Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

Anticoagulation Therapy in Children.

Venous thromboembolism (VTE) is very uncommon in children and adolescents compared with older adults, though its incidence has significantly increased over the past two decades. Given the rarity of the condition, the data on pediatric VTE lag behind the adult experience and consequently the management of VTE in children is, in large part, modeled on the adult strategies. This approach has certain limitations, given that young children have developmental particularities of the hemostatic system and differences in the pharmacokinetics and pharmacodynamics of various anticoagulant agents. The most commonly used anticoagulants in children continue to be the heparins and the vitamin K antagonists. Direct intravenous thrombin inhibitors, argatroban, bivalirudin, have very limited pediatric use. The non-vitamin K antagonist oral anticoagulant drugs (novel oral anticoagulants) present potential advantages in terms of efficacy, safety, and convenience, though pediatric data are limited to preclinical and small phase I trials. There are several ongoing phase I, II, and III trials for dabigatran rivaroxaban, apixaban, and edoxaban, the results of which are likely to change the future management of pediatric thromboses.

Venous Thromboembolic Disease in Children and Adolescents.

The VTE is mainly a disease of the older adult, though its incidence has increased significantly in the pediatric population over the past several years. This trend is likely due to enhanced awareness and recognition of VTE, as well as increased prevalence of thromboembolic associated risk factors, such as increases in the proportion of children with predisposing medical conditions. The evaluation and management of a child with VTE is similar to that of adults, however pediatric patients have their own distinct aspects of care, stemming from particularities of the hemostatic system, age-related risk factors and differences in response to anticoagulant and antithrombotic therapy. This review addresses the risk factors and the evaluation and management of children with VTE.

A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas.

Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony-forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls. At all timepoints, cases had significantly lower levels of CECs, but elevated ECFCs and a pCHSPC:nCHSPC ratio compared with controls (all P-values <0.05). There was no significant difference in any of the cell types analyzed based on tumor histology, stage (localized vs. metastatic), or tumor size. After treatment, only the CECs among the complete responders were significantly lower at end of therapy (P<0.01) compared with nonresponders, whereas the ECFCs among all cases significantly increased (P<0.05) compared with baseline. No decline in the pCHSPC:nCHSPC ratio was observed despite tumor response. On the basis of these results, a validation of CECs as prognostic biomarker is now warranted.

Impact of obesity on the risk of venous thromboembolism in an inpatient pediatric population.

INTRODUCTION: The incidence of venous thromboembolism in children has increased significantly over the past 20 years. Over the same period of time, there was an increase in the prevalence of obesity in the pediatric population. Obesity is a known risk factor for VTE in adults, but little information is available in children. METHODS: This study evaluates the relation between obesity and VTE using a retrospective, case-control design, comparing the body mass index (BMI) of patients admitted with a diagnosis of VTE versus patients admitted with other diagnoses, at a single institution, between 2007 and 2011. RESULTS: We studied 48 inpatients diagnosed with deep venous thrombosis or pulmonary embolism and a control group of 274 age and gender matched patients admitted with other diagnoses. We found obese patients (BMI > 95th percentile) to have significantly higher risk of VTE (odds ratio 2.1, with 95% CI 1.1-4.2) than patients of normal weight (BMI < 85th percentile). Overweight patients (BMI 85th-95th percentile) did not demonstrate a significant change in risk. Most of the VTE patients were adolescents and the majority of them had other identifiable risk factors for thrombosis. CONCLUSION: This study establishes a correlation between obesity and VTE in a group of hospitalized children, showing a risk for VTE in obese children similar to the one described in much larger adult cohorts.

Neuroblastoma in a Newborn Female.

Neuroblastoma is the most common solid tumor in neonates. Although often aggressive in older children, carrying high mortality rates despite multimodal therapies, neuroblastoma appears to behave differently in the neonatal population. When diagnosis is clear, the disease can often be managed with close observation alone. This is a case of neuroblastoma in a 4-day-old female managed with surgical resection. This case highlights the potential challenges of diagnosis of retroperitoneal masses on prenatal ultrasound and in newborns and the importance of utilizing available resources when making difficult decisions in management.

Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.

A case report of hyperthyroid-associated thymic hypertrophy in a child, presenting as an anterior mediastinal mass.

We present the case of an 8-year-old boy with an anterior mediastinal mass and signs of hyperthyroidism. The anterior mediastinal mass had radiologic characteristics suggestive of thymic hypertrophy and regressed with antithyroid therapy. Though thymic hypertrophy is a known manifestation of hyperthyroidism, this is the youngest reported case. In selected cases, the diagnosis may be made based on the clinical picture, radiologic appearance, and response to antithyroid therapy without the need of a thymic biopsy or thymectomy.

Spontaneous pyohaemothorax in a teenager with von Willebrand disease: a case report and review of literature.

An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.

Blood's Concentration of Lead and Arsenic Associated with Anemia in Peruvian Children.

This exploratory, descriptive cohort study (N = 60) determined lead (Pb) and arsenic (As) blood concentrations in Peruvian children and their association with hematological parameters of iron-deficient anemia (IDA) and anthropometric measurement. The mean age of children was 10.8 months (SD = 4.7) and ranged from 3 to 24 months old. Anemia (Hb levels below 10.5 g/dL) was found in 20% of this cohort. Additionally, microcytosis (MCV < 70 fL) was present in 54%, and hypochromia (MCH < 23 pg) in 42% of the group of children. Chi-square analysis showed that 88% of the children with anemia also had microcytosis and hypochromia (p < 0.001). Pb and As were detected in 100% of the infants' blood samples, and the concentrations were significantly higher in older infants than in younger ones. Pb and As were not associated with the sex, anthropomorphic parameters, or infant hemogram changes. Infants who received iron supplementation were 87% less likely to have low Hb compared with those who did not (OR = 0.13, 95% CI = 0.02-0.88, p=0.04). Herbal tea intake was significantly associated with microcytosis and hypochromia. Our finding uncovered that hematological parameters for anemia are modified in Peruvian children with high levels of microcytosis and hypochromia. Concentrations of Pb and As were above method detection limits in all Peruvian children, but these were not associated with IDA or anthropometric measurements. A large study, including other variables, would benefit from allowing a more complex model predicting anemia in Peruvian children.

A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE).

INTRODUCTION: High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. AIM: To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA). METHODS: SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. RESULTS: Fifty-four patients aged 11-58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. CONCLUSION: These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

A highly stable, nanotube-enhanced, CMOS-MEMS thermal emitter for mid-IR gas sensing.

The gas sensor market is growing fast, driven by many socioeconomic and industrial factors. Mid-infrared (MIR) gas sensors offer excellent performance for an increasing number of sensing applications in healthcare, smart homes, and the automotive sector. Having access to low-cost, miniaturized, energy efficient light sources is of critical importance for the monolithic integration of MIR sensors. Here, we present an on-chip broadband thermal MIR source fabricated by combining a complementary metal oxide semiconductor (CMOS) micro-hotplate with a dielectric-encapsulated carbon nanotube (CNT) blackbody layer. The micro-hotplate was used during fabrication as a micro-reactor to facilitate high temperature (>700 [Formula: see text]C) growth of the CNT layer and also for post-growth thermal annealing. We demonstrate, for the first time, stable extended operation in air of devices with a dielectric-encapsulated CNT layer at heater temperatures above 600 [Formula: see text]C. The demonstrated devices exhibit almost unitary emissivity across the entire MIR spectrum, offering an ideal solution for low-cost, highly-integrated MIR spectroscopy for the Internet of Things.

Validation of Appropriate Use Criteria for Coronary Computed Tomographic Angiography for Chest Pain Evaluation in a Tertiary Care Emergency Room.

PURPOSE: Appropriate use criteria (AUC) defines the appropriateness of imaging procedures for specific clinical scenarios to promote evidence-based utilization and improve cost-effective care. The goal of this study was to assess the diagnostic yield and downstream health care resource utilization according to the AUC categorization for coronary computed tomography angiography (CCTA) in emergency department (ED) patients presenting with chest pain. MATERIALS AND METHODS: A total of 789 consecutive patients in the ED with chest pain and no known coronary artery disease (CAD) who underwent CCTA were classified as appropriate, uncertain, or inappropriate use according to the 2010 AUC. We abstracted index and 30-day data from the electronic medical record to determine diagnostic yield (rate of obstructive CAD and revascularization) and health care resource utilization (downstream stress test and 30-d hospital return rate). RESULTS: Rates of appropriate, uncertain, and inappropriate utilization were 48.4%, 48.8%, and 2.8%. Among appropriate, uncertain, and inappropriate classifications, rates of obstructive CAD were 9%, 8%, and 32% (P=0.002); rates of revascularization were 3%, 1%, and 36% (P<0.001); downstream stress test utilization rates were 5% versus 5% versus 14% (P=0.17), and 30-day hospital return rates were 6% versus 6% versus 5% (P>0.99), respectively. CONCLUSIONS: Appropriate and uncertain uses were associated with low diagnostic yield compared with inappropriate use; however, our findings do not demonstrate differences between appropriate use categories with respect to downstream health care resource utilization. Further studies are needed to define the role of AUC for CCTA in the ED setting.

Integrated Wafer Scale Growth of Single Crystal Metal Films and High Quality Graphene.

We report on an approach to bring together single crystal metal catalyst preparation and graphene growth in a combined process flow using a standard cold-wall chemical vapor deposition (CVD) reactor. We employ a sandwich arrangement between a commercial polycrystalline Cu foil and c-plane sapphire wafer and show that close-spaced vacuum sublimation across the confined gap can result in an epitaxial, single-crystal Cu(111) film at high growth rate. The arrangement is scalable (we demonstrate 2″ wafer scale) and suppresses reactor contamination with Cu. While starting with an impure Cu foil, the freshly prepared Cu film is of high purity as measured by time-of-flight secondary ion mass spectrometry. We seamlessly connect the initial metallization with subsequent graphene growth via the introduction of hydrogen and gaseous carbon precursors, thereby eliminating contamination due to substrate transfer and common lengthy catalyst pretreatments. We show that the sandwich approach also enables for a Cu surface with nanometer scale roughness during graphene growth and thus results in high quality graphene similar to previously demonstrated Cu enclosure approaches. We systematically explore the parameter space and discuss the opportunities, including subsequent dry transfer, generality, and versatility of our approach particularly regarding the cost-efficient preparation of different single crystal film orientations and expansion to other material systems.

Understanding metal organic chemical vapour deposition of monolayer WS2: the enhancing role of Au substrate for simple organosulfur precursors.

We find that the use of Au substrate allows fast, self-limited WS2 monolayer growth using a simple sequential exposure pattern of low cost, low toxicity precursors, namely tungsten hexacarbonyl and dimethylsulfide (DMS). We use this model reaction system to fingerprint the technologically important metal organic chemical vapour deposition process by operando X-ray photoelectron spectroscopy (XPS) to address the current lack of understanding of the underlying fundamental growth mechanisms for WS2 and related transition metal dichalcogenides. Au effectively promotes the sulfidation of W with simple organosulfides, enabling WS2 growth with low DMS pressure (<1 mbar) and a suppression of carbon contamination of as-grown WS2, which to date has been a major challenge with this precursor chemistry. Full WS2 coverage can be achieved by one exposure cycle of 10 minutes at 700 °C. We discuss our findings in the wider context of previous literature on heterogeneous catalysis, 2D crystal growth, and overlapping process technologies such as atomic layer deposition (ALD) and direct metal conversion, linking to future integrated manufacturing processes for transition metal dichalcogenide layers.

Treatment of recurrent clear cell sarcoma of the kidney with brain metastasis.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is known for its propensity to metastasize to bone, but it also spreads to other sites including the brain. This study was undertaken to describe the treatment and outcomes of patients with recurrent CCSK involving the brain. METHODS: A retrospective records review was conducted on eight patients with CCSK who developed brain metastases after complete responses to initial therapy. RESULTS: The recurrences occurred at a median of 24.5 months after initial diagnosis (range, 12-53 months). At the time of recurrence, patients were treated with multimodal therapy including biopsy or resection, radiation therapy, and chemotherapy. All patients received a variable number of courses of ifosfamide, carboplatin, and etoposide (ICE), with or without other agents. Four patients received high-dose chemotherapy with autologous stem cell rescue. One patient died from complications of bacteremia 8 weeks after starting chemotherapy. The other seven patients achieved a complete response after either surgery or ICE chemotherapy. Of these, six patients were alive without disease with a median follow-up of 30 months from the time of recurrence (range, 24 to 71 months). All six survivors received radiation therapy and four had gross total resections. Three survivors received high-dose chemotherapy with stem cell rescue. CONCLUSION: Patients with recurrent CCSK involving the brain can have durable survival after recurrence. ICE chemotherapy, together with radiation therapy and surgery, provides a reasonable salvage regimen for recurrent CCSK. It is unclear whether high-dose chemotherapy confers a benefit compared to conventional-dose chemotherapy.

Management of venous thrombosis in the pediatric patient.

The incidence of venous thromboembolism in children has increased significantly over the past decade. The evaluation and management of the child with venous thromboembolism, while based on the adult experience, has its own particularities dictated by the differences in the hemostatic system of the newborn and child. The current review addresses the evaluation of pediatric patient with thrombosis as well as the established and emerging treatment interventions.

Prevalence and correlates of mitral annular calcification in adults with chronic kidney disease: Results from CRIC study.

BACKGROUND: Risk factors for mitral annular calcification (MAC) and cardiovascular disease (CVD) demonstrate significant overlap in the general population. The aim of this paper is to determine whether there are independent relationships between MAC and demographics, traditional and novel CVD risk factors using cardiac CT in the Chronic Renal Insufficiency Cohort (CRIC) in a cross-sectional study. METHODS: A sample of 2070 subjects underwent coronary calcium scanning during the CRIC study. Data were obtained for each participant at time of scan. SUBJECTS: were dichotomized into the presence and absence of MAC. Differences in baseline demographic and transitional risk factor data were evaluated across groups. Covariates used in multivariable adjustment were age, gender, BMI, HDL, LDL, lipid lowering medications, smoking status, family history of heart attack, hypertension, diabetes mellitus, phosphate, PTH, albuminuria, and calcium. RESULTS: Our study consisted of 2070 subjects, of which 331 had MAC (prevalence of 16.0%). The mean MAC score was 511.98 (SD 1368.76). Age and white race remained independently associated with presence of MAC. Decreased GFR was also a risk factor. African American and Hispanic race, as well as former smoking status were protective against MAC. In multivariable adjusted analyses, the remaining covariates were not significantly associated with MAC. Among renal covariates, elevated phosphate was significant. CONCLUSION: In the CRIC population, presence of MAC was independently associated with age, Caucasian race, decreased GFR, and elevated phosphate. These results are suggested by mechanisms of dysregulation of inflammation, hormones, and electrolytes in subjects with renal disease.