Acute gastrointestinal graft-versus-host disease in allogeneic hematopoietic stem cell transplanted children and adolescents : clinical aspects of histopathological evaluation and risk factors

Background Acute graft-versus-host disease (aGVHD), following allogeneic hematopoietic stem cell transplantation (HSCT), is a potentially life-threating condition. Gastrointestinal involvement of aGVHD (GI-aGVHD) affects approximately every fourth transplanted child. The diagnosis of GI-aGVHD is primarily symptom-based. However, symptoms associated with GI-aGVHD are nonspecific; thus, histopathological confirmation of the diagnosis, is recommended. The overall objectives of this thesis were: i) to evaluate the influence of two different conditioning regimens on the incidence of GI-aGVHD, and ii) to evaluate clinical aspects of the currently recommended diagnostic approach to GI-aGVHD, i.e., endoscopy-guided histopathological assessment, applied to pediatric HSCT patients. Patients and methods Four retrospective cohort studies were included in this thesis. Paper I enrolled all children with HSCT performed during 2000–2010 at Karolinska University Hospital Huddinge who also had underlying diagnoses of juvenile myelomonocytic leukemia (JMML) or myelodysplastic syndrome (MDS). The children were conditioned with busulfan (Bu) and cyclophosphamide (Cy), with or without addition of melphalan (Mel). Paper IIIV included all children who underwent HSCT at any of the four HSCT centers in Sweden between 2000 and 2012 and with endoscopy-guided histopathological assessment performed to confirm symptom-based GI-aGVHD within one-year post-HSCT. In paper III-IV a retrospective, blinded, histopathological assessment (RIHA) was carried out based on the National Institutes of Health (NIH) 2014 criteria for histopathology-based GI-GVHD. Paper IV only included those with at least a biopsy sampling from the rectosigmoid area and the area proximal to the left colonic flexure. Results Paper 1: Twenty-five children were enrolled. Forty-seven percent (8/17) of the children that received addition of Mel to the BuCy conditioning, versus none (0/8) in the BuCy group, developed GI-aGVHD (stages 2-4) (p<0.05). Paper II: Based on 68 children with 91 endoscopic occasions, treatment changes in response to histopathology reports occurred in 48% (44/91). Paper III: Seventy children with 92 endoscopic occasions were assessed. Histopathologybased GI-GVHD diagnosis was established in 67 of 92 (73%) endoscopic occasions in the RIHA and in 50 of 92 (54%) in the clinical standard histopathological assessment (p=0.014). The risk of a subsequent re-endoscopy within one-year post-HSCT was higher in endoscopic occasions with GI-GVHD solely detected in RIHA versus non-GI-GVHD in both assessments (p=0.005). Paper IV: Forty-four children with 51 endoscopic occasions were analyzed. Biopsies from the rectosigmoid area had 85% sensitivity for RIHA-based GI-GVHD diagnosis. The corresponding figure for combined biopsy sampling from both rectosigmoid area and upper gastrointestinal tract was 97% and was similarly high compared with biopsies collected from complete lower endoscopy. Conclusions I) Addition of Mel to the BuCy conditioning increased the incidence of symptom-based GI-aGVHD in children with JMML and MDS. II) Endoscopy-guided histopathological assessment was found to influence the treatment decisions and should therefore be considered in children with GI-aGVHD. III) In children with symptom-based GI-aGVHD, without confirmation of the diagnosis by clinical standard histopathological assessment, a second histopathological assessment based on the NIH 2014 criteria should be considered before performing a re-endoscopy. IV) Sigmoidoscopy combined with upper endoscopy, colonoscopy/ileocolonoscopy, or full upper and lower endoscopy should be considered as preferred choices for the endoscopic procedure in children with clinically suspected GI-aGVHD

Semiconductor Nanowires: Epitaxy and Applications

Semiconductor nanowires are nanoscale objects formed by bottom-up synthesis. In recent years their unique properties have been exploited in fields such as electronics, photonics, sensors and the life sciences. In this work, the epitaxial growth of nanowires and their applications were studied. Heteroepitaxial growth of III-V nanowires on silicon substrates was demonstrated. This may enable direct band gap materials for optoelectronic devices, as well as high-mobility, low-contact resistance materials for electronics, to be integrated directly on the Si platform. Furthermore, gold-free nanowire synthesis on Si was demonstrated, which offers an advantage in terms of compatibility with established Si processing. Controlled nanowire synthesis by employing lithography was demonstrated. This combination of established "top-down" planar processing, and "bottom-up" nanowire growth, enables deterministic synthesis with individual nanowire site control. The process was first demonstrated with electron beam lithography and later extended to nanoimprint lithography, which is a parallel, high-throughput method, suitable for commercial volumes. Nanowire applications were demonstrated by three examples: (i) Vertical light-emitting diodes (LEDs) based on GaAs/InGaP core/shell nanowires, epitaxially grown on GaP and Si substrates. LED functionality was established on both kinds of substrates. This provided a direct demonstration of light-emitting devices on Si made possible by heteroepitaxial III-V nanowire growth on Si. (ii) A single-electron transistor constructed from a heterostructured nanowire with an InAs island sandwiched between two InP barriers. The narrow diameter of the nanowire provides the lateral confinement, and the tunnel barrier resistances are tunable by varying the InP barrier thickness. Coulomb oscillations and Coulomb blockade with a charging energy of approx. 4 meV were observed. (iii) Sensory nerve cell interactions with nanowires. Substrates covered with 2.5 um long and 50 nm diameter nanowires supported cell adhesion and axonal outgrowth. The cells interacted closely with the nanostructures, and viable cells penetrated by wires were observed, as well as wire bending due to forces exerted by the cells

Diagnostic accuracy of foot length measurement for identification of preterm newborn in rural Sindh, Pakistan

Introduction: Assessing gestational age accurately is crucial for saving preterm newborns. In low and middle-income countries, such as Pakistan, where access to antenatal ultrasonography (A-USG) is limited, alternative methods are needed. This study evaluated the diagnostic accuracy of foot length (FL) measurement for identifying preterm newborns in rural Pakistan using A-USG as the reference standard.Methods: A test validation study was conducted between January and June 2023 in rural Sindh, Pakistan, within the catchment area of the Global Network for Maternal Newborn Health Registry, Thatta. Singleton newborns whose mothers had an A-USG before 20 weeks of gestation were enrolled. A research assistant measured FL three times using a rigid transparent plastic ruler within 48 hours of birth and the average FL was reported. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) and likelihood ratios were calculated. The optimal FL cut-off for the identification of preterm newborns was determined using the Youden Index.Results: A total of 336 newborns were included in the final analysis, of whom 75 (22.3%) were born before 37 weeks of gestation. The median gestational age of the newborns was 38.2 weeks, and the median FL was 7.9 cm. The area under the curve was 97.6%. The optimal FL cut-off for identifying preterm newborns was considered as ≤7.6 cm with a sensitivity of 90.8%, specificity of 96.0%, PPV of 86.7% and NPV of 97.3%. A lower cut-off of ≤7.5 cm had a sensitivity of 95.4%, specificity of 84.0%, PPV of 63.1% and NPV of 98.5%.Conclusion: In conclusion, this study highlights the utility of FL measurement for identifying preterm newborns in rural settings where A-USG is unavailable before 20 weeks of gestation. Optimal cut-offs of ≤7.6 and ≤7.5 cm provide a simple, cost-effective and reliable tool for clinicians and frontline healthcare providers in rural areas, respectively

Improvements on making BKW practical for solving LWE

The learning with errors (LWE) problem is one of the main mathematical foundations of post-quantum cryptography. One of the main groups of algorithms for solving LWE is the Blum–Kalai–Wasserman (BKW) algorithm. This paper presents new improvements of BKW-style algorithms for solving LWE instances. We target minimum concrete complexity, and we introduce a new reduction step where we partially reduce the last position in an iteration and finish the reduction in the next iteration, allowing non-integer step sizes. We also introduce a new procedure in the secret recovery by mapping the problem to binary problems and applying the fast Walsh Hadamard transform. The complexity of the resulting algorithm compares favorably with all other previous approaches, including lattice sieving. We additionally show the steps of implementing the approach for large LWE problem instances. We provide two implementations of the algorithm, one RAM-based approach that is optimized for speed, and one file-based approach which overcomes RAM limitations by using file-based storage.publishedVersio

The Role of the Pre-B Cell Receptor in B Cell Development, Repertoire Selection, and Tolerance

Around four decades ago, it had been observed that there were cell lines as well as cells in the fetal liver that expressed antibody μ heavy (μH) chains in the apparent absence of bona fide light chains. It was thus possible that these cells expressed another molecule(s), that assembled with μH chains. The ensuing studies led to the discovery of the pre-B cell receptor (pre-BCR), which is assembled from Ig μH and surrogate light (SL) chains, together with the signaling molecules Igα and β. It is expressed on a fraction of pro-B (pre-BI) cells and most large pre-B(II) cells, and has been implicated in IgH chain allelic exclusion and down-regulation of the recombination machinery, assessment of the expressed μH chains and shaping the IgH repertoire, transition from the pro-B to pre-B stage, pre-B cell expansion, and cessation

Surface μ Heavy Chain Signals Down-Regulation of the V(D)J-Recombinase Machinery in the Absence of Surrogate Light Chain Components

Early B cell development is characterized by stepwise, ordered rearrangement of the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the two alleles of these genes is used to produce a receptor, a phenomenon referred to as allelic exclusion. It has been suggested that pre–B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele. Using a mouse model, we show that expression of an inducible μHC transgene in Rag2−/− pro–B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts. Similar effects were also observed in the absence of surrogate LC (SLC) components, but not in the absence of the signaling subunit Ig-α. Furthermore, in wild-type mice and in mice lacking either λ5, VpreB1/2, or the entire SLC, the TdT protein is down-regulated in μHC+LC− pre–B cells. Surprisingly, μHC without LC is expressed on the surface of pro–/pre–B cells from λ5−/−, VpreB1−/−VpreB2−/−, and SLC−/− mice. Thus, SLC or LC is not required for μHC cell surface expression and signaling in these cells. Therefore, these findings offer an explanation for the occurrence of HC allelic exclusion in mice lacking SLC components

From Monodisciplinary via Multidisciplinary to an Interdisciplinary Approach Investigating Air-Sea Interactions – a SOLAS Initiative

Understanding the physical and biogeochemical interactions and feedbacks between the ocean and atmosphere is a vital component of environmental and Earth system research. The ability to predict and respond to future environmental change relies on a detailed understanding of these processes. The Surface Ocean-Lower Atmosphere Study (SOLAS) is an international research platform that focuses on the study of ocean-atmosphere interactions, for which Future Earth is a sponsor. SOLAS instigated a collaborative initiative process to connect efforts in the natural and social sciences related to these processes, as a contribution to the emerging Future Earth Ocean Knowledge-Action Network (Ocean KAN). This is imperative because many of the recent changes in the Earth system are anthropogenic. An understanding of adaptation and counteracting measures requires an alliance of scientists from both domains to bridge the gap between science and policy. To this end, three SOLAS research areas were targeted for a case study to determine a more effective method of interdisciplinary research: valuing carbon and the ocean’s role; air-sea interactions, policy and stewardship; and, air-sea interactions and the shipping industry