Summary Background In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by ...graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. Methods This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0–40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m2 infants <9 kg 1·2 mg/kg; one dose per day on days −8 to −3), serotherapy (anti-thymocyte globulin 10 mg/kg, one dose per day on days −4 to −1; or thymoglobuline 2·5 mg/kg, one dose per day on days −5 to −3; or low-dose alemtuzumab <1 mg/kg on days −8 to −6), and low-dose (50–72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45–65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days −5 to −3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. Results 56 patients (median age 12·7 years; IQR 6·8–17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14–39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16–22) for neutrophils and 21 days (IQR 16–25) for platelets. At median follow-up of 21 months (IQR 13–35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46–99·09) and of EFS was 91% (79·78–96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III–IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. Interpretation This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. Funding None.
The NASA K2 mission obtained high precision time-series photometry for four young clusters, including the near-twin 600-800 Myr-old Praesepe and Hyades clusters. Hot sub-Neptunes are highly prone to ...mass-loss mechanisms, given their proximity to the the host star and the weakly bound gaseous envelopes, and analyzing this population at young ages can provide strong constraints on planetary evolution models. Using our automated transit detection pipeline, we recover 15 planet candidates across the two clusters, including 10 previously confirmed planets. We find a hot sub-Neptune occurrence rate of 79-107% for GKM stars in the Praesepe cluster. This is 2.5-3.5 sigma higher than the occurrence rate of 16.54+1.00-0.98% for the same planets orbiting the ~3-9 Gyr-old GKM field stars observed by K2, even after accounting for the slightly super-solar metallicity (Fe/H~0.2 dex) of the Praesepe cluster. We examine the effect of adding ~100 targets from the Hyades cluster, and extending the planet parameter space under examination, and find similarly high occurrence rates in both cases. The high occurrence rate of young, hot sub-Neptunes could indicate either that these planets are undergoing atmospheric evolution as they age, or that planetary systems that formed when the Galaxy was much younger are substantially different than from today. Under the assumption of the atmospheric mass-loss scenario, a significantly higher occurrence rate of these planets at the intermediate ages of Praesepe and Hyades appears more consistent with the core-powered mass loss scenario sculpting the hot sub-Neptune population, compared to the photoevaporation scenario.
Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson’s disease (PD). To understand GBA-related disease mechanisms, we use a ...multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models.
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•Proteomic/PTMomic analysis of GBA patient iPSC neurons identify disease phenotypes•PTM changes are highly abundant on lysosomal proteins and PD GWAS-related proteins•mTOR activation and mitochondrial movement perturbations are identified•GBA patient neurons show neuritogenesis defects that are rescued by a GCase chaperone
Bogetofte et al. apply a post-translational proteomics pipeline to iPSC-dopaminergic neurons from patients with Parkinson’s with a GBA-N370S mutation. This workflow simultaneously quantifies changes in protein phosphorylation, sialylation, and cysteine modifications, identifying affected pathways and phenotypes including impaired neurite outgrowth in GBA-N370S patient dopaminergic neurons that can be rescued by a GBA chaperone.
Planets are born from disks of gas and dust, and observations of protoplanetary disks are used to constrain the initial conditions of planet formation. However, dust mass measurements of Class II ...disks with ALMA have called into question whether they contain enough solids to build the exoplanets that have been detected to date. In this paper, we calculate the mass and spatial scale of solid material around Sun-like stars probed by transit and radial velocity exoplanet surveys, and compare those to the observed dust masses and sizes of Class II disks in the same stellar mass regime. We show that the apparent mass discrepancy disappears when accounting for observational selection and detection biases. We find a discrepancy only when the planet formation efficiency is below 100%, or if there is a population of undetected exoplanets that significantly contributes to the mass in solids. We identify a positive correlation between the masses of planetary systems and their respective orbital periods, which is consistent with the trend between the masses and the outer radii of Class II dust disks. This implies that, despite a factor 100 difference in spatial scale, the properties of protoplanetary disks seem to be imprinted on the exoplanet population.
The demographics of young exoplanets can shed light onto their formation and evolution processes. Exoplanet properties are derived from the properties of their host stars. As such, it is important to ...accurately characterize the host stars since any systematic biases in their derivation can negatively impact the derivation of planetary properties. Here, we present a uniform catalog of photometrically-derived stellar effective temperatures, luminosities, radii, and masses for 4,865 young (<1 Gyr) stars in 31 nearby clusters and moving groups within 200 pc. We compared our photometrically-derived properties to a subset of those derived from spectra, and found them to be in good agreement. We also investigated the effect of stellar properties on the detection efficiency of transiting short-period young planets with TESS as calculated in Fernandes et al. 2022, and found an overall increase in the detection efficiency when the new photometrically derived properties were taken into account. Most notably, there is a 1.5 times increase in the detection efficiencies for sub-Neptunes/Neptunes (1.8-6 Re) implying that, for our sample of young stars, better characterization of host star properties can lead to the recovery of more small transiting planets. Our homogeneously derived catalog of updated stellar properties, along with a larger unbiased stellar sample and more detections of young planets, will be a crucial input to the accurate estimation of the occurrence rates of young short-period planets.
Assessing the safety of engineered nanomaterials (NMs) is paramount to the responsible and sustainable development of nanotechnology, which provides huge societal benefits. Currently, there is no ...evidence that engineered NMs cause detrimental health effects in humans. However, investigation of NM toxicity using in vivo, in vitro, in chemico, and in silico models has demonstrated that some NMs stimulate oxidative stress and inflammation, which may lead to adverse health effects. Accordingly, investigation of these responses currently dominates NM safety assessments. There is a need to reduce reliance on rodent testing in nanotoxicology for ethical, financial and legislative reasons, and due to evidence that rodent models do not always predict the human response. We advocate that in vitro models and zebrafish embryos should have greater prominence in screening for NM safety, to better align nanotoxicology with the 3Rs principles. Zebrafish are accepted for use by regulatory agencies in chemical safety assessments (e.g. developmental biology) and there is growing acceptance of their use in biomedical research, providing strong foundations for their use in nanotoxicology. We suggest that investigation of the response of phagocytic cells (e.g. neutrophils, macrophages) in vitro should also form a key part of NM safety assessments, due to their prominent role in the first line of defense. The development of a tiered testing strategy for NM hazard assessment that promotes the more widespread adoption of non-rodent, alternative models and focuses on investigation of inflammation and oxidative stress could make nanotoxicology testing more ethical, relevant, and cost and time efficient.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A ...reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking. OBJECTIVE: To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children’s hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018. MAIN OUTCOMES AND MEASURES: Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry. RESULTS: A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 71.4% and white (15 71.4%). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 66.7%) and white (22 73.3%). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 IL-8 and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was −15.2 (0.91) and normal was −19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) −2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and TH2 (IL-33 and IL-4R) and TH17/TH22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools). CONCLUSIONS AND RELEVANCE: In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.
OBJECTIVES:Transition and transfer to adult-oriented health care is an important yet challenging task for adolescents and young adults with chronic medical conditions. Transition practices vary ...widely, but a paucity of data makes determination of best practices difficult. We described North American pediatric gastroenterologists’ preferences and present transition practice patterns and explored whether experience affected providers’ perspectives.
METHODS:An online survey was distributed via e-mail to members of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition. Participation was voluntary and answers were anonymous. Quantitative and qualitative analysis was performed.
RESULTS:Almost three quarters of the 175 respondents describe providing transition or self-care management education, but only 23% use structured readiness assessments. Most respondents (88%) report having age cutoffs above which they no longer accept new referrals, with the most common age being 18 years (57%). One third report the ability to provide age-appropriate care to patients older than 21 years. Only 6% indicate that their practice or institution should provide care for individuals older than 25 years. Many (63%) indicate that their practice or institution has a policy regarding age of transfer, but most (79%) are flexible. Provider preferences for triggers to transfer to adult care diverge widely between age, milestones, and comorbidities. Overall, parent (81%) and patient (74%) attachment to pediatric health care providers are cited as the most common barriers to transition.
CONCLUSIONS:Preferences and practices surrounding transition preparation and transfer to adult care vary widely, reflecting continued uncertainty regarding optimal transition strategies.
We report the discovery of a close-in (\(P_{\mathrm{orb}} = 3.349\:\mathrm{days}\)) warm Neptune with clear transit timing variations (TTVs) orbiting the nearby (\(d=47.3\:\mathrm{pc}\)) active M4 ...star, TOI-2015. We characterize the planet's properties using TESS photometry, precise near-infrared radial velocities (RV) with the Habitable-zone Planet Finder (HP) Spectrograph, ground-based photometry, and high-contrast imaging. A joint photometry and RV fit yields a radius \(R_p~=~3.37_{-0.20}^{+0.15} \:\mathrm{R_\oplus}\), mass \(m_p~=~16.4_{-4.1}^{+4.1}\:\mathrm{M_\oplus}\), and density \(\rho_p~=~2.32_{-0.37}^{+0.38} \:\mathrm{g cm^{-3}}\) for TOI-2015b, suggesting a likely volatile-rich planet. The young, active host star has a rotation period of \(P_{\mathrm{rot}}~=~8.7 \pm~0.9~\mathrm{days}\) and associated rotation-based age estimate of \(1.1~\pm~0.1\:\mathrm{Gyr}\). Though no other transiting planets are seen in the TESS data, the system shows clear TTVs of super period \(P_{\mathrm{sup}}~\approx~430\:\mathrm{days}\) and amplitude $\sim$$100\:\mathrm{minutes}\(. After considering multiple likely period ratio models, we show an outer planet candidate near a 2:1 resonance can explain the observed TTVs while offering a dynamically stable solution. However, other possible two-planet solutions -- including 3:2 and 4:3 resonance -- cannot be conclusively excluded without further observations. Assuming a 2:1 resonance in the joint TTV-RV modeling suggests a mass of \)m_b~=~13.3_{-4.5}^{+4.7}\:\mathrm{M_\oplus}\( for TOI-2015b and \)m_c~=~6.8_{-2.3}^{+3.5}\:\mathrm{M_\oplus}$ for the outer candidate. Additional transit and RV observations will be beneficial to explicitly identify the resonance and further characterize the properties of the system.
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