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Itraconazole is recommended for treatment of blastomycosis in dogs. Some evidence suggests that fluconazole might be less hepatotoxic than itraconazole. To compare (1) incidence of clinical remission and death; (2) treatment duration; (3) total drug cost; (4) incidence of relapse; and (5) incidence of increased ALT activities in dogs with blastomycosis treated with fluconazole or itraconazole. One hundred and forty-four dogs with systemic blastomycosis treated with itraconazole or fluconazole from 1998 to 2008. Retrospective case review. Information obtained included signalment, body weight, clinical signs, drug regimen, treatment duration, time to clinical remission, and laboratory results. Neither treatment efficacy between fluconazole (75% remission) and itraconazole (90% remission) nor relapse rate (18% for itraconazole, 22% for fluconazole) was significantly different ( P= .13, .75, respectively). Treatment duration was significantly longer for fluconazole (median 183 days) than for itraconazole (138 days; P= .001). Costs for fluconazole (median $1,223) were significantly less than for itraconazole ($3,717; P < .001). Incidence of increased ALT activities was not significantly different between groups (17% [3/18] for fluconazole, 26% [6/23] for itraconazole; P= .71). Fluconazole is associated with survival to clinical remission in 75% of dogs with blastomycosis. Although dogs receiving fluconazole were treated longer, drug costs were one-third those of itraconazole. Hepatotoxicosis, as estimated by increases in serum ALT activity, can be observed with similar incidence for both drugs. [ABSTRACT FROM AUTHOR]

The article describes a case series of dogs with central nervous system (CNS) blastomycosis. The breeds in the study were a Golden Retriever, a German Shorthaird Pointer, a Samoyed and an English Springer Spaniel. These dogs manifested abnormal neurologic examinations revealing the location of the disease. According to researchers, CNS blastomycosis in dogs has a guarded prognosis.

Purpose: Between 30 and 68% of patients prematurely discontinue their antidepressant treatment, posing significant risks to patient safety and healthcare outcomes. Online healthcare forums have the potential to offer a rich and unique source of data, revealing dimensions of antidepressant discontinuation that may not be captured by conventional data sources., Methods: We analyzed 891 patient narratives from the online healthcare forum, "askapatient.com," utilizing content analysis to create PsyRisk-a corpus highlighting the risk factors associated with antidepressant discontinuation. Leveraging PsyRisk, alongside PsyTAR [a publicly available corpus of adverse drug reactions (ADRs) related to antidepressants], we developed a machine learning-driven algorithm for proactive identification of patients at risk of abrupt antidepressant discontinuation., Results: From the analyzed 891 patients, 232 reported antidepressant discontinuation. Among these patients, 92% experienced ADRs, and 72% found these reactions distressful, negatively affecting their daily activities. Approximately 26% of patients perceived the antidepressants as ineffective. Most reported ADRs were physiological (61%, 411/673), followed by cognitive (30%, 197/673), and psychological (28%, 188/673) ADRs. In our study, we employed a nested cross-validation strategy with an outer 5-fold cross-validation for model selection, and an inner 5-fold cross-validation for hyperparameter tuning. The performance of our risk identification algorithm, as assessed through this robust validation technique, yielded an AUC-ROC of 90.77 and an F1-score of 83.33. The most significant contributors to abrupt discontinuation were high perceived distress from ADRs and perceived ineffectiveness of the antidepressants., Conclusion: The risk factors identified and the risk identification algorithm developed in this study have substantial potential for clinical application. They could assist healthcare professionals in identifying and managing patients with depression who are at risk of prematurely discontinuing their antidepressant treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor LW declared a shared affiliation with author DF at the time of the review. The reviewer LT declared a shared affiliation with the authors MK and TP at the time of the review., (Copyright © 2023 Zolnour, Eldredge, Faiola, Yaghoobzadeh, Khani, Foy, Topaz, Kharrazi, Fung, Fontelo, Davoudi, Tabaie, Breitinger, Oesterle, Rouhizadeh, Zonnor, Moen, Patrick and Zolnoori.)

Multiple myeloma remains an incurable plasma cell malignancy despite the rapidly evolving treatment landscape. Chimeric antigen receptor T cells targeted against BCMA have recently shown great promise in relapsed refractory multiple myeloma; however, all patients ultimately still progress from their disease. Lack of CAR T-cell persistence, impaired T-cell fitness in autologous CAR T-cell products and the presence of an immunosuppressive bone marrow (BM) microenvironment are contributory factors to treatment failure. We generated anti-BCMA CAR T cells from healthy donors (HD) and patients with multiple myeloma at different stages of disease to compare their T-cell profile, fitness, and cytotoxic activity in preclinical studies. We also used an ex vivo assay with multiple myeloma BM biopsies from distinct genomic subgroups to test the efficacy of HD-derived CAR T cells in a clinically relevant model. HD volunteers showed increased T-cell counts, higher CD4/CD8 ratio, and expanded naïve T-cell population compared with patients with multiple myeloma. After anti-BCMA CAR T-cell production, patients with relapsed multiple myeloma had lower frequencies of CAR + T cells, decreased central memory phenotype, and increased checkpoint inhibitory markers compared with HD-derived products, which compromised their expansion and cytotoxicity against multiple myeloma cells in vitro . Importantly, HD-derived CAR T cells efficiently killed primary multiple myeloma cells within the BM microenvironment of different multiple myeloma genomic subgroups and their cytotoxic activity could be boosted with gamma secretase inhibitors. In conclusion, allogeneic anti-BCMA CAR T cells are a potential therapeutic strategy for patients with relapsed multiple myeloma and should be further developed in the clinic., Significance: Multiple myeloma is an incurable cancer of the plasma cells. A new therapy with anti-BCMA CAR T cells - the patient's own T cells genetically engineered to find and kill myeloma cancer cells - has shown encouraging results. Unfortunately, patients still relapse. In this study, we propose to use T cells from HD volunteers, which have a stronger T-cell fitness, higher cancer killing capacity, and are ready to be administered when needed., Competing Interests: A.M. Metelo reports grants from Allogene Therapeutics during the conduct of the study. A. Jozwik reports grants from Allogene during the conduct of the study and grants from Servier outside the submitted work. C. Graham reports grants from Allogene during the conduct of the study; grants from Servier outside the submitted work. M. Streetly reports personal fees from Bristol Myers Squibb / Celgene, personal fees from Janssen-Cilag, and personal fees from EuSa Pharma outside the submitted work. T. Bentley reports non-financial support and other from Allogene Therapeutics, Inc during the conduct of the study. B. Boldajipour reports personal fees from Pfizer, personal fees from Kite Pharma, and personal fees from Lyell Immunopharma outside the submitted work; in addition, B. Boldajipour has a patent to US10294304B2 issued. C. Sommer reports other from Allogene Therapeutics, Inc. outside the submitted work; in addition, C. Sommer has a patent to US Provisional Application Nos.: 62/962,014 and 63/117,281 pending. B. Sasu is an employee and receives stocks and salary from Allogene Therapeutics. R. Benjamin reports grants from Allogene Therapeutics during the conduct of the study. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: People donating blood more than twice annually are at risk of developing iron deficiency. Little is known about the iron status of dogs enrolled in blood donor programs., Hypothesis: Dogs donating blood ≥6 times annually will show evidence of iron deficiency based on their reticulocyte indices., Animals: Thirteen dogs enrolled in a blood donor program donating ≥6 times over the preceding 12 months and 20 healthy nondonor control dogs., Methods: Prospective observational study. Mature red blood cell (RBC) indices, reticulocyte indices, serum iron, serum ferritin, and total iron-binding capacity (TIBC) were compared between groups., Results: Packed cell volume (median 47%, range 40-52%, P < .01), hematocrit (median 46.4%, range 40.3-52.5%, P < .01), and reticulocyte count (median 16,000/μL, range 9,000-38,000/μL, P < .01) were significantly lower in the blood donor dogs. No statistically significant differences were noted in the mature RBC indices between groups. Both reticulocyte mean corpuscular volume (median 88.8 fL, range 83.4-95.5 fL, P = .03) and reticulocyte hemoglobin content (median 24.6 pg, range 23.1-26.6 pg, P < .01) were significantly lower in the blood donor group. Serum iron and ferritin were similar between groups; however, TIBC was significantly higher in the control group (median 403 μg/dL, range 225-493 μg/dL, P = .02)., Conclusions: The findings in dogs donating ≥6 times annually suggest the presence of iron-deficient erythropoiesis in this population., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.)

Background: Serum and urine Blastomyces antigen concentrations can be used to diagnose blastomycosis in dogs., Objectives: Blastomyces antigen concentrations correlate with clinical remission in dogs during antifungal treatment, and detect disease relapse after treatment discontinuation., Animals: 21 dogs with newly diagnosed blastomycosis monitored until clinical remission (Treatment Phase), and 27 dogs monitored over 1 year from the time of antifungal discontinuation or until clinical relapse (After Treatment Phase)., Methods: Prospective study. Dogs were monitored monthly during treatment and every 3 months after treatment discontinuation, with a complete history, physical exam, chest radiographs, and ocular exam. Urine and serum Blastomyces antigen concentrations were measured at each visit using a quantitative enzyme immunoassay., Results: At enrollment in the Treatment Phase, Blastomyces antigen was positive in all 21 urine samples (100% sensitivity; 95% CI 85-100%), and in 18 of 20 serum samples (90% sensitivity; 95% CI 70-97%). At 2-4 months of treatment, urine antigen was more sensitive for clinically detectable disease (82%; CI 60-94%) than serum antigen (18%; CI 6-41%). The sensitivity of the urine test for clinical relapse was 71% (CI 36-92%), with close to 100% specificity (CI 84-100%) during after treatment surveillance in this population., Conclusions: Urine Blastomyces antigen testing has high sensitivity for active disease at the time of diagnosis and during treatment, and moderate sensitivity but high specificity for clinical relapse. Urine testing should be useful at the time of diagnosis, when treatment discontinuation is being considered, and anytime there is poor clinical response or suspicion of relapse., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Background: The diagnosis of intestinal lymphangiectasia (IL) has been associated with characteristic duodenal mucosal changes. However, the sensitivity and specificity of the endoscopic duodenal mucosal appearance for the diagnosis of IL are not reported., Hypothesis/objectives: To evaluate the utility of endoscopic images of the duodenum for diagnosis of IL. Endoscopic appearance of the duodenal mucosal might predict histopathologic diagnosis of IL with a high degree of sensitivity and specificity., Animals: 51 dogs that underwent upper gastrointestinal (GI) endoscopy and endoscopic biopsies., Methods: Retrospective review of images acquired during endoscopy. Dogs were included if adequate biopsies were obtained during upper GI endoscopy and digital images were saved during the procedure. Images were assessed for the presence and severity of IL. Using histopathology as the gold standard, the sensitivity and specificity of endoscopy for diagnosing IL were calculated., Results: Intestinal lymphangiectasia (IL) was diagnosed in 25/51 dogs. Gross endoscopic appearance of the duodenal mucosa had a sensitivity and specificity (95% confidence interval) of 68% (46%, 84%) and 42% (24%, 63%), respectively for diagnosis of IL. Endoscopic images in cases with lymphopenia, hypocholesterolemia, and hypoalbuminemia had a sensitivity of 80%., Conclusions and Clinical Importance: Endoscopic duodenal mucosa appearance alone lacks specificity and has only a moderate sensitivity for diagnosis of IL. Evaluation of biomarkers associated with PLE improved the sensitivity; however, poor specificity for diagnosis of IL supports the need for histopathologic confirmation., (Copyright © 2012 by the American College of Veterinary Internal Medicine.)

Background: International humanitarian aid workers providing care in emergencies are subjected to numerous chronic and traumatic stressors., Objectives: To examine consequences of such experiences on aid workers' mental health and how the impact is influenced by moderating variables., Methodology: We conducted a longitudinal study in a sample of international non-governmental organizations. Study outcomes included anxiety, depression, burnout, and life and job satisfaction. We performed bivariate regression analyses at three time points. We fitted generalized estimating equation multivariable regression models for the longitudinal analyses., Results: Study participants from 19 NGOs were assessed at three time points: 212 participated at pre-deployment; 169 (80%) post-deployment; and 154 (73%) within 3-6 months after deployment. Prior to deployment, 12 (3.8%) participants reported anxiety symptoms, compared to 20 (11.8%) at post-deployment (p = 0.0027); 22 (10.4%) reported depression symptoms, compared to 33 (19.5%) at post-deployment (p = 0.0117) and 31 (20.1%) at follow-up (p = .00083). History of mental illness (adjusted odds ratio [AOR] 4.2; 95% confidence interval [CI] 1.45-12.50) contributed to an increased risk for anxiety. The experience of extraordinary stress was a contributor to increased risk for burnout depersonalization (AOR 1.5; 95% CI 1.17-1.83). Higher levels of chronic stress exposure during deployment were contributors to an increased risk for depression (AOR 1.1; 95% CI 1.02-1.20) comparing post- versus pre-deployment, and increased risk for burnout emotional exhaustion (AOR 1.1; 95% CI 1.04-1.19). Social support was associated with lower levels of depression (AOR 0.9; 95% CI 0.84-0.95), psychological distress (AOR = 0.9; [CI] 0.85-0.97), burnout lack of personal accomplishment (AOR 0.95; 95% CI 0.91-0.98), and greater life satisfaction (p = 0.0213)., Conclusions: When recruiting and preparing aid workers for deployment, organizations should consider history of mental illness and take steps to decrease chronic stressors, and strengthen social support networks.

The Mixed-Lineage Leukemia (MLL) gene encodes a Trithorax-related chromatin-modifying protooncogene that positively regulates Hox genes. In addition to their well-characterized roles in axial patterning, Trithorax and Polycomb family proteins perform less-understood functions in vertebrate hematopoiesis. To define the role of MLL in the development of the hematopoietic system, we examined the potential of cells lacking MLL. Mll-deficient cells could not develop into lymphocytes in adult RAG-2 chimeric animals. Similarly, in vitro differentiation of B cells required MLL. In chimeric embryos, Mll-deficient cells failed to contribute to fetal liver hematopoietic stem cell/progenitor populations. Moreover, we show that aorta-gonad-mesonephros (AGM) cells from Mll-deficient embryos lacked hematopoietic stem cell (HSC) activity despite their ability to generate hematopoietic progeny in vitro. These results demonstrate an intrinsic requirement for MLL in definitive hematopoiesis, where it is essential for the generation of HSCs in the embryo.

V(D)J recombination is targeted by short recombination signal (RS) sequences that are relatively conserved but exhibit natural sequence variations. To evaluate the potential of RS sequence variations to determine the primary and peripheral TCRbeta repertoire, we generated mice containing specific replacement of the endogenous Vbeta14 RS with the 3'Dbeta1 RS (Vbeta14/3'DbetaRS). These mice exhibited a dramatic increase in Vbeta14(+) thymocyte numbers at the expense of thymocytes expressing other Vbetas. In addition, the percentage of peripheral Vbeta14(+) alphabeta T lymphocytes was similarly increased. Strikingly, this altered Vbeta repertoire resulted predominantly from a higher relative level of primary Vbeta14/3'DbetaRS rearrangement to DbetaJbeta complexes, despite the ability of the 3'Dbeta1 RS to break B12/23 restriction and allow direct rearrangement of Vbeta14/3'DbetaRS to Jbeta segments.

Radiosensitive severe combined immune deficiency in humans results from mutations in Artemis, a protein which, when coupled with DNA-dependent protein kinase catalytic subunit (DNA-PKcs), possesses DNA hairpin-opening activity in vitro. Here, we report that Artemis-deficient mice have an overall phenotype similar to that of DNA-PKcs-deficient mice-including severe combined immunodeficiency associated with defects in opening and joining V(D)J coding hairpin ends and increased cellular ionizing radiation sensitivity. While these findings strongly support the notion that Artemis functions with DNA-PKcs in a subset of NHEJ functions, differences between Artemis- and DNA-PKcs-deficient phenotypes, most notably decreased fidelity of V(D)J signal sequence joining in DNA-PKcs-deficient but not Artemis-deficient fibroblasts, suggest additional functions for DNA-PKcs. Finally, Artemis deficiency leads to chromosomal instability in fibroblasts, demonstrating that Artemis functions as a genomic caretaker.

Leukocyte capture and rolling are mediated by selectins expressed on leukocytes (L-selectin) and the vascular endothelium (P- and E-selectin). To investigate the role of core 2 beta1-6-N-glucosaminyltransferase (C2GlcNAcT-I) for synthesis of functional selectin ligands in vivo, leukocyte rolling flux and velocity were studied in venules of untreated and tumor necrosis factor-alpha (TNFalpha)-pretreated autoperfused cremaster muscles of C2GlcNAcT-I-deficient (core 2(-/-)) and littermate control mice. In untreated core 2(-/-) mice, leukocyte rolling was dramatically reduced with markedly increased rolling velocities (81 +/- 4 microm/s vs 44 +/- 3 microm/s). The reduced rolling in core 2(-/-) mice was due mainly to severely impaired binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1). Some rolling remained after blocking PSGL-1 in controls but not in core 2(-/-) mice. In TNFalpha-pretreated mice, rolling was markedly reduced in core 2(-/-) mice owing to impaired P-selectin- and E-selectin-mediated rolling. Rolling velocities in core 2(-/-) mice treated with an E-selectin-blocking monoclonal antibody (59 +/- 4 microm/s) were significantly higher than in controls (14 +/- 1 microm/s), which provides further evidence for the severe impairment in P-selectin-mediated rolling. In conclusion, P-selectin ligands including PSGL-1 are largely C2GlcNAcT-I dependent. In addition, E-selectin-mediated rolling in vivo is partially dependent on the targeted C2GlcNAcT-I. (Blood. 2001;97:3812-3819)

Objectives: To compare the findings of continuous wave Doppler (CWD) with duplex ultrasound in the assessment of primary and uncomplicated varicose veins, and to determine how their relative roles might be best applied., Materials and Methods: One hundred consecutive limbs were studied in 73 patients with primary (no previous surgery) and uncomplicated (no significant skin change) varicose veins. CWD was employed by a single observer; followed by duplex scanning performed "blind" and independently., Results: There were 87 limbs with long saphenous incompetence on duplex; all but four of which were correctly identified by CWD, by which technique there were no false positives. (Sensitivity 95%, specificity 100%.) There were 21 limbs with short saphenous incompetence on duplex, all but two of which were recognised on CWD. However, CWD incorrectly diagnosed reflux at the saphenopopliteal junction in five limbs (false positives) with what was, in fact, segmental reflux in the long saphenous trunk on duplex (sensitivity 90%, specificity 93%.) This would have led to inappropriate exploration of the saphenopopliteal junction had surgery proceeded without checking with duplex., Conclusions: CWD is adequate for long saphenous incompetence. All "reflux" demonstrated on CWD in the popliteal fossa (about 25% of cases) should be checked by duplex. If this policy had been followed, all the patients in this study would have undergone the correct procedure. The only "errors" would have been missing coexistent short saphenous incompetence in two limbs undergoing appropriate long saphenous exploration.

Severe interpersonal problems are common in veterans with combat-related posttraumatic stress disorder (PTSD) and their families. The authors first detail the rationale and use of behaviorally based family therapy to help reduce avoidance and withdrawal symptoms of PTSD and improve the active coping capacities of both veterans and their loved ones, then present a case example of the model, and finally discuss the clinical application of behavioral family therapy to the unique concerns of veterans with combat-related PTSD.

This paper describes a needs analysis and resulting curriculum in Health Care Informatics. It is implemented as a track for the BS degree within the Department of Information Systems at the University of Maryland, Baltimore County. The track in Health Care Informatics is an interdisciplinary specialty within the broader field of Information Systems which is itself an interdisciplinary field. The needs analysis shows current thinking by practitioners and educators in the new field of Health Care Informatics. It also presents a survey of undergraduate students to monitor interest in and knowledge of this field. A curriculum design is presented that addresses these needs.

Social-skills training was used to modify abusive verbal outbursts displayed by two adult psychiatric patients. Five target behaviors--looking, irrelevant comments, hostile comments, inappropriate requests, and appropriate requests were monitored during role-played situations. Social-skills training, consisting of behavior rehearsal with modelling, focused instructions, and feedback, was introduced in a multiple-baseline design across individuals. Training improved all target behaviors. The improved behavior generalized to: (1) novel scenes role-played with the original respondent, (2) training and novel scenes role-played with a different respondent, and (3) interpersonal situations on the hospital ward.