Nestin expression in osteocytes following myeloablation and during bone marrow metastasis.

Nestin is an intermediate filament protein, which was originally detected in neuroepithelial stem cells. Besides its use as a phenotypic marker of mesenchymal stem cells in the hematopoeitic stem cell niche, the functional interpretation of nestin+ cells remains elusive. We investigated the cellular expression of nestin in bone marrow trephine biopsies of MPN patients, following myeloablation at a stage of hypocellularity during early regeneration. Here, nestin is highly expressed in mature osteocytes, arteriolar endothelial and perivascular cells and small capillaries within the bone marrow space, but not in sinusoid lining cells. This is in stark contrast to nestin expression pattern in myeloproliferative neoplasms that show hypercellularity due to oncogenic driver mutations. Here, nestin is expressed exclusively in endothelial cells of arterioles, but not in osteocytes or small capillaries. Thus, the pattern of nestin expression following myeloablation inversely correlates with cellularity in the bone marrow. This nestin expression pattern is mimicking early postnatal transcriptional programming during bone marrow development. We show that nestin expression in osteocytes occurs across different species following transplant and also in bone marrow metastasis.

Association between economic and arrhythmic burden of paroxysmal atrial fibrillation in patients with cardiac implanted electronic devices.

BACKGROUND: As the prevalence of atrial fibrillation (AF) increases, a greater understanding of the costs associated with AF care is required. While individuals with greater arrhythmic burden may interact with the health system more frequently, the relationship between AF burden and costs remains undefined. METHODS: In a longitudinal patient cohort with paroxysmal AF and newly implanted cardiovascular implantable electronic devices (CIED) (2010-2016), we linked CIED remote-monitoring data with Medicare claims to assess the association between the 30-day averaged device-detected daily percentage of time in AF ("AF burden") and healthcare costs. RESULTS: Among 39,345 patients, the mean age was 77.1 ± 8.7 years, 60.7% were male, and the mean CHA2DS2-VASc score was 4.9 ± 1.3. The mean total 1-year costs were $18,668 ± 29,173, driven by hospitalization costs where two-thirds of admissions were due to heart failure. Increasing AF burden was associated with increasing costs: $17,860 ± 28,525 for 0% daily AF burden; $18,840 ± 29,104 for 0-5% daily AF burden; and $20,968 ± 31,228 for 5-98% daily AF burden. There was a linear relationship between AF burden expressed as a continuous variable and 1-year costs (adjusted cost rate ratio 1.031 per 10% daily duration in AF, 95% confidence interval 1.023-1.038; P < .001). CONCLUSIONS: Among older patients with paroxysmal AF and CIEDs, increasing AF burden is associated with higher healthcare costs. As the observational study design is unable to determine causal relationships, prospective study is required to explore the intriguing hypothesis that targeted AF strategies, including comorbidity management, that reduce AF burden may also reduce the high annual costs associated with AF.

Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.

Healthcare Utilization for Medicaid-Insured Children with Medical Complexity: Differences by Sociodemographic Characteristics.

OBJECTIVE: To compare differences in healthcare utilization and costs for Medicaid-insured children with medical complexity (CMC) by race/ethnicity and rurality. METHODS: Retrospective cohort of North Carolina (NC) Medicaid claims for children 3-20 years old with 3 years continuous Medicaid coverage (10/1/2015-9/30/2018). Exposures were medical complexity, race/ethnicity, and rurality. Three medical complexity levels were: without chronic disease, non-complex chronic disease, and complex chronic disease; the latter were defined as CMC. Race/ethnicity was self-reported in claims; we defined rurality by home residence ZIP codes. Utilization and costs were summarized for 1 year (10/1/2018-9/30/2019) by complexity level classification and categorized as acute care (hospitalization, emergency [ED]), outpatient care (primary, specialty, allied health), and pharmacy. Per-complexity group utilization rates (per 1000 person-years) by race/ethnicity and rurality were compared using adjusted rate ratios (ARR). RESULTS: Among 859,166 Medicaid-insured children, 118,210 (13.8%) were CMC. Among CMC, 36% were categorized as Black non-Hispanic, 42.7% White non-Hispanic, 14.3% Hispanic, and 35% rural. Compared to White non-Hispanic CMC, Black non-Hispanic CMC had higher hospitalization (ARR = 1.12; confidence interval, CI 1.08-1.17) and ED visit (ARR = 1.17; CI 1.16-1.19) rates; Hispanic CMC had lower ED visit (ARR = 0.77; CI 0.75-0.78) and hospitalization rates (ARR = 0.79; CI 0.73-0.84). Black non-Hispanic and Hispanic CMC had lower outpatient visit rates than White non-Hispanic CMC. Rural CMC had higher ED (ARR = 1.13; CI 1.11-1.15) and lower primary care utilization rates (ARR = 0.87; CI 0.86-0.88) than urban CMC. DISCUSSION: Healthcare utilization varied by race/ethnicity and rurality for Medicaid-insured CMC. Further studies should investigate mechanisms for these variations and expand higher value, equitable care delivery for CMC.

Reverse sneezing as a clinical manifestation of nasopharyngeal-oropharyngeal fistula in a dog.

A 6-year-old spayed female Labrador retriever was evaluated for a 3-month history of intermittent reverse sneezing and gagging episodes. Pertinent findings at evaluation included frequent reverse sneezing and non-productive retching. No pathology was visible on sedated oral examination. Contrast-enhanced computed tomography of the skull revealed a gas-filled defect within the left ventral aspect of the soft palate. A non-eroded defect was present in the left caudoventral nasopharyngeal wall on nasopharyngoscopy. Surgical exploration revealed a nasopharyngeal-oropharyngeal fistula within the left palatine tonsillar fossa. The dog had a witnessed oropharyngeal stick injury (OSI) 3 months previous in the location of the fistula. The OSI had been allowed to heal by secondary intention and was treated with an oral antibiotic and NSAID. However, the dog lacked characteristic signs of a chronic OSI such as nasal discharge or abscess formation. The defect in the soft palate was surgically debrided and closed, and the left palatine tonsil was excised. The dog recovered completely with cessation of reverse sneezing and retching episodes.

Éternuements inversés comme manifestation clinique d'une fistule oropharyngée-nasopharyngée chez un chien. Une femelle Labrador stérilisée âgée de 6 ans a été évaluée pour une histoire de 3 mois d'épisodes intermittents d'éternuements inversés et d'étouffements. Les résultats pertinents lors de l'évaluation comprenaient des éternuements inversés fréquents et des haut-le-coeur non productifs. Aucune pathologie n'était visible à l'examen oral sous sédation. La tomodensitométrie à contraste amélioré du crâne a révélé une imperfection remplie de gaz dans la face ventrale gauche du palais mou. Une imperfection non érodée était présente dans la paroi nasopharyngée caudo-ventrale gauche à la nasopharyngoscopie. L'exploration chirurgicale a révélé une fistule nasopharyngée-oropharyngée au sein de la fosse amygdalienne palatine gauche. Le chien a eu une blessure oropharyngée par une branche (OSI) il y a 3 mois à l'emplacement de la fistule. L'OSI avait été laissée à guérir par seconde intention et a été traitée avec un antibiotique oral et un AINS. Cependant, le chien ne présentait pas de signes caractéristiques d'une OSI chronique comme un écoulement nasal ou la formation d'abcès. Le défaut du palais mou a été chirurgicalement débridé et fermé, et l'amygdale palatine gauche a été excisée. Le chien s'est complètement rétabli avec l'arrêt des épisodes d'éternuements inversés et de haut-le-coeur.(Traduit par Dr Serge Messier).

Glossitis in an older non-corgi dog: Diagnosis and long-term follow-up.

A 9-year-old spayed female 18.8 kg mixed breed boxer dog was referred for evaluation of a 7-month history of difficulty swallowing and prehending food, regurgitation, hypersalivation, and an abnormal dorsiflexion of the tongue. Prior to referral, a barium study was performed, which revealed a mildly dilated esophagus. Treatment with sucralfate, cisapride, and prednisone was initiated. Physical examination revealed bilateral, symmetric atrophy of the temporalis muscles, dorsiflexion of the distal aspect of the tongue with concurrent muscle atrophy, and a reduced gag reflex. Electrodiagnostic examinations revealed spontaneous electrical activity in the muscles of mastication and tongue. Biopsies from the right temporalis, tongue, and biceps femoris muscles were collected. An immune-mediated myositis with fibrosis, scattered CD3, CD4, and CD8+ T-lymphocytes, and upregulation of markers for major histocompatibility antigens were observed in the tongue and temporalis muscles. The dog was treated with a tapering course of prednisone over 2 months and cyclosporine long-term. The dog was maintained on cyclosporine alone for > 2 years and clinical signs remained static, although multiple episodes of aspiration pneumonia occurred. Ultimately, euthanasia was performed due to chronic kidney disease with associated anemia, lethargy, and anorexia.

Glossite chez un chien âgé non-corgi : diagnostic et suivi à long terme. Une chienne boxer de race mixte de 18,8 kg stérilisée âgée de 9 ans a été référée pour l'évaluation d'une histoire de 7 mois de difficulté à avaler et de préhension des aliments, de régurgitation, d'hypersalivation et d'une dorsiflexion anormale de la langue. Avant la référence, un examen baryté a été réalisée et a révélé un oesophage légèrement dilaté. Un traitement par sucralfate, cisapride et prednisone a été initié. L'examen physique a révélé une atrophie bilatérale et symétrique des muscles temporaux, une flexion dorsale de la face distale de la langue avec atrophie musculaire concomitante et un réflexe nauséeux réduit. Les examens électrodiagnostiques ont révélé une activité électrique spontanée dans les muscles de la mastication et de la langue. Des biopsies des muscles temporaux droits, de la langue et du biceps fémoral ont été recueillies. Une myosite à médiation immunitaire avec fibrose, des lymphocytes T CD3, CD4 et CD8+ dispersés et une régulation positive des marqueurs des principaux antigènes d'histocompatibilité ont été observées dans la langue et les muscles temporaux. Le chien a été traité avec une posologie décroissante de prednisone sur 2 mois et de cyclosporine à long terme. Le chien a été maintenu sous cyclosporine seule pendant > 2 ans et les signes cliniques sont restés stables, bien que plusieurs épisodes de pneumonie par aspiration se soient produits. En fin de compte, l'euthanasie a été pratiquée en raison d'une maladie rénale chronique associée à une anémie, une léthargie et une anorexie.(Traduit par Dr Serge Messier).

Prostatitis, steatitis, and diarrhea in a dog following presumptive flea-borne transmission of Bartonella henselae.

Bartonella henselae is increasingly associated with a variety of pathological entities, which are often similar in dogs and human patients. Following an acute flea infestation, a dog developed an unusual clinical presentation for canine bartonellosis. Comprehensive medical, microbiological, and surgical interventions were required for diagnosis and to achieve a full recovery.

The effect of feeding on serum concentrations of cobalamin, folate, trypsin-like immunoreactivity, and pancreatic lipase immunoreactivity in dogs with signs of chronic gastrointestinal disease.

BACKGROUND: It is unknown if serum concentrations of cobalamin, folate, canine pancreatic lipase immunoreactivity (cPLI), and canine trypsin-like immunoreactivity (cTLI) obtained postprandially are equivalent to measurements obtained after withholding food in dogs with suspected gastrointestinal disease. HYPOTHESIS/OBJECTIVES: Measurements of serum concentrations of cobalamin, folate, cPLI, and cTLI postprandially will be equivalent to measurements after 12 hours of withholding food in dogs with signs of chronic gastrointestinal disease. Changes observed will not alter clinical interpretation. ANIMALS: 51 client-owned dogs with signs of gastrointestinal disease. METHODS: Prospective single arm clinical trial. Serum concentrations of cobalamin, folate, cPLI and cTLI 2, 4, and 8 hours postprandially were compared by equivalence testing to values after withholding food for 12 hours (baseline). RESULTS: Mean serum cobalamin concentrations 2 hours (498.1 ± 213.1 ng/L; P = 0.024) and 4 hours (501.9 ± 207.4 ng/L; P = 0.008) postprandial were equivalent to baseline (517.3 ± 211.5 ng/L). Mean serum cTLI 2 hours (31.3 ± 14 µg/L; P < 0.001) and 4 hours (29.6 ± 13.1 µg/L; P = 0.027) postprandial were equivalent to baseline (31.1 ± 15 µg/L). Mean serum folate concentration 2 hours postprandial (15 ± 7.7 µg/L) was equivalent to baseline (13.7 ± 8.3 µg/L; P < 0.001). Equivalence could not be assessed for cPLI due to results below the lower limit of quantification. Feeding altered the clinical interpretation in 27% (cobalamin), 35% (folate), 20% (cTLI), and 12% (cPLI) of dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The clinical interpretation for a substantial number of samples changed after feeding, therefore withholding food before sample collection is prudent.

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

Effect of esomeprazole with and without a probiotic on fecal dysbiosis, intestinal inflammation, and fecal short-chain fatty acid concentrations in healthy dogs.

BACKGROUND: Proton pump inhibitors can cause diarrhea and a transient increase in fecal dysbiosis index in dogs. It is unknown if concurrent probiotic administration mitigates these effects. OBJECTIVE/HYPOTHESIS: To assess the fecal Canine Microbial Dysbiosis Index (CMDI), fecal short chain fatty acid (SCFA), and fecal calprotectin concentrations in dogs administered esomeprazole with and without a probiotic. ANIMALS: Eleven healthy dogs. METHODS: Prospective, within-subjects before and after study. All dogs received 7-day courses of esomeprazole (1 mg/kg PO q 24h) alone followed by esomeprazole with a probiotic (15 billion CFU/kg), separated by a 4-week washout period. Data were compared between phases using mixed effects ANOVA or generalized estimating equations with post-hoc Holm adjustment for 2-way comparisons. RESULTS: Compared to baseline (mean CMDI -2.66, SD 3.04), fecal CMDI was not different with esomeprazole administration alone (mean CMDI -1.48, SD 3.32, P = .08), but there was a significant increase (Diff 3.05, 95% CI [1.37, 4.74], P < .001, Effect size 2.02) when esomeprazole and a probiotic were administered concurrently (mean CMDI 0.39, SD 2.83). CMDI was significantly higher when esomeprazole was administered with a probiotic than alone (Diff 1.87, 95% CI [0.19, 1.87], P = .02, Effect size 1.24). Fecal calprotectin and SCFA concentrations did not differ between phases. The occurrence of vomiting and diarrhea was not different from baseline when esomeprazole was administered alone (36%/27%) or with a probiotic (46%/9%). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, concurrent administration of a probiotic is unlikely to lessen adverse effects associated with esomeprazole administration.

Clinical utility of an immunoglobulin A-based serological panel for the diagnosis of chronic enteropathy in dogs.

BACKGROUND: A panel of IgA-based serologic assays might aid in the diagnosis of chronic enteropathy (CE) in dogs, a syndrome encompassing conditions such as food-responsive enteropathy, immunosuppressant-responsive enteropathy, and inflammatory bowel disease (also referred to as chronic inflammatory enteropathy). However, it is unclear whether these biomarkers discriminate between CE and other types of primary intestinal disorders. OBJECTIVES: To evaluate a diagnostic panel that measures serum concentrations of IgA directed against OmpC (ACA), canine calprotectin (ACNA), and gliadin-derived peptides (AGA) in dogs with well-characterized intestinal diseases. ANIMALS: Fifty-five dogs with primary intestinal disease. METHODS: Serum ACA, ACNA, and AGA concentrations were measured in 30 dogs with CE and 25 dogs with other intestinal diseases (non-CE population), including histoplasmosis, parasitism, E. coli-associated granulomatous colitis, and lymphoma. Serum IgA concentrations were compared among populations, and sensitivities and specificities were calculated using laboratory-provided cut-points. RESULTS: Twenty-six of 30 (87%) CE dogs and 21 of 25 (84%) non-CE dogs had abnormal concentrations (intermediate or high) of at least 2 markers; these proportions were not significantly different (P = .99). A serum ACA concentration ≥15 EU/mL was 86.7% (95% confidence interval [CI], 69.3%-96.2%) sensitive and 24.0% (95% CI, 9.4%-45.1%) specific for CE diagnosis. High AGA concentrations were observed in 16 of 25 (64%) non-CE dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The evaluated serologic markers were poorly specific for CE diagnosis, which raises concerns that their use in clinical practice might lead to misdiagnoses and delayed or even detrimental treatments in dogs with non-CE intestinal diseases.

End-of-Life Care for Patients With Metastatic Renal Cell Carcinoma in the Era of Oral Anticancer Therapy.

PURPOSE: New therapies including oral anticancer agents (OAAs) have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, little is known about the quality of end-of-life (EOL) care and systemic therapy use at EOL in patients receiving OAAs or with mRCC. METHODS: We retrospectively analyzed EOL care for decedents with mRCC in two parallel cohorts: (1) patients (RCC diagnosed 2004-2015) from the University of North Carolina's Cancer Information and Population Health Resource (CIPHR) and (2) patients (diagnosed 2007-2015) from SEER-Medicare. We assessed hospice use in the last 30 days of life and existing measures of poor-quality EOL care: systemic therapy, hospital admission, intensive care unit admission, and > 1 ED visit in the last 30 days of life; hospice initiation in the last 3 days of life; and in-hospital death. Associations between OAA use, patient and provider characteristics, and EOL care were examined using multivariable logistic regression. RESULTS: We identified 410 decedents in the CIPHR cohort (53.4% received OAA) and 1,508 in SEER-Medicare (43.5% received OAA). Prior OAA use was associated with increased systemic therapy in the last 30 days of life in both cohorts (CIPHR: 26.5% v 11.0%; P < .001; SEER-Medicare: 23.4% v 11.7%; P < .001), increased in-hospital death in CIPHR, and increased hospice in the last 30 days in SEER-Medicare. Older patients were less likely to receive systemic therapy or be admitted in the last 30 days or die in hospital. CONCLUSION: Patients with mRCC who received OAAs and younger patients experienced more aggressive EOL care, suggesting opportunities to optimize high-quality EOL care in these groups.

A mechanistic study of the effect of doxorubicin/adriamycin on the estrogen response in a breast cancer model.

OBJECTIVE: Estrogen treatment limits the cytotoxic effects of chemotherapy in estrogen receptor-positive (ER+) breast cancer cell lines, suggesting that estrogen pathway signaling may confer chemotherapeutic resistance. This study investigates the molecular responses of ER+ breast cancer cell lines to the chemotherapeutic agent, doxorubicin, in the presence or absence of estrogen. METHODS: ER+ MCF-7 and T47-D cells were cultured in hormone-starved or estrogen-containing media with or without doxorubicin at concentrations mimicking the low concentrations seen in plasma and tumor microenvironments in humans following typical bolus administration. Protein levels, phosphorylations, and interactions of estrogen-signaling molecules were assessed following these treatments, as well the effects of ER signaling inhibitors on cell proliferation. RESULTS: Surprisingly, estrogen and doxorubicin co-treatment markedly induced pro-growth alterations compared to doxorubicin alone and modestly enhanced estrogen alone-induced changes. Several inhibitors suppressed cell proliferation in the presence of doxorubicin and estrogen. CONCLUSIONS: These findings demonstrate that molecular changes caused by doxorubicin in ER+ breast cancer cells can be reversed by estrogen, providing molecular evidence for the poorer responses of ER+ tumors to doxorubicin in the presence of physiologic estrogen levels. Our results also suggest that the addition of drugs targeting the ER, EGFR, the SFKs, MEK, PI3K, and/or the MMP proteins to a conventional chemotherapy regimen may improve chemosensitivity.

Specialists' approach to tracheal collapse: survey-based opinions on diagnostics, medical management, and comorbid diseases.

OBJECTIVE: To describe the current standard of care among specialists for the routine diagnostic evaluation and medical management of stable tracheal collapse in dogs, identifying gaps between practice and scientific evidence to facilitate the development of future prospective studies. A secondary objective was to describe the perceived incidence of selected comorbid disorders in dogs with tracheal collapse and the diagnostic tests performed to evaluate for those disorders. SAMPLE: 180 veterinary specialists in 22 countries. PROCEDURES: An electronic survey was sent to 4 specialty listservs to target diplomates. Respondents completed multiple-choice and free-response questions related to the diagnostic evaluation and treatment of a theoretical stable dog with suspected tracheal collapse. RESULTS: Most respondents routinely utilized radiography, tracheobronchoscopy, and fluoroscopy to diagnose tracheal collapse and performed airway sampling, sedated airway examination, and echocardiograms to rule out comorbidities. The most frequently perceived comorbid disorders included chronic bronchitis, bronchomalacia, and myxomatous mitral valve disease. Respondents most often prescribed opioid antitussives, glucocorticoids, anxiolytics, and antibiotics as treatments. Less frequently, they utilized bronchodilators and nonopioid medications for cough. CLINICAL RELEVANCE: Despite a lack of published guidelines, specialists have similar approaches in their diagnostic and therapeutic approach to a stable dog with suspected tracheal collapse and believe evaluating for comorbid disorders is important. A description of a typical diagnostic approach and knowledge of realistic treatment goals will assist the general practitioner managing dogs with stable tracheal collapse. Additionally, gaps between current practices established via this survey and data supporting those practices exist, specifically concerning the use of antibiotics and nonopioid medications for cough, representing areas for further study.

Genotoxicity from metronidazole detected in vitro, but not in vivo, in healthy dogs in a randomized clinical trial.

OBJECTIVE: To determine whether metronidazole (MTZ), at recommended therapeutic dosages in dogs, induces peripheral blood cell (PMBC) genotoxicity, using the γ-H2AX assay as a sensitive measure of DNA breaks. The secondary aim was to assess dose-dependent genotoxicity in vitro in dog and cat PBMCs exposed to increasing MTZ concentrations. ANIMALS: 12 healthy employee- and student-owned dogs and blood samples from 2 other healthy untreated dogs and 2 healthy untreated cats. PROCEDURES: Screened dogs were randomized to receive lower-dose MTZ (7.5 mg/kg, PO, q 12 h) or higher-dose MTZ (20 mg/kg, PO, q 12 h) for 7 days. Blood was drawn at baseline, after the 1 week of treatment, and after a 1-week washout, for DNA damage assessment and serum MTZ concentration measurements. For in vitro studies, PBMCs from untreated healthy dogs and cats were exposed to 0 to 500 µg/mL MTZ. RESULTS: No dogs showed a significant increase in DNA damage at these MTZ dosages for 1 week. The highest serum MTZ concentration observed 1 hour after dosing was 36 µg/mL. In vitro, MTZ led to a significant increase in DNA damage at 100 µg/mL in both canine and feline PBMCs. CLINICAL RELEVANCE: Although MTZ was not significantly genotoxic in vivo in the healthy dogs in this study, MTZ was significantly genotoxic to canine PBMCs in vitro at 3-fold higher concentrations than those documented in vivo. The safety of MTZ in clinically ill dogs, which may have impaired MTZ clearance or DNA repair, should be assessed next.

Association between cognitive impairment and oral anticancer agent use in older patients with metastatic renal cell carcinoma.

BACKGROUND: Kidney cancer is the fastest-growing cancer diagnosis in the developed world. About 16% of new cases are stage IV, which has a low five-year survival rate. Many patients with metastatic renal cell carcinoma (mRCC) are older and may have mild cognitive impairment or dementia (MCI/D). Given prior reports of patients with dementia initiating less cancer therapy and the importance of oral anticancer agents (OAAs) in mRCC treatment, we investigated the prevalence of preexisting MCI/D in patients with mRCC and their OAA use. METHODS: SEER-Medicare patients were analyzed who were ≥65 years, diagnosed with mRCC between 2007 and 2015, and had Medicare part D coverage. Patterns and predictors of (a) OAA utilization within the 12 months following mRCC diagnosis and (b) adherence (percent of days covered [PDC] ≥ 80%) during the first 90 days following treatment initiation were assessed. RESULTS: Of the 2792 eligible patients, 268 had preexisting MCI/D, and 907 initiated OAA treatment within 12 months of mRCC diagnosis. Patients with preexisting MCI/D were less likely to begin an OAA than those without MCI/D (fully-adjusted HR 0.53, 95% CI 0.38-0.76). Among OAA initiators, a preexisting MCI/D diagnosis did not alter the likelihood that a person would be adherent (adjusted RR 0.84, 95% CI 0.55-1.28). CONCLUSIONS: Patients with preexisting MCI/D were half as likely to start an OAA during the year following mRCC diagnosis than patients without comorbid MCI/D. The 90-day adherence of OAA initiators was not significantly different between those with and without preexisting MCI/D. In light of this, clinicians should assess mRCC patients for cognitive impairment and take steps to optimize OAA utilization by those with MCI/D.

Do Physiological Variables Predict the Need for Transport to Hospital From Music Festivals? An Analysis of Australian Festival Data.

OBJECTIVE: Using physiological markers to detect patients at risk of deterioration is common. Deaths at music festivals in Australia prompted scrutiny of tools to identify critically unwell patients for transport to hospital. This study evaluated initial physiological parameters to identify patients selected for transport to hospital from a music festival. METHODS: A retrospective audit of 2045 presentations at music festivals in Victoria, Australia, was performed. Presentation heart rate, systolic blood pressure, respiratory rate, oxygen saturation, temperature, and Glasgow Coma Scale were assessed using area under the receiver operating characteristic curve (AUROC) analysis, with a prespecified threshold of 0.7. RESULTS: The only measured variable to exceed the prespecified cutpoint was initial systolic blood pressure, with an AUROC of 0.72 and optimal cutpoint of 122 mmHg. Using commonly accepted cutpoints for variables did not improve detection performance to acceptable levels, nor did using combination systems of cutpoints. CONCLUSIONS: Initial physiological variables are poor predictors of the decision to transport to hospital from music festivals. Systolic blood pressure was significant, but only at a clinically insignificant value. Decisions on which patients to transport from an event site should incorporate more information than initial physiology. Senior clinicians should lead decision-making about hospital transport from music festivals.

Evaluation of mild cognitive impairment and dementia in patients with metastatic renal cell carcinoma.

BACKGROUND: Dementia and cancer are both more common in adults as they age. As new cancer treatments become more popular, it is important to consider how these treatments might affect older patients. This study evaluates metastatic renal cell carcinoma (mRCC) as a risk factor for older adults developing mild cognitive impairment or dementia (MCI/D) and the impact of mRCC-directed therapies on the development of MCI/D. METHODS: We identified patients diagnosed with mRCC in a Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset from 2007 to 2015 and matched them to non-cancer controls. Exclusion criteria included age < 65 years at mRCC diagnosis and diagnosis of MCI/D within the year preceding mRCC diagnosis. The main outcome was time to incident MCI/D within one year of mRCC diagnosis for cases or cohort entry for non-cancer controls. Cox proportional hazards models were used to measure associations between mRCC and incident MCI/D as well as associations of oral anticancer agent (OAA) use with MCI/D development within the mRCC group. RESULTS: Patients with mRCC (n = 2533) were matched to non-cancer controls (n = 7027). mRCC (hazard ratio [HR] 8.52, p < .001), being older (HR 1.05 per 1-year age increase, p < .001), and identifying as Black (HR 1.92, p = .047) were predictive of developing MCI/D. In addition, neither those initiating treatment with OAAs nor those who underwent nephrectomy were more likely to develop MCI/D. CONCLUSIONS: Patients with mRCC were more likely to develop MCI/D than those without mRCC. The medical and surgical therapies evaluated were not associated with increased incidence of MCI/D. The increased incidence of MCI/D in older adults with mRCC may be the result of the pathology itself or risk factors common to the two disease processes.

Single-cell analysis of cultured bone marrow stromal cells reveals high similarity to fibroblasts in situ.

Within the heterogenous pool of bone marrow stromal cells, mesenchymal stromal cells (MSCs) are of particular interest because of their hematopoiesis-supporting capacities, contribution to disease progression, therapy resistance, and leukemic initiation. Cultured bone marrow-derived stromal cells (cBMSCs) are used for in vitro modeling of hematopoiesis-stroma interactions, validation of disease mechanisms, and screening for therapeutic targets. Here, we place cBMSCs (mouse and human) in a bone marrow tissue context by systematically comparing the transcriptome of plastic-adherent cells on a single-cell level with in vivo counterparts. Cultured BMSCs encompass a rather homogenous cell population, independent of the isolation method used and, although still possessing hematopoiesis-supporting capacity, are distinct from freshly isolated MSCs and more akin to in vivo fibroblast populations. Informed by combined cell trajectories and pathway analyses, we illustrate that TGFb inhibition in vitro can preserve a more "MSC"-like phenotype.

Arrhythmic Burden and the Risk of Cardiovascular Outcomes in Patients With Paroxysmal Atrial Fibrillation and Cardiac Implanted Electronic Devices.

BACKGROUND: Whether the amount of atrial fibrillation (AF) patients experience conveys important prognostic information beyond that provided by the diagnosis of AF is uncertain. The study objective was to assess the dose-response relationship between device-detected AF burden and subsequent cardiovascular outcomes. METHODS: Among patients with paroxysmal AF who underwent cardiac implantable electronic device implantation (2010-2016), Merlin.net remote-monitoring data were linked to Medicare claims to assess the magnitude and strength of the associations between device-based AF burden (defined as a daily percentage of time spent in AF or maximal AF episode duration ascertained at baseline over 30 days) and key cardiovascular outcomes. RESULTS: Among 39 710 patients (mean age 77.1±8.7 years, 60.7% male, and a mean CHA2DS2-VASc score 4.9±1.3), all-cause mortality at 1-year increased with baseline AF burden: 8.54% with AF burden 0%, 8.9% with AF burden 0% to 5%, and 10.9% with AF burden 5% to 98% (P<0.001) There was also a dose-response relationship between increasing AF burden and all-cause or cardiovascular hospitalization and ischemic stroke. Updating AF burden data every 30 days did not alter the AF burden-prognostic relationships determined from the use of baseline data alone. Results were also consistent when 3-year outcomes were considered and after accounting for the use of oral anticoagulants. CONCLUSIONS: In paroxysmal AF, there is a clinically relevant dose-response relationship between increasing AF burden and rates of adverse outcomes at 1- and 3-years, including increasing risks of cardiovascular hospitalization, ischemic stroke, and mortality.