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Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes

Full list of authors: Jorstad, S. G.; Marscher, A. P.; Raiteri, C. M.; Villata, M.; Weaver, Z. R.; Zhang, H.; Dong, L.; Gomez, J. L.; Perel, M., V; Savchenko, S. S.; Larionov, V. M.; Carosati, D.; Chen, W. P.; Kurtanidze, O. M.; Marchini, A.; Matsumoto, K.; Mortari, F.; Aceti, P.; Acosta-Pulido, J. A.; Andreeva, T.; Apolonio, G.; Arena, C.; Arkharov, A.; Bachev, R.; Bonnoli, G.; Borman, G. A.; Bozhilov, V; Carnerero, M., I; Damljanovic, G.; Ehgamberdiev, S. A.; Elsasser, D.; Frasca, A.; Gabellini, D.; Grishina, T. S.; Gupta, A. C.; Hagen-Thorn, V. A.; Hallum, M. K.; Hart, M.; Hasuda, K.; Hemrich, F.; Hsiao, H. Y.; Ibryamov, S.; Irsmambetova, T. R.; Ivanov, D., V; Joner, M. D.; Kimeridze, G. N.; Klimanov, S. A.; Knoett, J.; Kopatskaya, E. N.; Kurtanidze, S. O.; Kurtenkov, A.; Kuutma, T.; Larionova, E. G.; Leonini, S.; Lin, H. C.; Lorey, C.; Mannheim, K.; Marino, G.; Minev, M.; Mirzaqulov, D. O.; Morozova, D. A.; Nikiforova, A. A.; Nikolashvili, M. G.; Ovcharov, E.; Papini, R.; Pursimo, T.; Rahimov, I; Reinhart, D.; Sakamoto, T.; Salvaggio, F.; Semkov, E.; Shakhovskoy, D. N.; Sigua, L. A.; Steineke, R.; Stojanovic, M.; Strigachev, A.; Troitskaya, Y., V; Troitskiy, I. S.; Tsai, A.; Valcheva, A.; Vasilyev, A. A.; Vince, O.; Waller, L.; Zaharieva, E.; Chatterjee, R., Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1,2,3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image. © 2022 Springer Nature Limited., The research reported here is based on work supported in part by US National Science Foundation grants AST-2108622 and AST-2107806, and NASA Fermi GI grants 80NSSC20K1567, 80NSSC21K1917 and 80NSSC21K1951; by Shota Rustaveli National Science Foundation of Georgia under contract FR-19-6174; by the Bulgarian National Science Fund of the Ministry of Education and Science under grants DN 18-10/2017, DN 18-13/2017, KP-06-H28/3 (2018), KP-06-H38/4 (2019) and KP-06-KITAJ/2 (2020), and by National RI Roadmap Project D01-383/18.12.2020 of the Ministry of Education and Science of the Republic of Bulgaria; by JSPS KAKENHI grant #19K03930 of Japan; by the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract 451-03-9/2021-14/200002) and observing grant support from the Institute of Astronomy and Rozhen NAO BAS through the bilateral joint research project ‘Gaia Celestial Reference Frame (CRF) and fast variable astronomical objects’; by the Agenzia Spaziale Italiana (ASI) through contracts I/037/08/0, I/058/10/0, 2014-025-R.0, 2014-025-R.1.2015 and 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF). H.Z. is supported by the NASA Postdoctoral Program at Goddard Space Flight Center, administered by ORAU. M.V.P. is partially supported by the Russian Foundation for Basic Research grant 20-02-00490. G.B. acknowledges support from the State Agency for Research of the Spanish MCIU through the ‘Center of Excellence Severo Ochoa’ award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709) and from the Spanish ‘Ministerio de Ciencia e Innovacíon’ (MICINN) through grant PID2019-107847RB-C44. M.D.J. thanks the Brigham Young University Department of Physics and Astronomy for continued support of the extragalactic monitoring programme under way at the West Mountain Observatory. R.C. thanks ISRO for support under the AstroSat archival data utilization programme and BRNS for support through a project grant (sanction no. 57/14/10/2019-BRNS). The measurements at the Hans Haffner Observatory, Hettstadt, Germany, were supported by Baader Planetarium, Mammendorf, Germany. This study was based (in part) on observations conducted using the 1.8-m Perkins Telescope Observatory (PTO) in Arizona, USA, which is owned and operated by Boston University. These results made use of the Lowell Discovery Telescope (LDT) at Lowell Observatory. Lowell Observatory is a private, non-profit institution dedicated to astrophysical research and public appreciation of astronomy, and operates the LDT in partnership with Boston University, the University of Maryland and the University of Toledo. This paper is partly based on observations made with the IAC-80 operated on the island of Tenerife by the Instituto de Astrofisica de Canarias in the Spanish Observatorio del Teide and on observations made with the LCOGT telescopes, one of whose nodes is located at the Observatorios de Canarias del IAC on the island of Tenerife in the Observatorio del Teide. This paper is partly based on observations made with the Nordic Optical Telescope, owned in collaboration by the University of Turku and Aarhus University, and operated jointly by Aarhus University, the University of Turku and the University of Oslo, representing Denmark, Finland and Norway, the University of Iceland and Stockholm University at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofisica de Canarias. The VLBA is an instrument of the NRAO, USA. The NRAO is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.

To test whether quantitative flow ratio (QFR)-based trans-stent gradient (TSG) is associated with adverse clinical events at follow-up. A post-hoc analysis of the multi-center HAWKEYE study was performed. Vessels post-PCI were divided into four groups (G) as follows: G1: QFR ≥ 0.90 TSG = 0 (n = 412, 54.8%); G2: QFR ≥ 0.90, TSG > 0 (n = 216, 28.7%); G3: QFR 0 (n = 86, 11.4%). Cox proportional hazards regression model was used to analyze the effect of baseline and prognostic variables. The final reduced model was obtained by backward stepwise variable selection. Receiver operating characteristic (ROC) was plotted and area under the curve (AUC) was calculated and reported. Overall, 449 (59.8%) vessels had a TSG = 0 whereas (40.2%) had TSG > 0. Ten (2.2%) vessel-oriented composite endpoint (VOCE) occurred in vessels with TSG = 0, compared with 43 (14%) in vessels with TSG > 0 (p 0 was an independent predictor of the VOCE (HR 2.95 [95% CI 1.77–4.91]). The combination of higher TSG and lower final QFR (G4) showed the worst long-term outcome while low TSG and high QFR showed the best outcome (G1) while either high TSG or low QFR (G2, G3) showed intermediate and comparable outcomes. Higher trans-stent gradient was an independent predictor of adverse events and identified a subgroup of patients at higher risk for poor outcomes even when vessel QFR was optimal (> 0.90).

To evaluate the feasibility of a new method of conjunctival transplantation to achieve recovery of the normal conjunctival epithelium over the bare sclera after pterygium excision and prevent its recurrence.After excision of the primary pterygium, we performed simple conjunctival epithelial transplantation (SCET) in which we glued an amniotic membrane patch pre-loaded with tiny autologous conjunctival tissue fragments over the scleral defect. Slit-lamp evaluation was performed at 2 and 7-10 days, and then at 1, 3, 6, and 12 months after surgery, together with confocal microscopy at 3, 6, and 12 months.Surgical excision and SCET for nasal primary pterygium were performed in 6 eyes (6 patients). No graft detachment occurred. An inflammatory granuloma was excised without sequelae in one patient 2 months after surgery. No signs of recurrence or sight-threatening complications were recorded at 12 months, and in vivo confocal microscopy showed progressive expansion of the conjunctival cell population and formation of a clear corneal-conjunctival transition.SCET takes advantage of the ability of the amniotic membrane and conjunctival cells to renew. Outcomes after SCET are comparable to conventional conjunctival flap surgery and can be achieved in less surgical time and with less donor tissue to be removed.

Background Empathic care is considered extremely important by patients and providers alike but there is still an ample need for assessing empathy among healthcare students and professionals and identifying appropriate educational interventions to improve it. This study aims to assess empathy levels and associated factors among students at different healthcare colleges at the University of Iowa. Methods An online survey was delivered to healthcare students, including nursing, pharmacy, dental, and medical colleges (IRB ID #202,003,636). The cross-sectional survey included background questions, probing questions, college-specific questions, and the Jefferson Scale of Empathy-Health Professionals Student version (JSPE-HPS). To examine bivariate associations, Kruskal Wallis and Wilcoxon rank sum tests were used. A linear model with no transformation was used in the multivariable analysis. Results Three hundred students responded to the survey. Overall JSPE-HPS score was 116 (± 11.7), consistent with other healthcare professional samples. There was no significant difference in JSPE-HPS score among the different colleges (P = 0.532). Conclusion Controlling for other variables in the linear model, healthcare students’ view of their faculty’s empathy toward patients and students’ self-reported empathy levels were significantly associated with students’ JSPE-HPS scores.

Background The study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach. Methods SOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression. Results In the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2–47.59, p=0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p=0.045) and PAF-AHβ (HR=0.372, CI95=0.171–0.809, p=0.013) Conclusions A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.

Objectives This study aimed to compare dimensional alterations of dental arches in children with unilateral complete cleft lip and palate before and after different techniques of primary plastic surgeries. Materials and methods The sample was divided into two groups: group 1-cheiloplasty by Millard's technique and one-stage palatoplasty by von Langenbeck's technique; group 2-cheiloplasty by Millard's technique and two-stage palatoplasty: anterior palatoplasty by Hans Pichler's technique and posterior palatoplasty by Sommerlad's technique. Dental arches were evaluated before (T1), after the first phase (T2), and 1 year after the second phase (T3) of primary surgeries. Linear measurements and palatal area were assessed. To analyze the method's error, interclass correlation coefficient was applied. ANOVA (followed by Tukey test), dependent, and independent t-test were used (p Results At T1, the intertuberosity distance was statistically greater in G2 (p = 0.004). At T2, the anterior length of the dental arch was statistically greater in G2 (p = 0.025), while the area of the smaller palatal segment (p = 0.001), cleft area (p = 0.014), and total area (p = 0.002) were statistically smaller in G2. At T3, the intertuberosity distance was statistically greater in G2 (p = 0.017). Conclusion This study suggests that cheiloplasty and one-stage palatoplasty resulted in smaller growth of maxilla than cheiloplasty and two-stage palatoplasty in the linear measurements (T-T' and I-CC') and total area of the dental arches. Clinical relevance Surgical protocols need to be evaluated to verify their effects aiming at improving the clinical practice of the interdisciplinary team, determining new parameters for the rehabilitation of individuals with cleft lip and palate.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Purpose To assess the long-term visual outcomes of children with PCG, irrespective of the type of surgical procedure, and to create visual acuity curves to help in predicting the development of visual function in these patients. The secondary aim is to identify associated factors for visual decline or loss, highlighting differences between neonatal and infantile subgroups. Methods The medical records of pediatric glaucoma patients from 1996 to 2017 at the University Hospital of Verona (Verona, Italy) were retrospectively reviewed. Visual acuities, surgeries, PCG subtype and etiology of vision impairment were recorded. Statistical analyses were performed to detect factors associated with vision decline. Results Sixty-seven eyes (40 patients) were included in the study. Developmental predictive curves of visual acuity showed that children with infantile PCG had a better visual outcome than children with neonatal PCG at each step of follow-up. A good-to-moderate VA (p Conclusions Visual outcomes of PCG significantly correlate with the age at diagnosis. Although a good long-term IOP control can often be achieved in PCG, often the visual acuity remains below the lower limits of the normal range. Poor vision in childhood is related to global developmental problems, and referral to third-level services should not be delayed to prevent vision impairment. In this regard, visual acuity curves can be a useful tool for the consultant ophthalmologist to define the visual development of children affected by PCG.

Made available in DSpace on 2022-04-29T08:30:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-09-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Interventions that can modulate subcutaneous white adipose tissue (scWAT) function, such as exercise training and nutritional components, like taurine, modulate the inflammatory process, therefore, may represent strategies for obesity treatment. We investigated the effects of taurine supplementation in conjunction with exercise on inflammatory and oxidative stress markers in plasma and scWAT of obese women. Sixteen obese women were randomized into two groups: Taurine supplementation group (Tau, n = 8) and Taurine supplementation + exercise group (Tau + Exe, n = 8). The intervention was composed of daily taurine supplementation (3 g) and exercise training for 8 weeks. Anthropometry, body fat composition, and markers of inflammatory and oxidative stress were determined in plasma and scWAT biopsy samples before and after the intervention. We found that, although taurine supplementation increased taurine plasma levels, no changes were observed for the anthropometric characteristics. However, Tau alone decreased interleukin-6 (IL-6), and in conjunction with exercise (Tau + Exe), increased anti-inflammatory interleukins (IL-15 and IL10), followed by reduced IL1β gene expression in the scWAT of obese women. Tau and Tau + Exe groups presented reduced adipocyte size and increased connective tissue and multilocular droplets. In conclusion, taurine supplementation in conjunction with exercise modulated levels of inflammatory markers in plasma and scWAT, and improved scWAT plasticity in obese women, promoting protection against obesity-induced inflammation. TRN NCT04279600 retrospectively registered on August 18, 2019. School of Physical Education and Sport of Ribeirão Preto University of São Paulo-EEFERP USP, Av. Bandeirantes, 3900, Vila Monte Alegre Internal Medicine Department Ribeirão Preto Medical School University of São Paulo-FMRP USP State University of Minas Gerais - UEMG, Divinopolis unit Laboratory of Molecular Biology of Exercise University of Campinas-FCA UNICAMP Department of Food and Nutrition School of Pharmaceutical Sciences of Araraquara São Paulo State University-FCFAR UNESP Department of Physical Education School of Technology and Science São Paulo State University-UNESP Laboratory of Nutritional Genomics University of Campinas-FCA UNICAMP Department of Food and Nutrition School of Pharmaceutical Sciences of Araraquara São Paulo State University-FCFAR UNESP Department of Physical Education School of Technology and Science São Paulo State University-UNESP FAPESP: 2017/08036-5 FAPESP: 2017/10080-2

Genome-wide association analysis of cohorts with thousands of phenotypes is computationally expensive, particularly when accounting for sample relatedness or population structure. Here we present a novel machine-learning method called REGENIE for fitting a whole-genome regression model for quantitative and binary phenotypes that is substantially faster than alternatives in multi-trait analyses while maintaining statistical efficiency. The method naturally accommodates parallel analysis of multiple phenotypes and requires only local segments of the genotype matrix to be loaded in memory, in contrast to existing alternatives, which must load genome-wide matrices into memory. This results in substantial savings in compute time and memory usage. We introduce a fast, approximate Firth logistic regression test for unbalanced case–control phenotypes. The method is ideally suited to take advantage of distributed computing frameworks. We demonstrate the accuracy and computational benefits of this approach using the UK Biobank dataset with up to 407,746 individuals. REGENIE is a whole-genome regression method based on ridge regression that enables highly parallelized analysis of quantitative and binary traits in biobank-scale data with reduced computational requirements.

This study aimed to determine the changes of lipidome in obese women undergoing combined physical exercise training. Fourteen adult women with obesity (mean BMI and age, 33 kg/m2 and 34 ± 5 years), were submitted to combined physical training (aerobic and strength exercises, alternately, 55 min at 75–90% of the maximum heart rate, 3 times a week) for 8 weeks. All participants were evaluated before and after the training intervention for lipidome, anthropometric measurements, muscle strength, and maximum oxygen consumption (VO2max). Untargeted liquid chromatography-mass spectrometry analyses allowed the identification of 1252 variables, of which 160 were significant (p p

Background This study aims to evaluate the mental health status of children, adolescents and their parents during the first year of COVID-19 pandemic in Belgium. Method Analysis compared results before and during the second national lockdown, which started on November 2nd 2020. A cross-sectional online survey was conducted between May 2020 and April 2021. Results Two hundred and eighteen adults and 273 children fully completed the survey. Almost one in five children (17.9%) presented moderate-to-severe scores of depression. Adolescents presented a higher level of depression than children (p = 0.007). The rate of moderate-to-severe depression scores (10.8% to 21%, p = 0.007) and internalized symptoms increased during the second lockdown (p Conclusion The second lockdown appears to worsen the effects of the pandemic on children’s and parents’ mental health. There is a need to implement specific interventions targeting both children/adolescents and their parents to support them during lockdown periods and improve mental health outcomes.

Complex morphological traits are the product of many genes with transient or lasting developmental effects that interact in anatomical context. Mouse models are a key resource for disentangling such effects, because they offer myriad tools for manipulating the genome in a controlled environment. Unfortunately, phenotypic data are often obtained using laboratory-specific protocols, resulting in self-contained datasets that are difficult to relate to one another for larger scale analyses. To enable meta-analyses of morphological variation, particularly in the craniofacial complex and brain, we created MusMorph, a database of standardized mouse morphology data spanning numerous genotypes and developmental stages, including E10.5, E11.5, E14.5, E15.5, E18.5, and adulthood. To standardize data collection, we implemented an atlas-based phenotyping pipeline that combines techniques from image registration, deep learning, and morphometrics. Alongside stage-specific atlases, we provide aligned micro-computed tomography images, dense anatomical landmarks, and segmentations (if available) for each specimen (N = 10,056). Our workflow is open-source to encourage transparency and reproducible data collection. The MusMorph data and scripts are available on FaceBase (www.facebase.org, https://doi.org/10.25550/3-HXMC) and GitHub (https://github.com/jaydevine/MusMorph).

Purpose To review recent progress, challenges, and future perspectives of stromal keratophakia for the treatment of advanced keratoconus. Methods We systematically reviewed the literature in the PubMed database, last update June 30, 2020. No language restriction was applied. The authors checked the reference lists of the retrieved articles to identify any additional study of interest. Results Several techniques have been proposed for the treatment of keratoconus in order to avoid or delay keratoplasty. This was primarily due to the lack of accessibility to donor corneas in many countries. The ease and predictability of the more advanced femtosecond lasers used to correct ametropias by stromal lenticule extraction lead to hypothesize that generated refractive lenticules could be implanted into corneal stromal layers to restore volume and alter the refractive properties of the cornea in patients with corneal ectasias. At the same time, new techniques for preservation, customization, and cellular therapy of the corneal stromal have been developed, directing to the valorization of otherwise discarded byproducts such as donor corneas unsuitable for either lamellar of penetrating keratoplasty. Conclusions Femtosecond laser-assisted stromal keratophakia could be a suitable therapeutic option for the treatment of corneal ectasias, especially in patients with advanced keratoconus, providing biomechanical support recovering the pachimetry to nearly normal value at the same time. The accuracy and predictability of the refractive outcome are yet a critical issue and the patient eligible for the procedure still has to be characterized.