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Kidney iron deposition measured by R2* (magnetic resonance imaging) MRI is posited to result from tubular reabsorption of filtered haemoglobin due to intravascular haemolysis. In chronically transfused sickle cell disease (SCD), R2* is elevated and positively correlated with lactate dehydrogenase (LDH). To account for contributions to renal iron from systemic iron overload, we evaluated kidney R2*, urinary iron and haemolysis markers in 62 non-transfused SCD patients. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (R2 = 0·55, P

Key Points CAR T-cell targeting of leukemic infiltrates in the optic nerve and retina caused retinal detachment as a presentation of pseudoprogression. Treatment of this intraocular inflammation with intravitreal triamcinolone and orbital radiation led to marked improvement in visual acuity.

Red cell distribution width (RDW) is an average of the variation in red blood cell (RBC) sizes reported on a complete blood count. An elevated RDW indicates a pathological process that is affecting erythropoiesis. Studies showed that as the severity of disease process increases, the RDW often increases as well. Particularly in resource-limited countries, RDW has been studied as an outcome predictor for conditions in a variety of disciplines and is offered as an adjunct monitoring tool that is cost effective, readily available, and indicative of pathological processes amenable to intervention. Particularly in pediatric critical care settings, RDW has been shown to be a reliable tool for surveillance of disease states such as sepsis. Despite the increased attention of RDW as a marker for disease outcome, collective evaluation on the utility of RDW as a marker for outcome in pediatric critical care settings is lacking. We offer a systematic review and meta-analysis of published studies to assess the ability of RDW to predict illness severity and mortality among pediatric critical care patients. Among eight studies of over 4,800 patients, we found over a two-fold increase in odds for mortality in critically ill children whose RDW was above 15.7%. This is the first systematic review of RDW being used to predict mortality in critically ill children and findings of this study may prompt early intervention in the pediatric critical care setting.

Migration ecology and habitat use of spring migrating birds using the Central Platte River is a well-explored topic, yet less is known about use of the North and South Platte rivers (NSPR) in western Nebraska. The efficiency and effectiveness of conservation efforts in the NSPR could be greatly improved with access to information about where and when birds roost and landscape prioritization tools. We used aerial surveys to determine population distribution and migration phenology of sandhill cranes Antigone canadensis, Canada geese Branta canadensis, and ducks using the NSPR for roosting during the mid-February to mid-April spring migration. We used these data and geospatial information to identify important river reaches for these species and habitat covariates that discriminate between those used at lower and higher densities. We found that sandhill cranes and waterfowl generally roosted in different segments of the NSPR and, subsequently, different factors were associated with high densities. Sandhill crane density was positively correlated with distance from obstructions greater than 1 m high and negatively correlated with area of unvegetated sandbar within 1 km. Density of Canada geese and ducks was high in segments positively associated with wetland and sand pit habitats. Human disturbance variables such as roads and bridges in this rural region had little effect on identification of roosting areas used by high densities of all groups. On the basis of our results, habitat conservation efforts that specifically target sandhill cranes will not have similar positive effects on waterfowl use and distribution in the NSPR. Our identification of the most important river segments should allow managers to better target land acquisition or management resources to areas that will have the greatest effect on either waterfowl or sandhill cranes during spring migration.

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Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.

The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2”. Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia. We describe identification of a FIP1L1-PDGFRA fusion in a 13-year-old boy who presented with T-lymphoblastic leukemia/lymphoma without eosinophilia. Detection of FIP1L1-PDGFRA driven neoplasms at diagnosis is usually critical for proper treatment, since almost all reported cases responded to tyrosine kinase inhibitors. However, our patient’s leukemia was refractory to standard chemotherapy, and did not show a meaningful response to tyrosine kinase inhibitor therapy. Testing for a FIP1L1-PDGFRA rearrangement is at present limited to patients with idiopathic hypereosinophilia, and we hypothesize that this abnormality may be under-diagnosed in children with acute leukemias.

Introduction Absence of alpha globin genes has long been known to influence the physiology of sickle cell disease (SCD). Individuals with SCD who are missing one or two alpha globin genes have decreased rates of cerebral vasculopathy, stroke, acute chest syndrome, and leg ulcers (Bernaudin, Blood 2008; Flanagan, Blood 2011; Nolan, Br J Haematol 2006). Although there is laboratory evidence of decreased hemolytic rate in these patients (Higgs, N Engl J Med 1982), the mechanism for their improved clinical outcomes has not been identified. Recently, the alpha globin protein has been shown to be present in the endothelial wall of human arterioles, where it modulates nitric oxide (NO) scavenging during vasoconstriction (Straub, Nature 2012). In mice, pharmacological inhibition of alpha globin leads to increased endothelial NO activity, independently of NO production, and results in increased blood perfusion, reduced systemic hypertension, and increased pulmonary artery vasodilation (Keller, Hypertension 2016; Alvarez, Am J Respir Cell Mol Biol 2017). The relationship between absence of alpha globin and arterial vasodilation, and the role of alpha globin in NO-mediated vascular signaling are potential mechanisms that could explain the beneficial effect of missing alpha globin genes in SCD. Using alpha thalassemia as a naturally occurring human model of alpha globin gene knockout, we hypothesized that loss of alpha globin genes leads to improvement in microvascular blood flow in thalassemia trait subjects without hemolysis. Methods Alpha thalassemia trait subjects missing one or two alpha globin genes, and healthy controls were recruited to the study, which was approved by the Children's Hospital Los Angeles Institutional Review Board. Blood samples were obtained from all subjects to test for hemoglobin, mean corpuscular volume (MCV), reticulocyte count, plasma hemoglobin, lactate dehydrogenase, and alpha globin genotype. We assessed flow-mediated dilation (FMD) of the brachial artery following distal forearm occlusion (Detterich, Blood 2015) simultaneously with laser Doppler flowmetry (LDF) and photoplethysmography (PPG) in the fingertip. We also measured the increase in microvascular perfusion with a thermal stimulus. The maximal change in vascular perfusion after provocation indicates vasodilatory capacity. Statistical analysis was performed in JMP® version 14 (SAS Institute Inc., USA). Results Twenty-seven subjects were enrolled, including 12 controls (4 alpha globin genes), 10 patients with 3 alpha globin genes and 5 with 2. The mean MCV was lower in subjects missing alpha globin genes than in controls (p=0.0099). Importantly, hemoglobin levels and markers of hemolysis were normal in both groups. There was no detectable difference in FMD between individuals missing one and two alpha globin genes; thus, these groups were combined and labeled as alpha trait for further analyses. FMD was significantly higher in alpha trait subjects after adjusting for age (Figure 1, p=0.0357). Missing alpha globin genes had no effect on microvascular flow by LDF or PPG (data not shown). Discussion FMD is an established and specific predictor of NO bioavailability (Thijssen, Am J Physiol Heart Circ Physiol 2011), and, in addition to shear-mediated NO circulation in conduit vessels, it reflects the sum of flow in multiple arteriolar networks downstream of the conduit artery. Using this method, a difference in endothelial function between control and alpha thalassemia trait was easily detected (Figure 1). Because endothelial alpha globin is present in arterioles rather than conduit vessels (Butcher, Free Radic Biol Med 2014), we measured microvascular flow in a 1-mm3 volume in the skin using a laser Doppler sensor, and in the fingertip by PPG, but were unable to detect an effect of alpha trait. As none of the subjects had anemia or evidence of hemolysis, the significantly increased FMD associated with loss of alpha globin genes is most likely due to increased NO as a result of decreased scavenging by alpha globin. The finding reported here that lower alpha globin gene number is associated with increased NO-related perfusion in humans may explain the beneficial effect of alpha thalassemia trait in SCD and suggests that the presence of alpha thalassemia trait may also play a role in other types of vascular disease. Disclosures Wood: BiomedInformatics: Consultancy; Imago Biosciences: Consultancy; BluebirdBio: Consultancy; Celgene: Consultancy; WorldcareClinical: Consultancy; Philips Medical Systems: Research Funding. Coates:apo pharma (Chiesi Pharma): Consultancy, Honoraria; Sangamo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios pharma: Consultancy, Honoraria; Vifor Pharma: Consultancy, Honoraria; Celgene, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background:Patient reported outcome measures (PROM) are important for clinical practice and research. Given the unmet need for a comprehensive PROM for systemic sclerosis (SSc), the ScleroID questionnaire was developed by a joint team of patients with SSc and medical experts. This is intended as a brief, specific, patient-derived, disease impact score for research and clinical use in SSc.Objectives:Here, we present the validation and final version of the ScleroID.Methods:This EULAR-endorsed project involves 9 European expert SSc centers. Patients fulfilling the ACR/EULAR 2013 criteria were prospectively included since 05/16 in a large observational cohort study. Patients completed the ScleroID and comparators SHAQ, EQ5D, SF36. They also weighted the 10 dimensions of the ScleroID by distributing 100 points according to the perceived impact on their health. The final score calculation is based on the ranking of the weights. The validation study included a reliability arm and a longitudinal arm, looking at sensitivity to change at follow-up.Results:Of the 472 patients included at baseline, 109 patients also had a reliability visit and 113 patients a follow-up visit. 84.5% of patients were female, 29.8% had diffuse SSc, mean age was 54.6 years, and mean disease duration 9.5 years. The highest weights were assigned by the patients to Raynaud`s phenomenon, fatigue, hand function and pain, confirming our previous results. The total ScleroID score showed good Spearman correlation coefficients with the comparators (SHAQ, 0.73; EQ5D -0.48; Patient’s global assessment, VAS 0.77; HAQ-DI 0.62; SF36 physical score -0.62; each pFigure 1.Conclusion:The EULAR ScleroID is a novel PROM designed for use in clinical practice and clinical trials to reflect the disease impact of SSc, showing good performance in the validation study. Importantly, Raynaud syndrome, impaired hand function, pain and fatigue were the main patient reported drivers of disease impact.Disclosure of Interests:Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Kim Fligelstone: None declared, Annelise Roennow: None declared, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Patricia Carreira Grant/research support from: Actelion, Roche, MSD, Consultant of: GlaxoSmithKline, VivaCell Biotechnology, Emerald Health Pharmaceuticals, Boehringer Ingelheim, Roche, Speakers bureau: Actelion, GlaxoSmithKline, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Roger Hesselstrand: None declared, Gunnel Sandqvist: None declared, Otylia Kowal-Bielecka Consultant of: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Speakers bureau: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Marco Matucci Cerinic: None declared, Carina Mihai: None declared, Ana Maria Gheorghiu: None declared, Ulf Müller-Ladner Speakers bureau: Biogen, Joe Sexton: None declared, Turid Heiberg: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

This work presents a model to estimate the performance of space-based, optical-based, quantum communication protocols. This model consists of components to account for optical channel propagation effects based on orbit selection and atmospheric conditions. The model presented is general purpose and can be leveraged to evaluate the performance of a variety of quantum communication protocols, of which, Quantum Key Distribution (QKD) systems served as our motivating use case of particular interest. To verify correctness, the model is used to produce estimates for QKD system scenarios and compared to published results. The performance of QKD systems is of interest as distance limitations for terrestrial-based systems have hindered their practical use, and satellite-based designs that can generate a shared key between two distant geographic locations have been proposed. For this application domain, a review of space-based designs that illuminate the need for a free space downlink channel model is presented followed by its development to estimate the performance of quantum exchanges between a satellite and ground site.

Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors’ vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.

Persistent konzo is low level incidence of konzo that is not associated with konzo epidemics due to drought or war. It has been reported from Mozambique and Tanzania. Various health factors associated with persistent konzo in four villages in Kasanji Health Area, Bandundu Province, DRC were studied, where there were 38 konzo cases in a population of 2283, with mean percentage konzo prevalence of 1.7%. Konzo occurred over the years since 1951 with 0 to 3 cases per year. Anthropometric measurements of children aged 0.5 to 14 y showed that 47% were stunted, 24% underweight, 16% had chronic energy deficiency and 16 to 24% suffered malnutrition. There was no significant difference between children from konzo households or from non-konzo households. The % konzo prevalence (%K) calculated from the equation %K = 0.06 %T + 0.035 %M, where %T = percentage of school children with urinary thiocyanate levels >350 µmol/L and %M = percentage of malnutrition, gave %K = 1.6 from non-konzo households and %K = 2.2 from konzo households, which agrees with the actual mean value of 1.7. However, the equation does not apply when either %T or %M is zero or for very high values of %K > 9.5. The value of %K is nearly twice as sensitive to changes in %T as to changes in %M, which partly explains the greater ease of prevention of konzo by reducing %T to zero, using the wetting method to remove cyanogens from cassava flour, than by reducing %M by broad based methods. Key words: Konzo prevalence, malnutrition, school children, urinary thiocyanate, cassava cyanide.

Konzo is an irreversible paralysis of the legs that occurs mainly in children and young women associated with large cyanide intake from bitter cassava coupled with malnutrition. In East Africa outbreaks occur during drought, when cassava plants produce much more cyanogens than normal. A wetting method that removes cyanogens from cassava flour was taught to the women of three konzo villages in Mozambique, to prevent sporadic konzo and konzo outbreaks in the next drought. The intervention was in three villages with 72 konzo cases and mean konzo prevalence of 1.2%. The percentage of children with high (>350 μmol/L) urinary thiocyanate content and at risk of contracting konzo in Cava, Acordos de Lusaka, and Mujocojo reduced from 52, 10, and 6 at baseline to 17, 0, and 4 at conclusion of the intervention. Cassava flour showed large reductions in total cyanide over the intervention. The percentage of households using the wetting method was 30–40% in Acordos de Lusaka and Mujocojo and less in Cava. If the wetting method is used extensively by households during drought it should prevent konzo outbreaks and chronic cyanide intoxication. We recommend that the wetting method be taught in all konzo areas in East Africa.

Konzo is a sudden spastic paraparesis that causes permanent paralysis of the legs and occurs mainly in children and young women. Konzo results from high cyanogen intake and malnutrition caused by a monotonous diet of bitter cassava. The known incidence of konzo in DRC up to 2009 is 3469 cases, but an estimate in 2002 was 100,000 cases. To help resolve this question a konzo survey was made in three health zones in Kwilu District, Bandundu Province, Democratic Republic of Congo (DRC), and the nutrition of those with konzo recorded. Thirty villages (population 22793) in Kwilu District were surveyed for konzo cases, and food consumption scores and mid upper arm circumferences obtained. There were 172 konzo cases with village konzo prevalences of 0.1-17%. The mean konzo prevalence in Masimanimba and Kingandu health zones was much less than in Payikongila health zone, probably because of the higher rate of malnutrition in Payikongila. Since 2009, konzo incidence has increased greatly in Kwilu District and also in 13 villages in nearby Kwango District, where incidence of new konzo cases has been prevented by use of the wetting method. Averaging the data over 495 konzo cases, 48% occurred from 2009 onwards and 52% occurred in the 20+ years before 2009. The very large increase of konzo incidence since 2009 is a public health problem in Bandundu Province, that could be solved by training women to use the wetting method, which removes cyanogens from cassava flour. The wetting method is more direct, effective and cheaper in preventing konzo than broad based interventions. Key words: Konzo survey, cassava, cyanide, nutrition, sulfur amino acids, food consumption score, mid upper arm circumference.

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy-Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P < 10−5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P = 4.4 × 10−6) and CFDP1(P = 2.6 × 10−6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P = 1.6 × 10−8; odds ratio (OR) = 1.8] is in linkage disequilibrium (r2 = 0.46) with the Class II allele HLA-DRB1*11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P = 1.6 × 10−8; OR = 0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P < 10−5,including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 which was ∼20 times more frequent in cases than controls. We are currently dissecting the potential biological implications of this locus. Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect size

To evaluate ferritin and zinc protoporphyrin-to-heme (ZnPP/H) ratios as biomarkers of iron status in neonates, determine how specific clinical events affected these measures, and assess how iron status changed during hospitalization.We performed a retrospective study of all infants with paired ferritin and ZnPP/H measurements between October 2014 and May 2016. Concordance of these measurements, effects of sepsis, red blood cell transfusion, erythropoietin treatment, and iron supplementation were assessed. Iron status was measured over time.A total of 228 patients (mean birth weight 1.3 kg, median gestational age 29 weeks) were evaluated. Mean log ZnPP/H values in infants with and without sepsis were not significantly different (4.98 µmol/mol vs 4.97 µmol/mol, adjusted P = .103), whereas log-transformed ferritin values increased significantly during infection (5.23 ng/mL vs 4.04 ng/mL, adjusted P .001). Ferritin also increased more significantly than ZnPP/H following red blood cell transfusion (ferritin: mean 5.03 ng/mL vs 4.0 ng/mL, P .001; ZnPP/H: mean 4.85 µmol/mol vs 4.98 µmol/mol, P .001). The mean iron supplementations at 30, 60, and 90 days were 5.4, 6.9, and 7.4 mg/kg/day, respectively. Ferritin values decreased with advancing postnatal age (adjusted P .001), with 66% of ferritin values less than 76 ng/mL. Treatment with erythropoietin increased ZnPP/H, but not ferritin levels.Ferritin is more significantly affected by inflammatory events such as sepsis and transfusion than ZnPP/H, thus, ZnPP/H may be a more reliable marker of iron status in this population. Infants showed worsening iron sufficiency over time despite supplementation above American Academy of Pediatrics guidelines.

Smartphone applications that promote symptom tracking and self-management may improve treatment of serious mental illness (SMI). Although feasibility has been established in chronic adult outpatient or inpatient SMI samples, no data exist regarding implementation of smartphone technology in adolescent and young adult populations as part of early psychosis (EP) outpatient care. We implemented a smartphone "app" plus clinician Dashboard as an add-on treatment tool in the University of California, Davis Early Psychosis Program. Participants completed daily and weekly surveys examining mood, symptoms, and treatment relevant factors via the app for up to 14 months. Clinicians discussed symptom ratings and surveys during regular treatment sessions using the Dashboard. We report methodological details of the study, feasibility metrics, and analyses of the validity of measuring symptoms via self-report using mobile health (mHealth) technology in comparison to gold-standard clinician-rated interviews based on a comprehensive longitudinal analysis of within-person data. Results demonstrate that integrating mHealth technology into EP care is feasible and self-report assessment of symptoms via smartphone provides symptom data comparable to that obtained via gold-standard clinician-rated assessments.

There were 68 konzo cases in three villages in Boko Health Zone, Bandundu Province, Democratic Republic of Congo (DRC), where yearly incidence had increased greatly since 2009. The nine months long intervention to prevent konzo started in the wet season. Village women were taught the wetting method, after which there were no new konzo cases and urinary thiocyanate levels were low. Using data from four different interventions in March 2010, July 2011, September 2013 and the present intervention in October-November 2012, a correlation was found between the monthly cyanide intake (measured by percentage of children with high urinary thiocyanate level) and the monthly konzo incidence. This dose response relationship between cyanide intake and konzo incidence, together with the prevention of konzo in many villages using the wetting method to reduce cyanogen intake, shows that konzo is very likely to be due to high cyanide/low sulfur amino acid intake in a diet of bitter cassava.

Background Mobile health applications offer ecologically valid, data-rich methods of modeling daily symptoms and functioning, which could inform treatment delivery and facilitate early intervention in individuals with psychosis. To date, most studies evaluate adoption of technology independent of care providers. However, successful implementation and long-term adoption of mobile technology likely also requires integration into outpatient settings as an add-on tool to enhance treatment. We implemented a smartphone “app” plus clinician Dashboard as an add-on treatment tool in the UC Davis Early Psychosis (EP) Programs and tested feasibility, validity, and predictive utility of symptom tracking via the app as part of EP care. A subsequent pilot study examined barriers to implementation within two additional community outpatient settings in Northern California. Methods Study 1 implemented the platform within the UC Davis EP Programs. For up to 14 months, EP clients completed daily and weekly surveys examining mood, symptoms, and treatment relevant factors via the app, as well as monthly in-person clinical assessments using the BPRS. Clinicians discussed symptom ratings and surveys during treatment sessions using the Dashboard. We examined client enrollment and survey completion to determine feasibility, and relationships between BPRS and weekly symptom ratings to evaluate validity of self-report symptom data collected via the app. Analysis of predictive utility determined if weekly self-report symptoms predicted symptom exacerbations 2 weeks later. Study 2 expanded recruitment to 2 additional community-based EP outpatient clinics. EP clients and their clinicians used the platform as part of care for 5 months and filled out satisfaction surveys at study-end regarding usability of the platform. Rate of survey completion in the absence of financial incentives was examined to determine real-world implementation of the platform. Results For study 1, 76 clients enrolled and remained in the study for an average of 183 days (SD=88). Survey completion rates remained high over the course of the study (weekly surveys: 77%; daily surveys: 69%) and were not significantly impacted by baseline symptom severity or length of time in the study. Weekly survey positive and depression/anxiety symptoms were significantly associated with BPRS positive (p

Introduction Kidney iron deposition has been described in hemolytic disorders including mechanical valves, paroxysmal nocturnal hematuria, and sickle cell disease (Roberts & Morrow, Circulation 1966; Leonardi & Ruol, Blood 1960). Circulating plasma hemoglobin is filtered at the glomerulus and reabsorbed via the megalin cubulin system in the proximal and distal tubules (Gburek et al, J Am Soc Nephrol 2002). On MRI, this manifests as signal loss on gradient and spin echo sequences in the cortex of the kidney with complete sparing of the medulla (Jeong et al, Radiographics 2002). The signal darkening is quantified by the parameter R2*, which has been shown to be directly proportional to tissue iron in the liver and heart. Kidney R2* has previously been demonstrated to rise proportionally to lactate dehydrogenase (LDH) in chronically transfused sickle cell disease (SCD) patients (Wood et al, Br J Haematol 2016; Schein et al, J Magn Reson Imaging 2008), but LDH is not a specific marker of hemolysis, and chronically transfused patients could potentially deposit iron in the kidney through other mechanisms. Therefore, we characterized the relationship between kidney R2*, urinary iron and markers of hemolysis in non-transfused SCD patients. Methods Sixty-five non-transfused SCD patients were recruited to the study, which was approved by the Institutional Review Board of Children's Hospital Los Angeles. Following medical history and physical exam, subjects completed blood and urine testing, and then abdominal MRI for assessment of somatic iron stores. R2* measurements were collected using multiple gradient echo pulse sequences on 1.5 Tesla magnets. Statistical analysis was performed using JMP® Pro, Version 14.0.0 (SAS Institute Inc., Cary, NC, 2018). Results Subjects were generally adults with a mean age of 32 years. Nearly three quarters of subjects had homozygous sickle cell disease, while a quarter had SC disease or S-Beta thalassemia, and one subject had sickle cell trait. Most subjects were anemic, and all subjects had elevated markers of hemolysis. Fifty-four percent of subjects had an elevated kidney R2* level (≥34 Hz). On univariate analysis, kidney R2* was associated with urinary iron (R2=0.52, p Discussion Our study supports previous findings that kidney R2* is associated with intravascular hemolysis, as measured by plasma hemoglobin and LDH, and inversely by hemoglobin (Kato et al, Blood 2006). The stronger association with urinary iron reinforces the concept that kidney R2* reflects filtered iron, which is insufficiently reabsorbed due to proximal and distal tubular injury in iron overload (van Raaij et al, Am J Physiol Renal Physiol 2019). Urinary iron is also elevated in diabetic nephropathy (Van et al, J Am Soc Nephrol 2017) and nephrotic syndrome (Niel et al, Blood 2011). These data raise important questions regarding the possible role of iron in sickle related renal disease. Disclosures Coates: apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy.

During the past century, clear-cut hardwood forests of the north central United States have regenerated, and trees have matured into size classes increasingly capable of producing cavities suitable for nesting ducks. We determined the density of natural cavities suitable for cavity-nesting ducks, compared suitable cavity-tree distribution by size class and species, and assessed how forest maturation impacted suitable cavity density and distribution over time at four sites in the north central United States. During 2006–2008, cavities suitable for nesting ducks occurred at densities of 1.76, 1.40, 1.84, and 0.92/ha at Mingo National Wildlife Refuge (NWR) in Missouri, Shiawassee NWR in Michigan, Muscatatuck NWR in Indiana, and a study site including Mead State Wildlife Area in Wisconsin, respectively. Suitable nest-cavity densities increased at Mingo NWR (+300%) since 1965 and Shiawassee NWR (+900%) since 1973, but they remained similar at study sites examined during the mid-1980s (Muscatatuck NWR and Mead Wildlife Area) when previous site-specific cavity-suitability criteria were applied to our cavity data. Differences among sites were due to variation in tree species composition, stage of forest maturation, and potentially forest harvest regimes. Comparison of size distributions of all trees and those with suitable nest cavities indicated these forests have yet to mature into the most prolific cavity-producing size classes. Our findings suggest nest sites are not limiting duck populations at these four sites and hardwood forests with similar composition and structure. Rather than using the traditional practice of supplementing duck nest sites, wildlife managers in the North Central region should assess actual limiting factors before developing habitat management prescriptions for local cavity-nesting duck populations.

Clearing of hardwood forests was widespread in the north central region of the United States at the turn of the 20th century, but largely subsided by the 1920s. Hardwood trees in the region have since regenerated and matured into sizes capable of producing nest cavities suitable for cavity-nesting ducks. We estimated regional nest-site abundance for cavity-nesting ducks during 2008, 2018, and 2028 from cavity density and tree-abundance estimates obtained at 4 hardwood forest sites in conjunction with Forest Inventory and Analysis data and tree-growth modeling software from the United States Forest Service (Forest Vegetation Simulator). Land cover data were used to determine area of hardwood forests � 0.5 km, 0.5-1 km, 1-1.5 km, 1.5-2 km, and >2 km from wetlands and open water available to cavity-nesting ducks. We estimated 13.2 million, 17.0 million, 19.0 million, and 20.1 million potential duck nest cavities available � 0.5 km, � 1 km, � 1.5 km, and � 2 km of water, respectively, in the region and predicted nest cavity abundance will increase 41% from 2008 to 2028. Hardwood forests in Indiana, Michigan, Ohio, and Wisconsin currently have the highest abundances of potential nest sites, but cavity-bearing forests in Minnesota, Michigan, and Wisconsin were more commonly proximate to wetlands and open water. Because current and future estimates indicate sufficient nest sites to support growing cavity- nesting duck populations in the north central United States, we recommend regional management efforts focus on protecting, restoring, and maintaining quality wetlands in proximity to hardwood forests. 2011 The Wildlife Society.

Current methods for processing cassava leaves to remove cyanogens involve pounding followed by boiling in water or boiling intact leaves for 30 min or longer. Boiling in water rapidly removes cyanogens but also breaks down vitamins, proteins and S-containing amino acids, which are necessary to detoxify ingested cyanide. Two methods have been developed to remove cyanogens whilst conserving these key nutrients present in cassava leaves. The first method involves pounding leaves in a pestle and mortar for a minimum of 10 min until the leaves are well macerated, followed by washing the pounded leaves twice in twice their weight of water at ambient temperature, which reduces the total cyanide remaining to 8%. Two further washes reduce the total cyanide to 3%. The second method is to immerse cassava leaves in ten times their weight of water at 50 ± 3 °C for 2 h followed by one change of water and further immersion for 2 h at 50 °C which reduces the total cyanide remaining to 7%.

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years.Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice.Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003).During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4% in lcSSc, p = 0.002). As previously observed, the rate of development of SRC was highest in the first 3 years of disease- 10% in dcSSc and 3% in lcSSc. All incidences of clinically important cardiac disease developed in the first 5 years from disease onset (7% in dcSSc v 1% in lcSSc, p < 0.001) and remained unchanged at 10 years. As expected, 10-year survival among lcSSc subjects was significantly higher (81%) compared to that of dcSSc patients (70%, p = 0.006). Interestingly, although over the first 5 years the death rate was much higher in the dcSSc cohort (16% v 6% in lcSSc), over the following years it became very similar for both subsets (14% and 13% between years 5 and 10, and 18% and 17% between years 10 and 15 for dcSSc and lcSSc respectively).Conclusions: Even though dcSSc patients have higher incidence for most organ complications compared to lcSSc subjects, the worse survival among them is mainly due to higher early mortality rate. Mortality rate after first 5 years of disease becomes comparable in the two disease subsets.Disclosure statement: The authors have declared no conflicts of interest.

Introduction: Vaso-occlusive pain crisis (VOC) is a significant contributor to the morbidity of Sickle Cell Disease (SCD) and cold exposure has long been associated with increased frequency and intensity of VOC. However, the mechanism by which cold exposure causes the transition from steady state to vaso-occlusion has not been well elucidated. Decreased regional blood flow results in red blood cells spending a longer period of time in the deoxygenated state in the capillaries, increasing the likelihood of hemoglobin S polymerization in the microvasculature and subsequent vaso-occlusion. Regional blood flow is primarily regulated by the autonomic nervous system (ANS) and recent literature shows evidence of cardiovascular autonomic dysfunction in SCD and of its role as a disease modulating factor. We hypothesized that cold exposure triggers a central autonomic response leading to vasoconstriction in the microvasculature and that SCD subjects will have a stronger response when compared to controls. Methods: 17 SCD and 16 control (healthy or sickle trait) subjects aged 13 to 39 years were exposed to thermal stimuli via a computer-controlled thermode (TSA-II) placed on the thenar eminence of the right hand. Predetermined individual threshold temperatures for heat detection, cold detection, heat pain and cold pain were applied, and changes in the microvascular blood flow (MBF) were measured at a sub-second sampling rate on the contralateral thumb using photo-plethysmography (PPG). Mean MBF was derived from the amplitude of the PPG signal, a greater decrease in mean MBF from baseline signifies stronger vasoconstriction. The vasoconstriction response within the PPG signal, and the time (in sec) to vasoconstriction were determined from the cross-correlation function of the pain stimulus signal and the vascular response. The R-to-R interval (RRI) derived from electrocardiogram was used to evaluate cardiac autonomic balance. Standard deviation of RRI represents total heart rate variability, Spectral indices of the RRI represent parasympathetic activity (high frequency power; HFP) and sympatho-vagal balance (Low to high Ratio; LHR = low frequency power(LFP)/HFP). Prior to the study, subjects were administered measures of current anxiety and general level of anxiety (STAI Y1 and Y2, respectively) as well as a measure of pain related anxiety (PASS). Results: All the thermal stimulation tasks caused a significant decrease in MBF from baseline (p values for cold detection, heat detection, heat pain and cold pain=0.027, At baseline and across all tasks, SCD subjects showed a significantly lower heart rate variability suggestive of autonomic dysfunction (standard deviation of RRI- 41.2 Vs 50 msec, p=0.007). Both cold and heat pain caused a significant increase in the mean LFP and LHR from baseline with no significant differences in HFP thus suggesting an overall increase in the cardiac sympathetic output with thermal pain. Conclusion: Using MBF as an objective marker of pain responses, cold pain causes significant decrease in MBF followed by other thermal stimuli. The rapid vasoconstriction responses to the thermal stimuli occurred in the contralateral hand, suggesting a neural mechanism. SCD subjects demonstrated an augmented peripheral vasoconstriction response with evidence of cardiac autonomic imbalance. Our findings imply that global autonomic mediated vasoconstriction and subsequent vaso-occlusion is the likely mechanistic link between cold exposure and VOC in SCD. Thus, vascular autonomic reactivity is a biomarker of basic SCD pathophysiology and serves as a potential target for prevention and treatment of pain in SCD. Disclosures Coates: ApoPharma: Consultancy, Honoraria; Sangamo: Consultancy, Honoraria; Vifor Pharma: Consultancy; Celgene Corp.: Consultancy.

Introduction Over the last two decades, sickle cell disease has become a model of diffuse endotheliopathy. In 2004, Gladwin and colleagues demonstrated that elevated tricuspid regurgitation jet velocity (TRJ) was an independent predictor of mortality and that chronic red blood cell hemolysis underlies pulmonary vascular disease (Gladwin et. al. NEJM, PMID:14985486). Belhassen and colleagues demonstrated that flow-mediated dilation of the brachial artery (FMD) was decreased in patients with sickle cell disease, specifically shear-mediated vasodilation (Belhassen et. al. Blood, PMID:11238095). Our group demonstrated that plasma free hemoglobin links decreased FMD and elevated TRJ in patients with sickle cell disease and that chronic transfusion therapy improves FMD (Detterich et. al. Blood, PMID:26036801). We aimed to determine whether markers of vascular function predict the risk of mortality in a cohort of patients with sickle cell disease. Methods This was a single center, prospective cohort study of non-transfused and chronically transfused sickle cell anemia patients at Children's Hospital of Los Angeles between 2009 and 2012 aiming to assess vascular function in sickle cell disease. This study was approved by the Children's Hospital Los Angeles Institutional Review Board. We used FMD, a test of shear-mediated endothelial nitric oxide release as the model for vascular function. We simultaneously measured the regional hemoglobin oxygen saturation in the hand using near infrared spectroscopy (NIRS). We also measured microcirculatory perfusion using laser doppler flowmetry (LDF) over the skin of the nailbed. Echocardiography was performed on the same day to assess tricuspid regurgitation jet velocity and cardiac function. Markers of inflammation, cell count and hemolysis were also measured on the day of the study. We prospectively followed them until 2018 to assess our primary outcome, survival. All of the measurements were made pre-transfusion for chronically transfused subjects. Kaplan Meier and Cox-Proportional Hazards multivariate model was used to determine independent predictors of survival. All statistics were performed using Stata/IC version 14.0. Results We enrolled 26 chronically transfused patients with SCD and 63 non-transfused SCD patients in a study assessing the effects of hemolysis on endothelial function. Overall mortality in our cohort was 20% with a median follow up time of 7.8 years (7.1-8.3 IQR). Median age was 24 years at the time of study (17-36 IQR). Median age at the time of death was 36 years(28-51 IQR) and at the last follow up for the alive patients was 30 years (25-41 IQR), p=0.01. In the patients who died, they had higher TRJ (median 270 vs 235, p=0.03) and had elevated plasma Hgb, median 26 vs 14, p=0.01. FMD, regional oxygen saturation and microcirculatory perfusion were not different between alive and deceased patients. There was no difference for inflammatory markers (white blood cell count, platelet count, high sensitivity C-reactive protein), hemoglobin S%/transfusion, or anemia (hemoglobin/hematocrit/reticulocytes) between alive or deceased patients. By Kaplan Meier analysis individual factors associated with mortality were TRJ>250 (p=0.04) and age>21 (p=0.02) (Fig 1 and Fig 2). By Cox-Proportional Hazards Model, both TR jet velocity and plasma hemoglobin remain significant after correcting for age (Table 1). Conclusions In our cohort, there are multiple abnormal markers of vascular function and elevated markers of hemolysis; however, the strongest predictors of mortality were age, plasma free hemoglobin and tricuspid regurgitation jet velocity. These findings support the association between hemolysis, pulmonary vascular disease and mortality, a controversial topic in sickle cell disease. Disclosures Coates: Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria; Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria.

The lactic acid content of gari, was determined by pH titration to be about 10 g lactic acid/kg gari. As the size of the gari particles increased from 400 to >1000 μm their total cyanide content increased from 5 to 21 ppm. The acetone cyanohydrin content of gari samples exposed to ambient laboratory conditions of temperature and relative humidity gradually decreased by 58% in 38 weeks whereas linamarin in cassava flour is 100% stable for 6 months. Cyanogens could not be removed from wet gari samples at 30 or 50 °C and were only slowly removed by repeated heating at 100 °C and rewetting. By mixing equal weights of gari (pH 4.1) and low cyanide cassava flour (pH 6.5), wetting and heating at 50 °C for 5 h, the cyanide content was reduced by about one half. Wetting a gari/flour (1:1) sample with 1.5 times its weight of water and standing in a 1 cm thick layer in the sun for 4 h reduced the cyanide content by about one half. This treated mixture may be cooked to prepare stiff porridge with lowered cyanide content, and may help reduce tropical ataxic neuropathy in West Africa.

In 2005 a simple wetting method was developed that reduced total cyanide content of cassava flour 3–6-fold. The method involved spreading wet flour in a thin layer and standing in the shade for five hours to allow evolution of HCN gas. We found that breakdown of linamarin catalysed by linamarase to acetone cyanohydrin, followed by its spontaneous decomposition to HCN and acetone was greatly increased by standing the wet flour in the sun. Treatment for two hours in the sun gave the same amount of total cyanide remaining as five hours in the shade. This rapid treatment in the sun may be more acceptable to rural women in Democratic Republic of Congo, than five hours in the shade. The two methods are offered as alternatives for use in rural Africa. With adequate linamarase present the residual cyanogen remaining after the wetting treatment was acetone cyanohydrin.

The constructal solution for cooling of electronics requires solution of a fundamental heat conduction problem in a composite slab composed of a heat generating slab and a thin strip of high conductivity material that is responsible for discharging the generated heat to a heat sink located at one end of the strip. The fundamental 2D heat conduction problem is solved analytically by applying an integral transform method. The analytical solution is then employed in a constructal solution, following Bejan, for cooling of electronics. The temperature and heat flux distributions of the elemental heat generating slabs are assumed to be the same as those of the analytical solution in all the elemental volumes and the high conductivity strips distributed in the different constructs. Although the analytical solution of the fundamental 2D heat conduction problem improves the accuracy of the distributions in the elemental slabs, the results following Bejan’s strategy do not affirm the accuracy of Bejan’s constructal solution itself as applied to this problem of cooling of electronics. Several different strategies are possible for developing a constructal solution to this problem as is indicated.

It is generally held that surface runoff in heavily forested ecosystems is minimal and therefore nutrient fluxes via runoff are unimportant. This is based in large measure on the absence of direct observation or remnant physical evidence. It is further held that protected forests with heavy understory and litter serve as a nutrient sink due to maximum uptake and interception. Our Sierran studies have detected the presence of surface runoff at several sites in the form of both overland and litter interflow with concentrations of NH4-N as high as 87.2 mg L−1, NO3-N as high as 95.4 mg L−1, and PO4-P as high as 24.4 mg L−1. Data suggest that nutrients are derived from the mature O-horizons, and that there has been little contact with the mineral soil or root zone where strong retention and/or uptake of these ions would be expected. Such contributions from overland/interflow could be particularly important in areas where ultra-oligotrophic lakes (e.g., Lake Tahoe) are now trending towards meso-oligotrophic status. We believe that fire exclusion in these systems may have exacerbated N and P inputs to Lake Tahoe and elsewhere by allowing unnatural buildups of O-horizons that are apparently a source of nutrients to surface runoff.

There appear to be some fundamental disagreements between those scientists and engineers who adhere to the principles of macroscopic classical thermodynamics and those who adhere to the principles of finite time thermodynamics. In many instances, the disagreements can be traced to differing assumptions concerning fundamental principles, definitions, etc., as well as differing interpretations of fundamental principles, definitions, etc. This paper is an attempt to clarify the issues by consideration, in somewhat laborious detail, of the basic definitions and their interpretations, considering the fundamental principles of classical thermodynamics and nonequilibrium thermodynamics. It appears to the author that nonequilibrium thermodynamics might offer a reconciliation of the disagreements and provide an approach acceptable to both sides. The work is purposely limited to considerations of importance in thermal cycles, mostly isothermal heat addition and rejection, and no attempt is made to treat even this broad field comprehensively. It is hoped that such discussions will lead to resolution of the disagreements, at least in part. Given the tendency of thermodynamicists to argue, in all probability, the discussions will lead to additional disagreements.

Background Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes. Procedure We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS). Results We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS. Conclusions Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.

Background Konzo is an irreversible paralysis of the legs that occurs mainly among children and young women in remote villages in tropical Africa and is associated with a monotonous diet of bitter cassava. Konzo was discovered in 1938 by Dr. G. Trolli in the Democratic Republic of Congo (DRC). It also occurs in Mozambique, Tanzania, Cameroon, Central African Republic, and Angola. It was first controlled in Kay Kalenge village, DRC, in 2011 with the use of a wetting method to remove cyanogens from cassava flour. Fourteen months later, another visit was made to Kay Kalenge. Objective To determine whether Kay Kalenge women were still using the wetting method, whether there were new cases of konzo, and whether the wetting method had spread to other villages. Methods Meetings were held with chiefs, leaders, and heads of mothers' groups, women from 30 households were interviewed, and three nearby villages were visited. Total cyanide and thiocyanate were analyzed in cassava flour and urine samples, respectively. Results The women in Kay Kalenge village still used the wetting method. There were no new cases of konzo. The mean cyanide content of the flour samples was 9 ppm, and no child had a mean urinary thiocyanate content greater than 350 μmol/L. The use of the wetting method had spread naturally to three adjacent villages. Conclusions The wetting method has been readily accepted by rural women as a simple and useful method to control konzo by removing cyanide from cassava flour, and its use has spread to nearby villages. The wetting method should be promoted by health authorities to control konzo and reduce cyanide poisoning from high-cyanide cassava flour.