ELEVATED LEVELS OF PLATELETS AND MDM2 EXPRESSION ARE CONTRIB-UTING FACTORS TO FACILITATING THE METASTASIS OF OSTEOSARCOMA

poster abstractOsteosarcoma (OS) is the most common form of primary bone cancer and the 6th leading cause of cancer in pediatric patients. A chart review of OS patients treated at this institution suggests that a high platelet count at di-agnosis is significantly (p=0.023) and inversely associated with the first year of survival. As the effects of platelet interaction with OS have been exten-sively researched and suggest that platelets may facilitate tumor metastasis, and the most important prognostic factor for OS patient survival is metasta-sis to the lungs, we hypothesized that platelets increase metastasis to the lungs and reduce survival. Therefore, we sought to determine whether in-creasing platelet numbers in a well characterized OS mouse model would de-crease survival and/or increase metastasis to the lungs. We found that thrombopoietin (TPO) treated mice, had increased platelet numbers, died earlier than placebo treated controls, and that lungs from TPO treated mice contained a small number of large tumor cells (most metastatic lesions were 2-4 cells), whereas lungs from placebo treated controls showed no signs of metastases. Next, an OS tissue microarray (TMA) was built from OS patients seen at our institution over the past 10 years. Mdm2, p53, TPO, and c-mpl expression were evaluated by immunohistochemical (IHC) staining followed by quantitation using the Aperio Imaging system and analysis software. C-mpl (TPO receptor) expression was higher in the metastatic than the primary tumors, suggesting that platelets may contribute to the metastasis of OS. Elevated levels of Mdm2 correlated with metastasis and lower levels of p53, as detected by IHC. In conclusion, both the mouse model and the human OS data were similar, suggesting that both platelets and Mdm2 promote metas-tases in OS

Performance of the lateral flow assay and the latex agglutination serum cryptococcal antigen test in cryptococcal disease in patients with and without HIV

Cryptococcal epidemiology is shifting toward HIV-negative populations who have diverse presentations. Cryptococcal antigen (CrAg) testing is also changing, with development of the lateral flow assay (LFA) having reported increased sensitivity and specificity, but with minimal knowledge in the HIV-negative population. In this study, we evaluate the real-life performance of CrAg testing in patients with cryptococcal disease. We conducted a retrospective review of patients with cryptococcosis from 2002 to 2019 at Barnes-Jewish Hospital. Latex agglutination (LA) was used exclusively until April 2016, at which point LFA was used exclusively. Demographics, presentations, and testing outcomes were evaluated. Serum CrAg testing was completed in 227 patients with cryptococcosis. Of 141 HIV-negative patients, 107 had LA testing and 34 had LFA testing. In patients with disseminated disease, serum CrAg sensitivity by LA was 78.1% compared to 82.6% for LFA. In patients with localized pulmonary disease, serum CrAg sensitivity was 23.5% compared to 90.9% for LFA. Of 86 people living with HIV (PLWH), 76 had LA testing, and 10 had LFA testing. Serum CrAg sensitivity for LA was 94.7% compared to 100% for LFA in patients with disseminated disease. We noted a significant improvement in sensitivity from LA testing to LFA testing, predominantly in those with localized pulmonary disease. However, both LFA and LA appear to be less sensitive in HIV-negative patients than previously described in PLWH

Potential missed opportunities for diagnosis of cryptococcosis and the association with mortality: A cohort study

BACKGROUND: Cryptococcosis is one of the most common life-threatening opportunistic mycoses worldwide. Insidious presentation and slow onset of symptoms make it difficult to recognize, complicating the diagnostic process. Delays in diagnosis may lead to increased mortality. We aim to determine the frequency of missed opportunities for diagnosis of cryptococcosis and its effects on mortality. METHODS: To estimate the proportion of individuals with a potentially missed diagnosis for cryptococcosis in hospitalized patients, we conducted a retrospective cohort study using the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2015 from eight states. All hospitalized adult patients diagnosed with cryptococcal infection or cryptococcal meningitis were included. Potentially missed diagnoses were defined as admissions coded for a procedure or diagnosis suggestive of cryptococcosis in the 90-days prior to the initial cryptococcosis admission. Generalized estimating equations models were used to evaluate the association between underlying comorbidities and potential missed diagnosis of cryptococcosis and 90-day all-cause in-hospital mortality. FINDINGS: Of 5,354 patients with cryptococcosis, 2,445 (45·7%) were people living with HIV (PLWH). Among PLWH, 493/2,445 (20·2%) had a potentially missed diagnosis, of which 83/493 (16·8%) died while hospitalized compared with 265/1,952 (13·6%) of those without a potentially missed diagnosis (relative risk [RR] 1·04, 95% CI 0·99-1·09). Among HIV-negative patients, 977/2,909 (33·6%) had a potentially missed diagnosis, of which 236/977 (24·2%) died while hospitalized compared with 298/1,932 (15·4%) of those not missed (RR 1·12, 95% CI 1·07-1·16). INTERPRETATION: Missed opportunities to diagnose cryptococcosis are common despite highly efficacious diagnostic tests and are associated with increased risk of 90-day mortality in HIV-negative patients. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality. FUNDING: National Center for Advancing Translational Sciences, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality

Different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development

<p>Abstract</p> <p>Background</p> <p>Nearly 50% of U.S. women of child-bearing age are overweight or obese, conditions linked to offspring obesity and diabetes.</p> <p>Methods</p> <p>Utilizing the sheep, females were fed a highly palatable diet at two levels of overfeeding designed to induce different levels of maternal body weight increase and adiposity at conception, and from conception to midgestation. Fetal growth and organ development were then evaluated at midgestation in response to these two different levels of overfeeding. Ewes were fed to achieve: 1) normal weight gain (control, C), 2) overweight (125% of National Research Council [NRC] recommendations, OW125) or 3) obesity (150% of NRC recommendations, OB150) beginning 10 wks prior to breeding and through midgestation. Body fat % and insulin sensitivity were assessed at three points during the study: 1) diet initiation, 2) conception and 3) mid-gestation. Ewes were necropsied and fetuses recovered at mid-gestation (day 78).</p> <p>Results</p> <p>OB150 ewes had a higher % body fat than OW125 ewes prior to breeding (P = 0.03), but not at mid-gestation (P = 0.37). Insulin sensitivity decreased from diet initiation to mid-gestation (P = 0.04), and acute insulin response to glucose tended to be greater in OB150 ewes than C ewes (P = 0.09) and was greater than in OW125 ewes (P = 0.02). Fetal crown-rump length, thoracic and abdominal girths, and fetal perirenal fat were increased in the OW125 and OB150 versus C ewes at mid-gestation. However, only fetal heart, pancreas, and liver weights, as well as lipid content of fetal liver, were increased (P < 0.05) in OB150 ewes versus both C and OW125 ewes at midgestation.</p> <p>Conclusions</p> <p>These data demonstrate that different levels of overfeeding, resulting in differing levels of maternal weight gain and adiposity prior to and during pregnancy, lead to differential effects on fetal overgrowth and organ development.</p

Aluminum Effects in Infants and Children

Aluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease

Effect of four-week cannabidiol treatment on cognitive function: secondary outcomes from a randomised clinical trial for the treatment of cannabis use disorder

RATIONALE: Chronic cannabis use is associated with impaired cognitive function. Evidence indicates cannabidiol (CBD) might be beneficial for treating cannabis use disorder. CBD may also have pro-cognitive effects; however, its effect on cognition in people with cannabis use disorder is currently unclear. OBJECTIVES: We aimed to assess whether a 4-week CBD treatment impacted cognitive function. We hypothesised that CBD treatment would improve cognition from baseline to week 4, compared to placebo. METHODS: Cognition was assessed as a secondary outcome in a phase 2a randomised, double-blind, parallel-group and placebo-controlled clinical trial of 4-week daily 200 mg, 400 mg and 800 mg CBD for the treatment of cannabis use disorder. Participants had moderate or severe DSM-5 cannabis use disorder and intended to quit cannabis use. Our pre-registered primary cognitive outcome was delayed prose recall. Secondary cognitive outcomes were immediate prose recall, stop signal reaction time, trail-making task performance, verbal fluency and digit span. RESULTS: Seventy participants were randomly assigned to placebo (n = 23), 400 mg CBD (n = 24) and 800 mg CBD (n = 23). A 200 mg group was eliminated from the trial because it was an inefficacious dose at interim analysis (n = 12) and was not analysed here. For the primary cognitive outcome, there was no effect of CBD compared to placebo, evidenced by a lack of dose-by-time interaction at 400 mg (0.46, 95%CIs: - 1.41, 2.54) and 800 mg (0.89, 95%CIs: - 0.99, 2.81). There was no effect of CBD compared to placebo on secondary cognitive outcomes, except backwards digit span which increased following 800 mg CBD (0.30, 95%CIs: 0.02, 0.58). CONCLUSIONS: In this clinical trial for cannabis use disorder, CBD did not influence delayed verbal memory. CBD did not have broad cognitive effects but 800 mg daily treatment may improve working memory manipulation. CLINICAL TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000,361-36)

Effectiveness of GonaCon as an immunocontraceptive in colony-housed cats

Objectives Non-surgical contraceptive management of free-roaming cat populations is a global goal for public health and humane reasons. The objectives of this study were to measure the duration of contraception following a single intramuscular injection of a gonadotropin-releasing hormone-based vaccine (GonaCon) and to confirm its safe use in female cats living in colony conditions. Methods GonaCon (0.5 ml/cat) was administered intramuscularly to 20 intact female cats (queens), and saline was administered to 10 queens serving as sham-treated controls. Beginning in late February, 4 months after injection, all cats were housed with fertile male cats in a simulated colony environment. Time to pregnancy, fetal counts and vaccine-elicited injection-site reactions were evaluated. Results All control cats (n = 10/10) and 60% (n = 12/20) of vaccinated cats became pregnant within 4 months of the introduction of males. Two additional vaccinates became pregnant (70%; n = 14/20) within 1 year of treatment. Average fetal counts were significantly lower in vaccinated cats than in control cats. Vaccinates had a significantly longer (P = 0.0120) median time to conception (212 days) compared with controls (127.5 days). Injection-site reactions ranging from swelling to transient granulomatous masses were observed in 45% (n = 9/20) of vaccinated cats. Conclusions and relevance A single dose of GonaCon provided contraception lasting for a minimum of 1 year in 30% (n = 6/20) of treated cats. The level of contraception induced by this GonaCon dose and vaccine lot was not sufficiently effective to be recommended for use in free-roaming cats

Effectiveness of GonaCon as an immunocontraceptive in colony-housed cats

Objectives Non-surgical contraceptive management of free-roaming cat populations is a global goal for public health and humane reasons. The objectives of this study were to measure the duration of contraception following a single intramuscular injection of a gonadotropin-releasing hormone-based vaccine (GonaCon) and to confirm its safe use in female cats living in colony conditions. Methods GonaCon (0.5 ml/cat) was administered intramuscularly to 20 intact female cats (queens), and saline was administered to 10 queens serving as sham-treated controls. Beginning in late February, 4 months after injection, all cats were housed with fertile male cats in a simulated colony environment. Time to pregnancy, fetal counts and vaccine-elicited injection-site reactions were evaluated. Results All control cats (n = 10/10) and 60% (n = 12/20) of vaccinated cats became pregnant within 4 months of the introduction of males. Two additional vaccinates became pregnant (70%; n = 14/20) within 1 year of treatment. Average fetal counts were significantly lower in vaccinated cats than in control cats. Vaccinates had a significantly longer (P = 0.0120) median time to conception (212 days) compared with controls (127.5 days). Injection-site reactions ranging from swelling to transient granulomatous masses were observed in 45% (n = 9/20) of vaccinated cats. Conclusions and relevance A single dose of GonaCon provided contraception lasting for a minimum of 1 year in 30% (n = 6/20) of treated cats. The level of contraception induced by this GonaCon dose and vaccine lot was not sufficiently effective to be recommended for use in free-roaming cats