Effect of Central Nervous System Metastases on Treatment Discontinuation and Survival in Older Women Receiving Trastuzumab for Metastatic Breast Cancer

Background. Trastuzumab improves survival in HER2-positive women with metastatic breast cancer (MBC). The consequences of longer survival include a higher likelihood of additional metastases, including those in the central nervous system (CNS). The effect of CNS metastases on both trastuzumab discontinuation and survival in older patients has not been described. Patients and Methods. We used the Surveillance Epidemiology and End Results (SEER) Medicare data to identify a cohort of 562 women age 66 or older with MBC who were diagnosed between January 1, 2000 and December 31, 2005, free of CNS metastases, and initiated trastuzumab after MBC diagnosis. Time to discontinuation and time to death were analyzed using proportional hazards models. Results. Newly diagnosed CNS metastases were associated with both higher risk of trastuzumab discontinuation (relative hazard [RH] = 1.78, 95% CI 1.11–2.87) and higher risk of death (RH = 2.49, 95% CI 1.84–3.37). The incidence rate of new CNS metastases was comparable among various sites of metastasis (10.7 to 14.7 per 1,000 patient-months), except for bone which was higher (24.1 per 1,000). Conclusion. The diagnosis of CNS metastases was associated with an increase in both the likelihood of discontinuing trastuzumab therapy as well as the risk of death

Patterns of Hemodialysis Catheter Dysfunction Defined According to National Kidney Foundation Guidelines As Blood Flow <300 mL/min

Blood flow rate (BFR) <300 mL/min commonly is used to define hemodialysis catheter dysfunction and the need for interventions to prevent complications. The objective of this study was to describe patterns of unplanned BFR <300 mL/min during catheter hemodialysis using data from DaVita dialysis facilities and the United States Renal Data System. Patients were included if they received at least eight weeks of hemodialysis exclusively through a catheter between 08/04 and 12/06, and catheter hemodialysis was the first treatment modality following diagnosis of end-stage renal disease (first access), or it immediately followed at least one 30-day period of dialysis exclusively through a fistula or graft (replacement access). Actual BFR <300 mL/min despite a planned BFR ≥300 mL/min defined catheter dysfunction during each dialysis session. There were 3,364 patients, 268,363 catheter dialysis sessions, and 19,118 (7.1%) sessions with catheter dysfunction. Almost two-thirds of patients had ≥1 catheter dysfunction session, and 30% had ≥1 catheter dysfunction session per month. Patients with catheter as a replacement access had a higher rate of catheter dysfunction than those with a catheter as first access (hazard ratio: 1.13; P = 0.04). Catheter dysfunction affects almost one-third of catheter dialysis patients each month and two-thirds overall

Lower Mortality with Andexanet Alfa vs 4-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor-Related Major Bleeding in a U.S. Hospital-Based Observational Study

BACKGROUND: Well-designed studies with sufficient sample size comparing andexanet alfa vs 4-factor prothrombin complex concentrate (4F-PCC) in routine clinical practice to evaluate clinical outcomes are limited. OBJECTIVES: To compare in-hospital mortality in patients hospitalized with rivaroxaban- or apixaban-related major bleeding who were treated with andexanet alfa or 4F-PCC. METHODS: An observational cohort study (ClinicalTrials.gov identifier: NCT05548777) was conducted using electronic health records between May 2018 and September 2022 from 354 U.S. hospitals. Inclusion criteria were age ≥18 years, inpatient admission with diagnosis code D68.32 (bleeding due to extrinsic anticoagulation), a record of use of the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa or 4F-PCC treatment during index hospitalization, and a documented discharge disposition. Multivariable logistic regression on in-hospital mortality with andexanet alfa vs 4F-PCC was performed. The robustness of the results was assessed via a supportive propensity score-weighted logistic regression. RESULTS: The analysis included 4395 patients (andexanet alfa, CONCLUSION: In this large observational study, treatment with andexanet alfa in patients hospitalized with rivaroxaban- or apixaban-related major bleeds was associated with 50% lower odds of in-hospital mortality than 4F-PCC. The magnitude of the risk reduction was similar in ICH and GI bleeds

Impact of Hemodialysis Catheter Dysfunction on Dialysis and Other Medical Services: An Observational Cohort Study

Practice guidelines define hemodialysis catheter dysfunction as blood flow rate (BFR) <300 mL/min. We conducted a study using data from DaVita and the United States Renal Data System to evaluate the impact of catheter dysfunction on dialysis and other medical services. Patients were included if they had ≥8 consecutive weeks of catheter dialysis between 8/2004 and 12/2006. Actual BFR <300 mL/min despite planned BFR ≥300 mL/min was used to define catheter dysfunction during each dialysis session. Among 9,707 patients, the average age was 62,53% were female, and 40% were black. The median duration of catheter dialysis was 190 days, and the cohort accounted for 1,075,701 catheter dialysis sessions. There were 70,361 sessions with catheter dysfunction, and 6,33 1 (65.2%) patients had at least one session with catheter dysfunction. In multivariate repeated measures analysis, catheter dysfunction was associated with increased odds of missing a dialysis session due to access problems (Odds ratio [OR] 2.50; P < 0.001), having an access-related procedure (OR 2.10; P < 0.001), and being hospitalized (OR 1.10; P = 0.001). Catheter dysfunction defined according to NKF vascular access guidelines results in disruptions of dialysis treatment and increased use of other medical services

A Merger Scenario for the Dynamics of Abell 665

We present new redshift measurements for 55 galaxies in the vicinity of the rich galaxy cluster Abell 665. When combined with results from the literature, we have good velocity measurements for a sample of 77 confirmed cluster members from which we derive the cluster's redshift z=0.1829 +/- 0.0005 and line-of-sight velocity dispersion of 1390 +/- 120 km/s. Our analysis of the kinematical and spatial data for the subset of galaxies located within the central 750 kpc reveals only subtle evidence for substructure and non-Gaussianity in the velocity distribution. We find that the brightest cluster member is not moving significantly relative to the other galaxies near the center of the cluster. On the other hand, our deep ROSAT high resolution image of A665 shows strong evidence for isophotal twisting and centroid variation, thereby confirming previous suggestions of significant substructure in the hot X-ray--emitting intracluster gas. In light of this evident substructure, we have compared the optical velocity data with N-body simulations of head-on cluster mergers. We find that a merger of two similar mass subclusters (mass ratios of 1:1 or 1:2) seen close to the time of core-crossing produces velocity distributions that are consistent with that observed.Comment: 30 pages and 7 figures. Accepted by the Astrophysical Journal Full resoultion figures 1 and 3 available in postscript at http://www.physics.rutgers.edu/~percy/A665paper.htm

Testing the causal relationships of physical activity and sedentary behaviour with mental health and substance use disorders: a Mendelian randomisation study

Observational studies suggest that physical activity can reduce the risk of mental health and substance use disorders. However, it is unclear whether this relationship is causal or explained by confounding bias (e.g., common underlying causes or reverse causality). We investigated the bidirectional causal relationship of physical activity (PA) and sedentary behaviour (SB) with ten mental health and substance use disorders, applying two-sample Mendelian Randomisation (MR). Genetic instruments for the exposures and outcomes were derived from the largest available, non-overlapping genome-wide association studies (GWAS). Summary-level data for objectively assessed PA (accelerometer-based average activity, moderate activity, and walking) and SB and self-reported moderate-to-vigorous PA were obtained from the UK Biobank. Data for mental health/substance use disorders were obtained from the Psychiatric Genomics Consortium and the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. MR estimates were combined using inverse variance weighted meta-analysis (IVW). Sensitivity analyses were conducted to assess the robustness of the results. Accelerometer-based average PA was associated with a lower risk of depression (b = -0.043, 95% CI: -0.071 to -0.016, effect size[OR] = 0.957) and cigarette smoking (b = -0.026; 95% CI: -0.035 to -0.017, effect size[β] = -0.022). Accelerometer-based SB decreased the risk of anorexia (b = -0.341, 95% CI: -0.530 to -0.152, effect size[OR] = 0.711) and schizophrenia (b = -0.230; 95% CI: -0.285 to -0.175, effect size[OR] = 0.795). However, we found evidence of reverse causality in the relationship between SB and schizophrenia. Further, PTSD, bipolar disorder, anorexia, and ADHD were all associated with increased PA. This study provides evidence consistent with a causal protective effect of objectively assessed but not self-reported PA on reduced depression and cigarette smoking. Objectively assessed SB had a protective relationship with anorexia. Enhancing PA may be an effective intervention strategy to reduce depressive symptoms and addictive behaviours, while promoting sedentary or light physical activities may help to reduce the risk of anorexia in at-risk individuals

Capturing the holistic value of biosimilars in Europe–part 1:a historical perspective

Introduction: Approved biosimilars exhibit comparable efficacy, safety, and immunogenicity to reference products. This report provides perspectives on the societal value of biosimilars within Europe and potential factors that have influenced market dynamics. Methods: An independent, self-administered survey or one-on-one in-depth interview was used to collect viewpoints about the impact of biosimilar medicines within European markets. Key insights were also sought from an expert panel of European stakeholders. Results: Survey respondents were clinicians, pharmacists, and payers from Europe (N = 103). Perceived benefits of biosimilars included increased access to innovative medicines (73% of respondents) or biologic treatments (66%). Biosimilar competition was thought to expand access to biologics (~50% of respondents) or drug combinations (~36%) and reduce biologic access time (34%). Key drivers of biologic access after biosimilar competition included increased biologic awareness (51%) and changes to prescribing guidelines (37%) and/or treatment paradigms (28%). The expert panel developed a market maturity framework of biosimilar adoption/opportunities comprising three stages: ‘Invest,’ ‘Expand,’ and ‘Harvest.’ Findings were supported by published literature. Conclusions: In Europe, the perceptions of well-informed survey/interview respondents are that biosimilars have improved patient outcomes via increased access to biologics and innovative biologic products, contributing to earlier and longer treatment of a broader population.</p

Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival

The XMM Cluster Survey: Active Galactic Nuclei and Starburst Galaxies in XMMXCS J2215.9-1738 at z=1.46

We use Chandra X-ray and Spitzer infrared observations to explore the AGN and starburst populations of XMMXCS J2215.9-1738 at z=1.46, one of the most distant spectroscopically confirmed galaxy clusters known. The high resolution X-ray imaging reveals that the cluster emission is contaminated by point sources that were not resolved in XMM observations of the system, and have the effect of hardening the spectrum, leading to the previously reported temperature for this system being overestimated. From a joint spectroscopic analysis of the Chandra and XMM data, the cluster is found to have temperature T=4.1_-0.9^+0.6 keV and luminosity L_X=(2.92_-0.35^+0.24)x10^44 erg/s extrapolated to a radius of 2 Mpc. As a result of this revised analysis, the cluster is found to lie on the sigma_v-T relation, but the cluster remains less luminous than would be expected from self-similar evolution of the local L_X-T relation. Two of the newly discovered X-ray AGN are cluster members, while a third object, which is also a prominent 24 micron source, is found to have properties consistent with it being a high redshift, highly obscured object in the background. We find a total of eight >5 sigma 24 micron sources associated with cluster members (four spectroscopically confirmed, and four selected using photometric redshifts), and one additional 24 micron source with two possible optical/near-IR counterparts that may be associated with the cluster. Examining the IRAC colors of these sources, we find one object is likely to be an AGN. Assuming that the other 24 micron sources are powered by star formation, their infrared luminosities imply star formation rates ~100 M_sun/yr. We find that three of these sources are located at projected distances of <250 kpc from the cluster center, suggesting that a large amount of star formation may be taking place in the cluster core, in contrast to clusters at low redshift.Comment: Accepted for publication in ApJ, 16 pages, 10 figure

Herschel-ATLAS: Blazars in the science demonstration phase field

To investigate the poorly constrained sub-mm counts and spectral properties of blazars we searched for these in the Herschel-ATLAS (H-ATLAS) science demonstration phase (SDP) survey catalog. We cross-matched 500 μm sources brighter than 50 mJy with the FIRST radio catalogue. We found two blazars, both previously known. Our study is among the first blind blazar searches at sub-mm wavelengths, i.e., in the spectral regime where little is still known about the blazar SEDs, but where the synchrotron peak of the most luminous blazars is expected to occur. Our early results are consistent with educated extrapolations of lower frequency counts and question indications of substantial spectral curvature downwardsand of spectral upturns at mm wavelengths. One of the two blazars is identified with a Fermi/LAT Υ-ray source and a WMAP source. The physical parameters of the two blazars are briefly discussed. These observations demonstrate that the H-ATLAS survey will provide key information aboutthe physics of blazars and their contribution to sub-mm counts.We are grateful to the referee, P. Padovani, for very useful comments. Thanks are due to the PACO collaboration for having made available the data on the 2 blazars. M.M. and L.B. thanks the staff at the Australia Telescope Compact Array site, Narrabri (NSW), for the valuable support they provide in running the telescope. Work partially supported by the Italian Space Agency (contract I/016/07/0 "COFIS'' and ASI/INAF Agreement I/072/09/0 for the Planck LFI Activity of Phase E2). This research has made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration