DNA methyltransferase 3A (DNMT3A) mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). ...Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here, we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant MPN with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell-autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.
The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of ...healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plant pathology has developed a wide range of concepts and tools for improving plant disease management, including models for understanding and responding to new risks from climate change. Most of ...these tools can be improved using new advances in artificial intelligence (AI), such as machine learning to integrate massive data sets in predictive models. There is the potential to develop automated analyses of risk that alert decision-makers, from farm managers to national plant protection organizations, to the likely need for action and provide decision support for targeting responses. We review machine-learning applications in plant pathology and synthesize ideas for the next steps to make the most of these tools in digital agriculture. Global projects, such as the proposed global surveillance system for plant disease, will be strengthened by the integration of the wide range of new data, including data from tools like remote sensors, that are used to evaluate the risk ofplant disease. There is exciting potential for the use of AI to strengthen global capacity building as well, from image analysis for disease diagnostics and associated management recommendations on farmers' phones to future training methodologies for plant pathologists that are customized in real-time for management needs in response to the current risks. International cooperation in integrating data and models will help develop the most effective responses to new challenges from climate change.
Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the ...potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept‐based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus‐based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low‐intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade‐based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor–free immunosuppression.
This retrospective clinical experience highlights the use of belatacept and transient tacrolimus therapy to control rejection, limit donor‐specific antibody production, and improve long‐term renal allograft function.
The Johnson and Johnson Ad26.COV2.S single-dose vaccine represents an attractive option for coronavirus disease 2019 (COVID-19) vaccination in countries with limited resources. We examined the effect ...of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus or infected in the second wave when Beta predominated. Prior infection significantly boosts spike-binding antibodies, antibody-dependent cellular cytotoxicity, and neutralizing antibodies against D614G, Beta, and Delta; however, neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses are induced after vaccination, regardless of prior infection. T cell recognition of variants is largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination after infection could result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.
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•Infection before Ad26CoV2.S vaccination boosts binding, neutralization, and ADCC•Antibody boosting is not affected by time between infection and vaccination•Neutralization breadth for VOCs is determined by the sequence of the infecting virus•T cell responses are moderately boosted by prior infection and cross-react with VOCs
Keeton, Richardson, Moyo-Gwete, et al. show that SARS-CoV-2 infection prior to Ad26CoV2.S vaccination significantly boosts cross-reactive ADCC and binding and neutralizing antibodies and moderately boosts T cell responses against variants of concern. Furthermore, the infecting virus spike sequence determines the cross-reactivity of neutralizing responses, with implications for second-generation vaccine design.
Study objective Drug-related emergency department (ED) visits have steadily increased, with substance users relying heavily on the ED for medical care. The present study aims to identify clinical ...correlates of problematic drug use that would facilitate identification of ED patients in need of substance use treatment. Methods Using previously validated tests, 15,224 adult ED patients across 6 academic institutions were prescreened for drug use as part of a large randomized prospective trial. Data for 3,240 participants who reported drug use in the past 30 days were included. Self-reported variables related to demographics, substance use, and ED visit were examined to determine their correlative value for problematic drug use. Results Of the 3,240 patients, 2,084 (64.3%) met criteria for problematic drug use (Drug Abuse Screening Test score ≥3). Age greater than or equal to 30 years, tobacco smoking, daily or binge alcohol drinking, daily drug use, primary noncannabis drug use, resource-intense ED triage level, and perceived drug-relatedness of ED visit were highly correlated with problematic drug use. Among primary cannabis users, correlates of problematic drug use were age younger than 30 years, tobacco smoking, binge drinking, daily drug use, and perceived relatedness of the ED visit to drug use. Conclusion Clinical correlates of drug use problems may assist the identification of ED patients who would benefit from comprehensive screening, intervention, and referral to treatment. A clinical decision rule is proposed. The correlation between problematic drug use and resource-intense ED triage levels suggests that ED-based efforts to reduce the unmet need for substance use treatment may help decrease overall health care costs.
Abstract Lack of sexual interest is the most common sexual complaint among women. However, factors affecting sexual desire in women have rarely been studied. While the role of the brain in ...integrating the sensory, attentional, motivational, and motor aspects of sexual response is commonly acknowledged as important, little is known about specific patterns of brain activation and sexual interest or response, particularly among women. We compared 20 females with no history of sexual dysfunction (NHSD) to 16 women with hypoactive sexual desire disorder (HSDD) in a functional magnetic resonance imaging (fMRI) study that included assessment of subjective sexual arousal, peripheral sexual response using a vaginal photoplethysmograph (VPP), as well as brain activation across three time points. Video stimuli included erotic, sports, and relaxing segments. Subjective arousal to erotic stimuli was significantly greater in NHSD participants compared with HSDD. In the erotic–sports contrast, NHSD women showed significantly greater activation in the bilateral entorhinal cortex than HSDD women. In the same contrast, HSDD females demonstrated higher activation than NHSD females in the medial frontal gyrus (Brodmann area (BA) 10), right inferior frontal gyrus (BA 47) and bilateral putamen. There were no between group differences in VPP-correlated brain activation and peripheral sexual response was not significantly associated with either subjective sexual response or brain activation patterns. Findings were consistent across the three experimental sessions. The results suggest differences between women with NHSD and HSDD in encoding arousing stimuli, retrieval of past erotic experiences, or both. The findings of greater activation in BA 10 and BA 47 among women with HSDD suggest that this group allocated significantly more attention to monitoring and/or evaluating their responses than NHSD participants, which may interfere with normal sexual response.
ABSTRACT
Background and objective
A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether ...treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk.
Methods
The Australasian Severe Asthma Web‐Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non‐severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months.
Results
In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non‐severe asthma. Allergic sensitization, upper‐airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea.
Conclusion
Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non‐severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.
We assessed the prevalence of treatable traits in severe asthma compared with non‐severe asthma, and assessed the relationship between treatable traits and future exacerbation risk. We demonstrate the usefulness of the treatable traits approach in severe asthma and which specific treatable traits are predictive of future asthma attacks.
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