ALBERT

Description: The estimation of the Fraction of Absorbed Photosynthetically Active Radiation in forests (forest fAPAR) from multi-spectral Landsat-8 data is investigated in this paper using a physically based radiative transfer model (Invertible Forest Reflectance Model, INFORM) combined with an inversion strategy based on artificial neural nets (ANN). To derive the forest fAPAR for the Dabie mountain test site in China in 30 m spatial resolution (size approximately 3000 km2), a database of forest canopy spectral reflectances was simulated with INFORM taking into account structural variables such as leaf area index (LAI), crown coverage and stem density as well as leaf composition. To establish the relationship between forest fAPAR and the reflectance modeled by INFORM, a logarithmic relationship between LAI and fAPAR was used previously established using on-site field measurements. On this basis, predictive models between Landsat-8 reflectance and fAPAR were established using an artificial neural network. After calibrating INFORM for the test site, forty-two forest stands were used to validate the performance of the method. The results show that spectral signatures modeled by INFORM correspond reasonably well with the forest canopy reflectance spectra derived from Landsat data. Deviations increase with increasing angle between surface normal of the hilly terrain and sun incidence. The comparison of estimated and measured fAPAR (R2 = 0.47, RMSE = 0.11) demonstrates that INFORM can be inverted using neural nets to provide acceptable estimates of forest fAPAR. The accuracy of the predictions increased significantly when excluding pixels located in very steep terrain. This demonstrates that the applied topographic correction was not sufficiently accurate and should be improved for making optimum use of radiative transfer models such as INFORM.

Description: Environmental Science & Technology DOI: 10.1021/es403646x

Description: Environmental Science & Technology DOI: 10.1021/es201686j

Description: Environmental Science & Technology DOI: 10.1021/es3035347

Description: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, characterized by the presence of BCR/ABL fusion gene. It is unclear which cellular events drive BCR/ABL gene translocation or initiate leukemogenesis in CML. Bcl-2 promotes survival of hematopoietic stem cells. Accordingly, apoptosis-related pathway may involve in the leukemogenesis of CML. In the current study, we evaluated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n = 30), angiogenesis (n = 7), myeloid cell growth (n = 14), xenobiotic metabolism (n = 13), WT1 signaling (n = 7), interferon signaling (n = 4), and others (n = 5) in 170 CML patients and 182 healthy controls. In a single-marker analysis, the following SNPs were identified including VEGFA, BCL2, CASP7, JAK3, CSF3, and HOCT1. In the multivariate logistic model with these SNPs and covariates, only BCL2 (rs1801018) was significantly associated with the susceptibility to CML (P = .05; odds ratio [OR] 2.16 [1.00-4.68]). In haplotype analyses, haplotype block of BCL2 consistently showed significant association with the susceptibility to CML. Risk allele analysis showed that a greater number of risk alleles from BCL2 SNP correlated to increasing risk of CML (overall P = .1, OR 1.84 [1.06-3.22] for 3-4 risk alleles vs 0-1 risk alleles). The current study indicated that BCL2 SNP seemed to be associated with increasing susceptibility to CML.

Description: Introduction Early detection of joint problems and musculoskeletal (MSK) abnormities is a priority in hemophilia care worldwide; however, there is no standard approach to screening. The World Haemophilia Federation Hemophilia Joint Health Score (HJHS) is well validated but requires time-intensive evaluation by a MSK expert (e.g. physical therapist, PT). Joint screening popularized for the US Center for Disease Control Universal Data Collection (UDC) focuses on range of motion (ROM) assessment only but is quick and easy to implement with modest staff training of non-experts. The approach used at our center, here dubbed UDC-plus, combines ROM measurements with pain and functional evaluation. In 2012 our center found that HJHS was sensitive but non-specific (high false positive rate) and correlated poorly with need for MSK referral or imaging [Morrison et al, Haemophilia, 18 suppl. 3 p.120]. The aim of this study was to evaluate the utility of using HJHS in clinical practice to predict need for MSK referral within 5 years of initial assessment. We also evaluated the ability of UDC-plus to predict actionable MSK findings at 5 years. Methods This is a single center, retrospective, observational study. Patients diagnosed with hemophilia A or B of any severity, a HJHS assessment between 2009 and 2011 and a PT evaluation 5 years later (between 2014-2016) during annual comprehensive visits at Boston Children's Hospital were eligible for the study. HJHS includes evaluation of 6 joints (elbows, knees, ankles) with score range from 0 to 124 points, considered positive if greater than 0. UDC-plus score includes the same joints with score range from 0 to 3, considered positive when 2 or greater. Outcomes included need for MSK-related referral during the 5-year observation period. Clinical and demographic characteristics were summarized using descriptive statistics; logistic regression was used to determine whether baseline joint scores were prognostic of referral. Sensitivity and specificity of joint scores were calculated. Results Seventy-one male patients met inclusion. Median observation time was 5.7 years (range: 3.2-6.8); median baseline age was 10.3y (3-21). Thirty-six (51%) had severe, 8 (11%) moderate and 27 (38%) mild hemophilia; 92% of severe and 25% of moderate patients were on regular prophylaxis. Nine (13%) patients had at least one TJ, reflecting that even for young patients in the prophylaxis era (after 1996 at our center), TJs are not eliminated. An abnormal score was found in 47 (66%) patients; only 6 (13%) of them required referral for PT, orthopedic or radiologic assessments. Of patients with abnormal baseline HJHS without initial MSK referral, 17/41 (42%) required at least one referral by 5 years while only 4/41 (10%) had an MSK concern at the 5-year comprehensive visit (other concerns were transient). Of patients with a normal baseline HJHS, 11/24 (46%) required at least one referral by 5 years and 3/24 (12.5%) required a referral at 5 years. Baseline HJHS was not prognostic of need for referral at 5 years, Table 1. An abnormal UDC-plus score occurred at baseline in 38 (54%) patients, 6 of whom (16%) received a referral. The sensitivity and specificity for the UDC-plus score were slightly less sensitive but more specific than HJHS. Conclusion While high sensitivity of HJHS makes it useful in a research setting, the time requirement by an expert PT and its poor correlation with need for either acute or long-term clinical intervention (low specificity) render it less desirable for screening in routine hemophilia care. UDC-plus, has modest sensitivity for acute and 5-year referral prediction, but is correspondingly more specific. Hemophilia comprehensive clinics require a basic joint assessment, which is neither time- nor resource-intensive. These data suggest HJHS does not meet this need; however, a more concise examination focusing on ROM of key joints, pain and functional status may be an important foundation. The UDC-plus with revised scoring criteria may support routine integration into hemophilia care without compromising clinic flow or costs. Disclosures Neufeld: Novartis: Consultancy.

Description: Background: Transplant associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT) and in a pediatric cohort, a prevalence rate of 39% is reported (Jodele, et al 2016). However, TA-TMA is challenging to diagnose as features are common to and may occur concurrently with many post HCT complications, i.e. acute graft versus host disease (aGVHD) and infection. Outcomes are historically poor, though it is unclear if this is secondary to TA-TMA or to concurrent morbid conditions. We aimed to describe the prevalence and outcomes of TA-TMA at a single large pediatric center. Methods: In this retrospective study, data were extracted from the medical records of all children who received an HCT at Boston Children's Hospital from 1/2015-08/2017. Records were reviewed for evidence of TA-TMA in the first 100 days after HCT. According to "probable diagnostic TA-TMA criteria" (Cho et al, 2010), all the following had to occur concurrently and during at least 2 consecutive time points: 1) elevated lactate dehydrogenase, 2) platelet count

Description: To generate the billions of new erythrocytes required on a daily basis, erythroid progenitor cells must exponentially increase in number before undergoing terminal differentiation. A limited number of cell divisions occur during erythropoietin (EPO)-regulated erythroid terminal differentiation, but the principal regulation of erythroid transit-amplification occurs earlier in erythropoiesis between the burst forming unit-erythroid (BFU-E) and colony forming unit-erythroid (CFU-E) stages of development. The importance of this EPO-independent early erythropoietic process is highlighted in Diamond-Blackfan Anemia (DBA). DBA is characterized by pure red cell aplasia, loss of BFU-E and CFU-E progenitors in the bone marrow, and severe anemia despite high circulating EPO levels. The only known effective medical therapy for DBA also provides insight into the regulation of erythroid transit-amplification. In patients responsive to glucocorticoid treatment, there are increased numbers of BFU-E and CFU-E progenitors in the bone marrow, and ex vivo culture studies indicate that the synthetic glucocorticoid dexamethasone (Dex) predominantly increases proliferative capacity of BFU-Es, with minimal effect on proliferative capacity of CFU-Es. These findings led to a prevailing model that glucocorticoids increase BFU-E proliferative capacity by stimulating several rounds of self-renewal cell divisions. However, a limitation of this model is that there is no mechanistic explanation for how BFU-Es regulate the fate choice of undergoing a self-renewal cell division versus a differentiation cell division in the presence or absence of glucocorticoids. In this study, we address this question by examining progression of early erythroid progenitor development at single cell resolution, and subsequently elucidate the true mechanistic nature of glucocorticoid-induced erythroid progenitor proliferative capacity amplification. By performing single cell transcriptome profiling (scRNAseq) of primary-isolated mouse fetal liver BFU-Es, CFU-Es, and their developmental intermediates, we identify a continuum of transcriptomic states during erythroid transit-amplification when performing principle component analysis (PCA) on transcriptomes of individual cells. We show that ex vivo culture of primary-isolated BFU-Es in serum free media supplemented with stem cell factor, insulin-like growth factor 1, and EPO results in developmental progression along the transcriptome continuum when performing scRNAseq and PCA on cultured BFU-Es. The addition of Dex into this culture system does not result in self-renewal of BFU-Es at the transcriptome level, but rather still results in developmental progression, albeit to less of a degree per cell division than BFU-Es cultured without Dex. We additionally show that the continuum of transcriptome states in erythroid transit-amplification is reflective of a continuum of functional states, with developmental progression characterized by decreasing proliferative capacity and decreasing glucocorticoid-responsiveness. Lastly, through manual separation of daughter cells resulting from a BFU-E cell division, we demonstrate that BFU-E cell division is a symmetric process at the transcriptome level, both with and without the addition of Dex. Our results clarify the nature of how glucocorticoids amplify BFU-E proliferative capacity. As opposed to stimulating a finite number of BFU-E self-renewal cell divisions, glucocorticoids decrease the extent of progression through the erythroid transit-amplifying developmental continuum per cell division. Thus, a decreased rate of progression through the developmental continuum is associated with an increased number of transit-amplifying cell divisions prior to terminal differentiation. These findings are important not only for the rational development of glucocorticoid-alternatives for treating DBA, but also for all bone marrow failure syndromes characterized by progenitor cell hypoplasia. Disclosures No relevant conflicts of interest to declare.

Description: Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). First described as a distinct entity from generalized lymphatic anomaly (GLA) in 2014, KLA is histologically defined by spindled "kaposiform" endothelial cells associated with abnormal proliferation of lymphatic vessels. High risk features include pleural/pericardial effusions and coagulopathy. Respiratory failure, infections, and hemorrhage are common causes of death. In the largest case series of patients with KLA (n=20), five-year survival was 51%. Mean interval between diagnosis and death was 2.75 years. In recent years, the oral agent sirolimus has been used to treat KLA as a single agent or in combination with steroids and vincristine. No update has been published about overall outcomes for patients since the more widespread use of sirolimus. Methods: We conducted a retrospective chart review of 44 patients with biopsy-proven KLA referred to the Vascular Anomalies Center at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center between 1995 and 2018. Twenty patients were previously analyzed in a retrospective review. Patient data were gathered through the electronic medical record and and the Lymphatic Anomalies Registry. Response to treatment was defined by clinical assessment via extraction from the medical record, improvement in patient or parent-reported quality-of-life, improved coagulopathy, and decreased size of lesions on imaging. Toxicities were graded according to the NIH CTCAE grading scale. Clinical outcomes were evaluated up until July 2018. Results: Among 44 patients with KLA, the median age at onset of symptoms was 7 years (range=0-40.6 years). The median time from development of first symptoms to diagnosis of KLA was 16.4 months (range=0-12 years). Seventy-eight percent of patients had pleural or pericardial effusions at presentation (Figure 1). Anatomic involvement varied, with 65% of patients having bony involvement and 68% of patients having visceral disease. Bleeding was also common, with 14% of patients requiring transfusions of blood products. Twenty-four (56%) of 44 patients were treated with sirolimus. Of those 24 patients, 20 (83%) patients reported ever having a sustained response to sirolimus (〉6 months) based on our criteria. Despite improvement in disease symptoms, there was no significant difference in overall survival between patients who were treated with sirolimus and those who were not (log-rank p=0.62; Figure 1). Of the 44 patients evaluated in our study, fourteen died. Nine of the patients did not receive sirolimus (they died prior to its use in treating vascular anomalies). Of the 5 patients who received sirolimus and subsequently died, one reported marked improvement in his quality of life, but died from a pneumothorax during chest tube placement for a pleural effusion. The other patient who responded died from respiratory failure after a period of non-adherence with taking sirolimus. The remaining three patients did not respond to sirolimus and died of multi-organ failure. Among the 14 patients who died, the median time from diagnosis to death was 2.2 years (range 0.2- 7.1 years). Among 24 patients treated with sirolimus, 16 (67%) patients were treated concurrently with either vincristine (n=10) and/or steroids (n=15). Eight patients had sustained response with sirolimus alone. Minimal side effects were observed; there was only one grade 3 thrombocytopenia that did not require cessation of sirolimus. Sixteen patients remained on sirolimus at last follow-up. Conclusions: Most patients treated with sirolimus report stabilization of their disease symptoms and improvement in quality of life. Sirolimus is well-tolerated and most patients who respond remain on sirolimus as a form of chronic therapy. However, overall mortality for KLA remains high, even for those patients treated with sirolimus. More research is needed to investigate possible risk factors for poor outcomes. Investigation regarding phenotype-genotype correlation for KLA is ongoing, with the hope of identifying additional treatment options. In our study, there was a gap of 〉 1 year between time of symptom onset and diagnosis of KLA, highlighting a need for increased awareness of this unique disease entity and prompt referral of patients to a center with expertise in vascular anomalies. Disclosures No relevant conflicts of interest to declare.