time periods. In general, tree cover showed a weak and inconclusive association with particulate pollution levels., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The New York Heart Association (NYHA) functional classification system has poor inter-rater reproducibility. A previously published pilot study showed a statistically significant difference between the daily step counts of heart failure (with reduced ejection fraction) patients classified as NYHA functional class II and III as measured by wrist-worn activity monitors. However, the study's small sample size severely limits scientific confidence in the generalizability of this finding to a larger heart failure (HF) population., Objective: This study aimed to validate the pilot study on a larger sample of patients with HF with reduced ejection fraction (HFrEF) and attempt to characterize the step count distribution to gain insight into a more objective method of assessing NYHA functional class., Methods: We repeated the analysis performed during the pilot study on an independently recorded dataset comprising a total of 50 patients with HFrEF (35 NYHA II and 15 NYHA III) patients. Participants were monitored for step count with a Fitbit Flex for a period of 2 weeks in a free-living environment., Results: Comparing group medians, patients exhibiting NYHA class III symptoms had significantly lower recorded 2-week mean daily total step count (3541 vs 5729 [steps], P=.04), lower 2-week maximum daily total step count (10,792 vs 5904 [steps], P=.03), lower 2-week recorded mean daily mean step count (4.0 vs 2.5 [steps/minute], P=.04,), and lower 2-week mean and 2-week maximum daily per minute step count maximums (88.1 vs 96.1 and 111.0 vs 123.0 [steps/minute]; P=.02 and .004, respectively)., Conclusions: Patients with NYHA II and III symptoms differed significantly by various aggregate measures of free-living step count including the (1) mean and (2) maximum daily total step count as well as by the (3) mean of daily mean step count and by the (4) mean and (5) maximum of the daily per minute step count maximum. These findings affirm that the degree of exercise intolerance of NYHA II and III patients as a group is quantifiable in a replicable manner. This is a novel and promising finding that suggests the existence of a possible, completely objective measure of assessing HF functional class, something which would be a great boon in the continuing quest to improve patient outcomes for this burdensome and costly disease., (©Jonathan-F Baril, Simon Bromberg, Yasbanoo Moayedi, Babak Taati, Cedric Manlhiot, Heather Joan Ross, Joseph Cafazzo. Originally published in JMIR Cardio (http://cardio.jmir.org), 17.05.2019.)

Background and Aims: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis., Methods: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug., Results: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I., Conclusions: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit., Competing Interests: N.N.A., G.S., R.R., T.P.‐M., S.K.‐B., Y.Y., and N.M. are employees of AbbVie and may hold stock or stock options. T.A.: Clinical Investigator/Speaker/Consultant: AbbVie, Boehringer Ingelheim, BMS, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, Roche C.M.: Research grants: AbbVie, Gilead Sciences, Janssen; Consultant: AbbVie, Gilead Sciences, Janssen, Merck Sharp & Dohme, BMS S.P.: Consultant/Lecturer: BMS, Boehringer Ingelheim, Janssen, Gilead, MSD, Novartis, AbbVie; Grant/Research support: BMS, Gilead, Roche, MSD S.K.: Research grant: AbbVie M.G.: Advisor/Speaker: Janssen, MSD, BMS, Gilead, AbbVie; Grants: Gilead, AbbVie, MSD Y.H.: AbbVie, Gilead, Janssen, MSD, BMS I.E.: Advisor/Speaker: Gilead, AbbVie, MSD, BMS; Research grants: Gilead, AbbVie D.L.: Participation in clinical studies: AbbVie C.F.: Consultant: AbbVie, Gilead, Arrowhead, Humabs, MSD, Chiesi, Abivax; Research grants: Janssen, Cilag, Roche, BMS, Gilead, AbbVie M.R.: Participation in clinical studies: AbbVie A.O.: Consultant: AbbVie, MSD J.L.C.: Consultant and Lecturer: AbbVie, BMS, MSD, Gilead Sciences S.B.: Participation in clinical studies: AbbVie R.Q.: Participation in clinical studies: AbbVie

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status., (© 2018 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3-99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6-98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection., Competing Interests: Graham R Foster has received fees for serving as a speaker, consultant, and advisory board member for Gilead, Janssen, AbbVie, Merck, and GSK. Tarik Asselah has been a clinical investigator, speaker, and consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche. Sarah Kopecky-Bromberg, Yang Lei, Armen Asatryan, Roger Trinh, Neddie Zadeikis, and Federico J Mensa are employees of AbbVie and may hold stock or options. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Data will be made available to all interested researchers upon request.

In AGATE-II, treatment with ombitasvir coformulated with paritaprevir/ritonavir plus ribavirin (RBV) in Egyptians infected with hepatitis C virus genotype 4 resulted in high rates of sustained virologic response at post-treatment week 12. This subanalysis examined the effects of treatment in AGATE-II on liver biomarkers in patients with compensated cirrhosis. AGATE-II was a phase 3, open-label, partly randomized trial of ombitasvir/paritaprevir/ritonavir with weight-based RBV daily once in treatment-naive or treatment-experienced patients. Patients without cirrhosis received treatment for 12 weeks and patients with compensated cirrhosis were randomized 1:1 to the same regimen for either 12 or 24 weeks. Sixty patients with compensated cirrhosis were randomized to treatment for 12 weeks (n = 31) or 24 weeks (n = 29). In the 12-week arm, significant improvements were observed in biomarkers of liver injury (alanine aminotransferase: -53.7 U/L, P < 0.001; aspartate aminotransferase: -35.9 U/L, P < 0.001) and liver fibrosis (aspartate aminotransferase to platelet ratio index: -0.987, P < 0.001; fibrosis-4 index: -1.165, P < 0.001). Similar results were reported in the 24-week arm. Treatment with ombitasvir/paritaprevir/ritonavir plus RBV in hepatitis C virus genotype, 4-infected Egyptians with compensated cirrhosis resulted in improvements in certain biomarkers of liver synthetic function, injury, and fibrosis, independent of treatment duration., (© 2018 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.)

Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (≥10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation., Conclusion: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260)., (© 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Lymph node (LN) is a secondary lymphoid organ with highly organized and compartmentalized structure. LNs harbor B, T, and other cells among fibroblastic reticular cells (FRCs). FRCs are characterized by both podoplanin (PDPN/gp38) expression and by the lack of CD31 expression. FRCs are involved in several immune response processes but mechanisms underlying their function are still under investigation. Double-negative cells (DNCs), another cell population within LNs, are even less understood. They do not express PDPN or CD31, their localization within the LN is unknown, and their phenotype and function remain to be elucidated. This study evaluates the gene expression and cytokines and chemokines profile of human LN-derived FRCs and DNCs during homeostasis and following inflammatory stimuli. Cytokines and chemokines secreted by human FRCs and DNCs partially diverged from those identified in murine models that used similar stimulation. Cytokine and chemokine secretion and their receptors expression levels differed between stimulated DNCs and FRCs, with FRCs expressing a broader range of chemokines. Additionally, dendritic cells demonstrated increased migration toward FRCs, possibly due to chemokine-induced chemotaxis since migration was significantly decreased upon neutralization of secreted CCL2 and CCL20. Our study contributes to the understanding of the biology and functions of FRCs and DNCs and, accordingly, of the mechanisms involving them in immune cells activation and migration.

Background: Conservative surgical treatment has been the treatment of choice for early breast cancer. It allows feasible oncological treatment with a satisfactory cosmetic approach and fast recovery. However, in some cases mastectomy is necessary. This study proposes a surgical approach with only one surgical access through the same incision, which is in line with precepts mentioned above. It is called the prime incision and modified moving window techniques., Methods: Thirty one patients with a breast cancer diagnosis who would have to undergo surgery were enrolled. The proposed technique was used and its advantages and feasibility were assessed and evaluated., Results: Twenty three conservative surgeries, 7 adenectomies and 1 axillary surgery were performed. All cases were appropriately treated and progressed without complications and had adequate aesthetic results. The technique presented allows only one surgical access to approach the axilla and breast cancer treatment., Conclusion: This study proved the aesthetic advantage provided by only one surgical incision access feasible for surgical treatment as a secure approach. The minimally invasive approaches of prime incision and modified moving window were shown to provide adequate surgical access with only one scar, thus having a better cosmetic result.

This paper evaluates the relation between Alcohol Withdrawal Syndrome tremors in the left and right hands of patients. By analyzing 122 recordings from 61 patients in emergency departments, we found a weak relationship between the left and right hand tremor frequencies (correlation coefficient of 0.63). We found a much stronger relationship between the expert physician tremor ratings (on CIWA-Ar 0-7 scale) of the two hands, with a correlation coefficient of 0.923. Next, using a smartphone to collect the tremor data and using a previously developed model for obtaining estimated tremor ratings, we also found a strong correlation (correlation coefficient of 0.852) between the estimates of each hand. Finally, we evaluated different methods of combining the data from the two hands for obtaining a single tremor rating estimate, and found that simply averaging the tremor ratings of the two hands results in the lowest tremor estimate error (an RMSE of 0.977). Looking at the frequency dependence of this error, we found that higher frequency tremors had a much lower estimation error (an RMSE of 1.102 for tremors with frequencies in the 3-6Hz range as compared to 0.625 for tremors with frequencies in the 7-10Hz range).

In this paper, we propose a signal processing method of assessing the severity tremors caused by alcohol withdrawal (AW) syndrome. We have developed an iOS application to calculate the Clinical Institute Withdrawal Assessment (CIWA) score which captures iPod movements using the built-in accelerometer in order to reliably estimate the tremor severity component of the score. We report on the characteristics of AW tremor, the accuracy of electronic assessment of tremor compared to expert clinician assessment, and the potential for using signal processing assessment to differentiate factitious from real tremor in patients seen in the emergency department, as well as in nurses mimicking a tremor. Our preliminary results are based on 84 recordings from 61 subjects (49 patients, 12 nurses). In general we found a linear relationship between energy measured by the accelerometer (in the 4.4-10 Hz range) and the expert rating of tremor severity. Additionally, we demonstrate that 75% of the recordings from patients with actual AW syndrome had a mean peak frequency higher than 7 Hz whereas only 17% of the nurses' factitious tremors were above 7 Hz, suggesting that tremor above 7 Hz could be a potential discriminator of real versus factitious tremors.

We examined hazard perception (HP) abilities among elderly experienced and experienced drivers, with regard to the presence of pedestrians in residential areas. Two evaluation methods were used: (a) observation of traffic scene videos and pressing a button when a hazardous situation was identified, and (b) driving in a driving simulator. The results of the video observation method showed that elderly drivers had a longer response time for hazard detection. In addition, four of the eight pedestrian-related events were difficult for elderly drivers to perceive when compared to experienced drivers. Elderly drivers, shown to have limited useful field of view, may also be limited in their ability to detect hazards, particularly when located away from the center of the screen. Results from the simulator drive showed that elderly drivers drove about 20% slower than experienced drivers, possibly being aware of their deficiencies in detecting hazards and slower responses. Authorities should be aware of these limitations and increase elderly drivers' awareness to pedestrians by posting traffic signs or dedicated lane marks that inform them of potential upcoming hazards., (2011 Elsevier Ltd. All rights reserved.)

The Rat Genome Database (RGD, http://rgd.mcw.edu) is one of the core resources for rat genomics and recent developments have focused on providing support for disease-based research using the rat model. Recognizing the importance of the rat as a disease model we have employed targeted curation strategies to curate genes, QTL and strain data for neurological and cardiovascular disease areas. This work has centered on rat but also includes data for mouse and human to create 'disease portals' that provide a unified view of the genes, QTL and strain models for these diseases across the three species. The disease curation efforts combined with normal curation activities have served to greatly increase the content of the database, particularly for biological information, including gene ontology, disease, pathway and phenotype ontology annotations. In addition to improving the features and database content, community outreach has been expanded to demonstrate how investigators can leverage the resources at RGD to facilitate their research and to elicit suggestions and needs for future developments. We have published a number of papers that provide additional information on the ontology annotations and the tools at RGD for data mining and analysis to better enable researchers to fully utilize the database.