BACKGROUND: Canine T‐cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common ...subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas. OBJECTIVE: To test the hypothesis that canine CD4+ T‐cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course. ANIMALS: Sixty‐seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics. METHODS: Retrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features. RESULTS: The majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45− and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached). CONCLUSIONS AND CLINICAL IMPORTANCE: Although the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma.
Background: Class II major histocompatibility complex (MHC) is an independent predictor of outcome in human B‐cell lymphoma. We assessed class II expression together with other markers for their ...impact on prognosis in canine B‐cell lymphoma.
Hypothesis: Low class II MHC expression, large cell size, and expression of CD34 will predict a poorer outcome in canine B‐cell lymphoma. Expression of CD5 and CD21 on tumor cells also may be associated with outcome.
Animals: One hundred and sixty dogs with cytologically confirmed lymphoma.
Methods: Patient signalment, treatment type, and flow cytometry characteristics were analyzed for their influence on outcome. A multivariable predictive model of survival was generated using 2/3 of the patients and validated on the remaining 1/3 of the dataset.
Results: Class II MHC expression had a negative association with mortality and relapse. Treatment type also influenced relapse and mortality, whereas cell size and patient age was only associated with mortality. CD34, CD21, and CD5 expression was not associated with disease outcome. The constructed model performed variably in predicting the validation group's outcome at the 6‐month time point.
Conclusions and Clinical Importance: Low levels of class II MHC expression on B‐cell lymphoma predict a poor outcome, as in human B‐cell lymphoma. This finding has implications for the use of dogs to model human lymphomas. Class II expression, cell size, treatment, and age can be combined to predict mortality with a high level of specificity.
Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD).
Multicenter, retrospective chart review was conducted on patients treated ...with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid.
After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 μM (p < 0.001), a - 25.3 μM (p < 0.001) and a - 84.5 μM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 μM (p < 0.001), a - 38.1 μM (p < 0.001) and a - 80.1 μM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved.
Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.
The Galactic center supermassive black hole Sagittarius A* (Sgr A*) is one of the most promising targets to study the dynamics of black hole accretion and outflow via direct imaging with very long ...baseline interferometry (VLBI). At 3.5 mm (86 GHz), the emission from Sgr A* is resolvable with the Global Millimeter VLBI Array (GMVA). We present the first observations of Sgr A* with the phased Atacama Large Millimeter/submillimeter Array (ALMA) joining the GMVA. Our observations achieve an angular resolution of ∼87 as, improving upon previous experiments by a factor of two. We reconstruct a first image of the unscattered source structure of Sgr A* at 3.5 mm, mitigating the effects of interstellar scattering. The unscattered source has a major-axis size of 120 34 as (12 3.4 Schwarzschild radii) and a symmetrical morphology (axial ratio of ), which is further supported by closure phases consistent with zero within 3 . We show that multiple disk-dominated models of Sgr A* match our observational constraints, while the two jet-dominated models considered are constrained to small viewing angles. Our long-baseline detections to ALMA also provide new constraints on the scattering of Sgr A*, and we show that refractive scattering effects are likely to be weak for images of Sgr A* at 1.3 mm with the Event Horizon Telescope. Our results provide the most stringent constraints to date for the intrinsic morphology and refractive scattering of Sgr A*, demonstrating the exceptional contribution of ALMA to millimeter VLBI.
The Earth Observing System (EOS) Microwave Limb Sounder (MLS) aboard the Aura satellite has provided essentially daily global measurements of ozone (O3) profiles from the upper troposphere to the ...upper mesosphere since August of 2004. This paper focuses on validation of the MLS stratospheric standard ozone product and its uncertainties, as obtained from the 240 GHz radiometer measurements, with a few results concerning mesospheric ozone. We compare average differences and scatter from matched MLS version 2.2 profiles and coincident ozone profiles from other satellite instruments, as well as from aircraft lidar measurements taken during Aura Validation Experiment (AVE) campaigns. Ozone comparisons are also made between MLS and balloon‐borne remote and in situ sensors. We provide a detailed characterization of random and systematic uncertainties for MLS ozone. We typically find better agreement in the comparisons using MLS version 2.2 ozone than the version 1.5 data. The agreement and the MLS uncertainty estimates in the stratosphere are often of the order of 5%, with values closer to 10% (and occasionally 20%) at the lowest stratospheric altitudes, where small positive MLS biases can be found. There is very good agreement in the latitudinal distributions obtained from MLS and from coincident profiles from other satellite instruments, as well as from aircraft lidar data along the MLS track.
Background: Canine lymphoproliferative disease often presents with lymphocytosis and is immunophenotypically diverse.
Hypothesis: Immunophenotype predicts prognosis in canine lymphoproliferative ...disorders involving circulating lymphocytosis.
Animals: Dogs that had peripheral blood evaluation performed by flow cytometry by the Clinical Immunology Service at Colorado State University between 2003 and 2005.
Methods: Outcome data regarding treatment and survival were sought on patients with lymphocytosis comprising a single lymphocyte subset. Ninety‐six patients that met the inclusion criteria had sufficient follow‐up information to be included in the study.
Results: Four main phenotypic classifications were found: CD8+ T‐cell, CD21+ B‐cell, CD4‐8‐5+ (aberrant T‐cell phenotype), and CD34+ (undifferentiated progenitor). Expression of CD34 predicted poor outcome with median survival of 16 days (P < .0001) compared with other phenotypes. Within the CD8+ phenotype, dogs presenting with a lymphocytosis >30,000 lymphocytes/μL had significantly shorter median survival (131 days) than those presenting with <30,000 lymphocytes/μL (1098 days, P < .0008). Within the T‐cell leukemias, there was no difference in outcome between dogs with CD4‐8‐5+ leukemia and dogs with the CD8+ T‐cell phenotype nor was the loss of expression of the pan‐leukocyte marker CD45 associated with decreased survival time. A CD21+ lymphocytosis composed of large cells was associated with shorter survival time (129 days) than those with smaller circulating cells (median survival not reached, P < .01).
Conclusions and Clinical Importance: Immunophenotyping provides an objective method for determining prognosis in lymphoproliferative disorders characterized by lymphocytosis.
Many antiretroviral (ARV) drugs have large blood plasma‐to‐seminal plasma (BP/SP) concentration ratios. Concern exists that these drugs do not adequately penetrate the male genital tract (MGT), ...resulting in the MGT becoming a “pharmacological sanctuary” from these agents, with ineffective MGT concentrations despite effective blood concentrations. Efavirenz (EFV) is the most highly protein‐bound ARV drug, with >99% binding in blood plasma and the largest BP/SP total EFV concentration ratio, reportedly ranging from 11 to 33. To evaluate protein binding as an explanation for the differences between the drug concentrations in blood and semen, we developed a novel ultrafiltration method, corrected for the duration of centrifugation, to measure protein binding in the two matrices. In six subjects, protein‐free EFV concentrations were the same in blood and semen; the median (interquartile range (IQR)) protein‐free EFV SP/BP ratio was 1.21 (0.99–1.35); EFV protein binding was 99.82% (99.79–99.86) in BP and 95.26% (93.24–96.67) in SP. This shows that the MGT is not a sanctuary from EFV.
Clinical Pharmacology & Therapeutics (2011) 90 1, 151–156. doi:10.1038/clpt.2011.99
We wished to investigate the influence of metal debris exposure on the subsequent immune response and resulting soft-tissue injury following metal-on-metal (MoM) hip arthroplasty. Some reports have ...suggested that debris generated from the head-neck taper junction is more destructive than equivalent doses from metal bearing surfaces.
We investigated the influence of the source and volume of metal debris on chromium (Cr) and cobalt (Co) concentrations in corresponding blood and hip synovial fluid samples and the observed agglomerated particle sizes in excised tissues using multiple regression analysis of prospectively collected data. A total of 199 explanted MoM hips (177 patients; 132 hips female) were analysed to determine rates of volumetric wear at the bearing surfaces and taper junctions.
The statistical modelling suggested that a greater source contribution of metal debris from the taper junction was associated with smaller aggregated particle sizes in the local tissues and a relative reduction of Cr ion concentrations in the corresponding synovial fluid and blood samples. Metal debris generated from taper junctions appears to be of a different morphology, composition and therefore, potentially, immunogenicity to that generated from bearing surfaces.
The differences in debris arising from the taper and the articulating surfaces may provide some understanding of the increased incidence of soft-tissue reactions reported in patients implanted with MoM total hip arthroplasties compared with patients with hip resurfacings. Cite this article: Bone Joint J 2016;98-B:925-33.
Canine T‐zone lymphoma (TZL) is a subtype of T‐cell lymphoma characterized by unique histologic pattern and cytomorphology, immunophenotypic loss of CD45 expression, and an indolent clinical ...behaviour. Dogs with TZL typically present with 1 or more enlarged lymph nodes and/or lymphocytosis. We describe a novel extranodal presentation of TZL involving the tongue. Twelve dogs with tongue masses were diagnosed with lingual TZL based on a variable combination of immunophenotyping via flow cytometry, cytology, histopathology, immunohistochemistry and/or PCR for antigen receptor rearrangement (PARR) assay. Eleven dogs exhibited concurrent lymphocytosis and/or lymph node enlargement. Three cases were initially diagnosed as plasma cell tumours based on histology alone, thereby revealing a potential diagnostic challenge. Seven dogs achieved clinical remission and 4 achieved stable disease following variable treatment, consistent with the indolent nature of typical TZL involving the lymph nodes and peripheral blood. In 1 case the TZL resulted in progressive disease and failure to respond to treatment. In this case, the TZL exhibited histologic features of a higher grade neoplasm. This case series highlights a unique presentation of TZL and identifies a new differential diagnosis for lingual neoplasia. In this study, we characterize the clinical presentation, diagnostic features and patient outcomes of 12 dogs with lingual TZL.
Recycling of metal waste for feedstock material in additive manufacturing (AM) is typically carried out through energy extensive melting and solidification processing techniques. However, in austere ...environments, energy production can be limited and thus melting down scrap into powder through an atomization process is not a viable approach to producing feedstock from reclaimed waste. However, advancements in solid-state material processing has led to a novel additive manufacturing process that uses solid, macroscale structural feed-rods that allow for high deposition rates with wrought-like mechanical properties. This process, additive friction stir deposition (AFS-D), leverages friction between the rotating feed-rod and the substrate (or previous deposition layer) to soften and promote material flow that creates a plasticized and metallurgically bonded material layer. As such, the AFS-D approach is ideally suited to directly process metal waste with minimal material preparation. To illustrate this concept, we demonstrate AM builds with refined microstructure and wrought-like properties made using loose machines chips. The results of this study demonstrate the potential to recycle metal machine chips by feeding them directly into the AFS-D process and produce structurally sound depositions that can be used for Point-of-Need manufacturing within austere environments.
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