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Background: Anaphylaxis following influenza vaccination is a rare but serious problem. The underlying immune responses are not well understood. This study elucidated the IgE and IgG antibody responses in healthy children and adolescents following inactivated influenza vaccines (IIVs). Methods: The efficacy and safety of quadrivalent IIV (QIV) and trivalent IIV (TIV) were compared in healthy subjects aged 0-18 years. Serum IIV-specific IgE, IgG and IgG4 levels (sIgE, sIgG, sIgG4) were measured with ImmunoCAP. Hemagglutinin inhibition (HI) assay was performed for each influenza virus subtype. Sera from earlier patients who developed anaphylaxis to different IIVs were similarly tested. Results: A total of 393 subjects were enrolled: 96 were 6 months -2 years old, 100 were 3-5 years old, 100 were 6-12 years old, and 97 were 13-18 years old. No anaphylaxis was observed. Generally, QIV and TIV induced similar antibody responses. IIV-sIgE levels rose significantly after vaccination in the 6m-2y and 3-5y groups, did not change in the 6-12y group, and decreased in the 13-18y group. In contrast, the IIV-sIgG4/sIgE ratio increased significantly after vaccination in all age groups. Sensitized subjects had significantly higher HI titers and IIV-sIgG levels in the youngest age group and higher IIV-sIgG4 levels in all age groups compared with the non-sensitized. The IIV-sIgG4/sIgE ratio in 5 patients with anaphylaxis was significantly lower than in age-matched healthy subjects. Conclusion: IIVs induce IgE sensitization in healthy children, but also robust IgG4 responses that may protect them from anaphylaxis.

Alex Nicol-Harper

and 4 more

Cost-effective use of limited conservation resources requires understanding which data can most contribute to alleviating biodiversity declines. Interventions might reasonably prioritise life-cycle transitions with the greatest influence on population dynamics, yet some contributing vital rates are particularly challenging to document; such pragmatic decision-making risks suboptimal management if less is known about influential rates. We aimed to explore whether study effort aligns with demographic impact on population growth rate, λ. We parameterised a matrix population model using meta-analysis of vital rates for the common eider (Somateria mollissima), an increasingly threatened yet comparatively data-rich species of seaduck. Female common eiders exhibit intermittent breeding, with some established breeders skipping one or more years between breeding attempts. We accounted for this behaviour by building breeding propensity (= 0.72) into our model with a discrete and reversible ‘non-breeder’ stage (to which surviving adults transition with a probability of 0.28). The transitions between breeding and non-breeding states had twice the influence on λ than fertility (summed matrix-element elasticities of 24% and 11%, respectively), whereas almost 15 times as many studies document components of fertility than breeding propensity (n = 103 and n = 7, respectively). Through comparative re-analyses, we find similar results for two amphibian species, further supporting our finding that study effort does not always occur in proportion to relative influence on λ. Our workflow could form part of the toolkit informing future investment of finite resources, to avoid repeated disconnects between data needs and availability thwarting evidence-driven conservation.

Fabiën Belle

and 6 more

Background: Cancer diagnosis and its treatment may impair the long-term body image of childhood cancer survivors. This may be particularly relevant in adolescence, a critical period of psycho-social development. We compared the body image between adolescent cancer survivors and their siblings, and determined whether survivors’ body image is associated with socio-demographic characteristics, clinical characteristics, and health conditions. Procedure: As part of the nationwide Swiss Childhood Cancer Survivor Study, we sent questionnaires to adolescents (aged 16-19 years), who survived >5 years after having been diagnosed with childhood cancer between 1976-2010. Siblings received the same questionnaire. We assessed the level of agreement with three body image statements referring to body satisfaction and preferences for changes. Chronic health conditions were classified into cardiovascular, pulmonary, endocrine, musculoskeletal, renal/ digestive, neurological, and hearing or vision impairment. We used ordered logistic regression models to identify determinants of a more negative body image. Results: Our study included 504 survivors (48% female) with a median age at study of 17.7 years (IQR 16.8-18.6) and 136 siblings. Survivors and siblings reported overall comparable levels of the three body image statements (all p>0.05). Female survivors (all ORs ≥ 1.7), survivors treated with haematopoietic stem cell transplantation (all ORs ≥ 2.2), and survivors with ≥ 2 chronic health conditions (all ORs ≥ 1.4) reported a more negative body image. This was particularly pronounced for survivors suffering from musculoskeletal or endocrine conditions. Conclusion: Clinicians should address body image concerns in adolescent survivors with chronic conditions and offer psycho-social support if necessary.

Xiao Li

and 6 more

Accurate monthly runoff prediction is of significance to extreme flood control and water resources management. However, traditional models without multivariable input for predicting monthly runoff may fail to capture runoff changes effectively due to the dual effect of climate change and human activities. Here, a Multi-input Artificial Intelligence Framework (MAIF) was put forward using five Artificial Intelligence (AI) models to predict monthly runoff, where multiple global circulation indices and surface meteorological indices are selected as explanatory variables by the Stepwise Regression or Copula Entropy methods. Besides, four univariate models were adopted as benchmarks. The MAIF was tested at two typical hydrological stations (i.e., Gaochang and Cuntan) in the Upper Yangtze River. The results indicate that the LSTM_Copula (Long short-term memory model combined with Copula entropy method) model outperformed the other models for both the Gaochang Station and Cuntan Station, whereas the GRU_Step (Gate recurrent unit model combined with Stepwise regression method) model and the RF_Copula (Random forest model combined with Copula entropy method) model showed satisfactory performances. In addition, the AI models with multi-variables input provide better predictability compared with four univariate models, with improvements of 5.10%, 4.16%, 5.34%, and 0.43% in the MAPE, RMSE, NSE, and R values for the Gaochang Station and 10.84%, 17.28%, 13.68%, and 3.55% for the Cuntan Station, making it an effective approach for monthly runoff forecasting in large rivers.

Simon Cazaurang

and 7 more

The hydraulic properties of ground vegetation cover are important for high resolution hydrological modeling of permafrost regions, due to its insulating and draining role. In this study, the morphological and effective hydraulic properties of Western Siberian Lowland ground vegetation samples (lichens, Sphagnum mosses, peat) are numerically assessed based on tomography scans. After numerical pre-processing, porosity is estimated through a void voxels counting algorithm, showing the existence of representative elementary volumes (REV) of porosity for most samples. Then, two methods are used to estimate hydraulic conductivity depending on the sample’s homogeneity. For the most homogeneous samples, Direct Numerical Simulations (DNS) of a single-phase flow are performed, leading to a definition of hydraulic conductivity related to REV, which is larger than those obtained for porosity. For more heterogeneous samples, no adequate REV may be defined. To bypass this issue, a pore network representation of the whole sample is created from computerized scans. Morphological and hydraulic properties are then estimated through this simplified representation. Both methods converged on similar results for porosity. Some discrepancies are observed in the morphological properties (specific surface area). Hydraulic conductivity fluctuates by two orders of magnitude, depending on the method used, and yet this uncertainty is less than that found in experimental studies. Therefore, biological and sampling artifacts are predominant over numerical biases. Porosity values are in line with previous values found in the literature, showing that arctic cryptogamic cover can be considered as an open and well-connected porous medium (over 99% of overall porosity is open porosity). Meanwhile, digitally estimated hydraulic conductivity is higher compared to previously obtained results based on field and laboratory experiments. This could be related to compressibility effects, occurring during field or laboratory measurements. Thus, some supplementary studies are compulsory for assessing syn-sampling and syn-measurement perturbations in experimentally estimated, effective hydraulic properties of such a biological porous medium.

Marc Ohmer

and 2 more

Karst springs are the natural outflow of karst water to the surface. These springs occur where the water table can reach the surface unimpeded. This study examines the effect of alluvial deposits with varying thickness and permeability, covering the main outlet (karst spring) of a karst network on karst drainage (e.g., development of the karst water, drainage patterns, conduit-matrix interaction) as a result of a positive base level shift. This was realized with a numerical conceptual model (FEFLOW) of a hypothetical karst aquifer with 6 model configurations (inactive vs. active conduit flow, free vs. confined spring conditions with 20 m and 50 m sediment cover, respectively, with low and high hydraulic conductivity). Conduit flow and coupled conduit-matrix interactions were incorporated into the model with one-dimensional discrete feature elements. The results show that the permeability of the sediments has a more distinctive effect on conduit discharge than their thickness. The conduit network significantly contributes to the drainage even with a fully confined spring outlet. The conduit system acts as a water collector from the matrix in the recharge zone. The buried outlet increases the hydrostatic pressure farther along the conduit, and water is pushed upwards back into the matrix in the vicinity of the stratigraphic contact. Depending on the depositional setting, this results in the evolution of one to multiple new flow systems towards new potential spring sites. The results obtained here provide insight into the likely responses of natural karst systems.

Cody Millar

and 6 more

Ecohydrological investigations commonly use the stable isotopes of water (hydrogen and oxygen) as a conservative ecosystem tracer. This approach requires accessing and analyzing water constrained within plant and soil matrices. Generally, there are six steps that researchers must pass through to retrieve hydrogen and oxygen isotope values from these plant and soil matrices: (i) sampling, (ii) sample storage and transport, (iii) extraction, (iv) pre-analysis processing, (v) isotopic analysis, and (vi) post-processing and correction. At each of these steps cumulative errors can be introduced which sum to non-trivial magnitudes. These errors can impact subsequent interpretations about water cycling through the soil-plant-atmosphere continuum. But these steps in the research ‘process chain’ are just the tip of the iceberg when it comes to uncertainly in published findings. At each of these discreet steps, there are multiple possible options to select from resulting in, as we will show, tens of thousands of possible combinations used by researchers to go from plant and soil samples to isotopic data. In a newly emerging science, so many options can create interpretive confusion and major issues with data comparability. This points to the need for the development of shared standardized approaches. Here we critically examine the state of the process chain, reflecting on the issues associated with each step, and end with suggestions to move our community towards standardization. We hope that critically assessing this common approach will help us see the current problem in its entirety and facilitate community action toward agreed upon standardized approaches.

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Yuval Shafir

and 8 more

INTRODUCTION: Transvenous Lead Extraction (TLE) is usually performed via a superior approach. Predictors and outcomes of TLE requiring femoral vein bailout are poorly defined. We aimed to analyze predictors and consequences of TLE requiring femoral bailout. METHODS: A single tertiary center cohort of 421 consecutive patients who underwent TLE between May 2010 and February 2020 were analyzed. Venography was routinely performed before system upgrade to identify occluded veins. Patients were divided into 2 groups according to their need for femoral bailout extraction. RESULTS: A total of 928 leads were extracted with femoral bailout approach was needed in 71 leads(7.7%) among 49 patients(11.6%). A higher proportion of right ventricular(RV) leads required femoral bailout approach compared with right atrial(RA) leads[51/499(10.2%) vs 18/326(5.5%);p=0.02]. Femoral bailout was more common among younger patients, longer lead dwell time, more pocket entries, higher number of extracted leads, presence of abandoned leads and among patients with vascular occlusion. Following multivariate analysis, presence of abandoned leads, vascular occlusion and younger age remained a significant predictor for femoral bailout. Femoral bailout resulted in higher rates of major complications [5/49(10.2%) vs 12/372(3.2%);p=0.05] without intra-procedural mortality and no additional 30-day mortality[2/49(4.1%) vs 33/377(8.8%);p=0.39]. CONCLUSION: TLE of abandoned leads, occluded veins and younger age were found to be predictors of femoral bailout requirement. Despite higher rates of major complications in femoral TLE bailout, mortality was not increased. Venography prior to TLE should be considered for procedure planning.

Manuel E. Izquierdo

and 21 more

Background:  Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic  CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of  CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare  CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) ( Regression-based models tested for association between  CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic  CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic  CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic  CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for  CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Hanan Al-Abboh

and 2 more

A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Hoda Abdelgawad

and 2 more

57-years old man presented with exertional dyspnea. An early systolic murmur was heard over the aortic areas 2D and 3D Echocardiography revealed unicuspid , unicommissural aortic valve (UAV) with a characteristic “teardrop” lateral orifice (Figure A) and moderate valve stenosis (3D planimetered aortic valve area (AVA) is 1.1cm2) (Figure B) Continuous wave Doppler across aortic valve (AV) showed high peak and mean systolic gradients of 85 and 60mmHg respectively.(Figure C). 2D /3D Transesophageal Echocardiography (TOE) revealed a subaortic ridge attached to the posterior annulus (Arrow) (Figure D) Further En-face viewing of the aortic valve from the left ventricular outflow tract (LVOT) perspective showed a shelf-like ridge extending from the commissure to the cusp (Arrow) (Figure E) Zoomed mode of the aortic- LVOT junction confirmed the presence of the subaortic ridge seen attached to the posterior aortic annulus near the commissural opening (Figure F) The patient was referred for surgical consultation .. Unicupid aortic valve (UAV) is a rare congenital anomaly that has.2 subtypes ; unicomissural and acommissural subtypes. Both can present with variable degrees of the aortic stenosis (AS) and/or aortic valve regurgitation (AR).UAV has more early, accelerated and severe valvular degeneration in addition to smaller orifice in comparison with bicuspid and tricuspid aortic valve. Echocardiography is the gold standard for diagnosis and evaluation of the AV morphology and function and the associated disorders such as ventricular septal defect , aortopathy and subaortic obstruction.. Surgical aortic valve replacement (AVR) and repair of the associated anomalies are the most common treatment modality .

Esin Isik

and 7 more

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