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Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.
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COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Linfócitos T CD8-Positivos , COVID-19/prevenção & controle , Humanos , Imunidade Humoral , RNA Mensageiro/genética , Síndrome , Vacinação , Proteínas do Envelope ViralRESUMO
Tropical forests play a critical role in the hydrological cycle and can influence local and regional precipitation1. Previous work has assessed the impacts of tropical deforestation on precipitation, but these efforts have been largely limited to case studies2. A wider analysis of interactions between deforestation and precipitation-and especially how any such interactions might vary across spatial scales-is lacking. Here we show reduced precipitation over deforested regions across the tropics. Our results arise from a pan-tropical assessment of the impacts of 2003-2017 forest loss on precipitation using satellite, station-based and reanalysis datasets. The effect of deforestation on precipitation increased at larger scales, with satellite datasets showing that forest loss caused robust reductions in precipitation at scales greater than 50 km. The greatest declines in precipitation occurred at 200 km, the largest scale we explored, for which 1 percentage point of forest loss reduced precipitation by 0.25 ± 0.1 mm per month. Reanalysis and station-based products disagree on the direction of precipitation responses to forest loss, which we attribute to sparse in situ tropical measurements. We estimate that future deforestation in the Congo will reduce local precipitation by 8-10% in 2100. Our findings provide a compelling argument for tropical forest conservation to support regional climate resilience.
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Conservação dos Recursos Naturais , Agricultura Florestal , Florestas , Chuva , Árvores , Clima Tropical , Congo , Conservação dos Recursos Naturais/tendências , Ciclo HidrológicoRESUMO
Friedreich's ataxia (FRDA) is caused by expansions of GAAâ¢TTC repeats in the first intron of the human FXN gene that occur during both intergenerational transmissions and in somatic cells. Here we describe an experimental system to analyze large-scale repeat expansions in cultured human cells. It employs a shuttle plasmid that can replicate from the SV40 origin in human cells or be stably maintained in S. cerevisiae utilizing ARS4-CEN6. It also contains a selectable cassette allowing us to detect repeat expansions that accumulated in human cells upon plasmid transformation into yeast. We indeed observed massive expansions of GAAâ¢TTC repeats, making it the first genetically tractable experimental system to study large-scale repeat expansions in human cells. Further, GAAâ¢TTC repeats stall replication fork progression, while the frequency of repeat expansions appears to depend on proteins implicated in replication fork stalling, reversal, and restart. Locked nucleic acid (LNA)-DNA mixmer oligonucleotides and peptide nucleic acid (PNA) oligomers, which interfere with triplex formation at GAAâ¢TTC repeats in vitro, prevented the expansion of these repeats in human cells. We hypothesize, therefore, that triplex formation by GAAâ¢TTC repeats stall replication fork progression, ultimately leading to repeat expansions during replication fork restart.
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Ataxia de Friedreich , Oligonucleotídeos , Ácidos Nucleicos Peptídicos , Expansão das Repetições de Trinucleotídeos , Humanos , DNA , Replicação do DNA/efeitos dos fármacos , Ataxia de Friedreich/genética , Proteínas de Ligação ao Ferro/genética , Oligonucleotídeos/farmacologia , Ácidos Nucleicos Peptídicos/farmacologia , Saccharomyces cerevisiae/genéticaRESUMO
PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.
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Agamaglobulinemia , Anticorpos Antivirais , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Doenças Genéticas Ligadas ao Cromossomo X , Imunoglobulina G , Linfócitos T , Humanos , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/diagnóstico , Encefalite Transmitida por Carrapatos/terapia , Masculino , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Anticorpos Antivirais/sangue , Linfócitos T/imunologia , Resultado do Tratamento , Adulto , Imunização Passiva/métodosRESUMO
Several genetic and immunological risk factors for severe COVID-19 have been identified, with monogenic conditions relating to 13 genes of type I interferon (IFN) immunity proposed to explain 4.8% of critical cases. However, previous cohorts have been clinically heterogeneous and were not subjected to thorough genetic and immunological analyses. We therefore aimed to systematically investigate the prevalence of rare genetic variants causing inborn errors of immunity (IEI) and functionally interrogate the type I IFN pathway in young adults that suffered from critical COVID-19 yet lacked comorbidities. We selected and clinically characterized a cohort of 38 previously healthy individuals under 50 years of age who were treated in intensive care units due to critical COVID-19. Blood samples were collected after convalescence. Two patients had IFN-α autoantibodies. Genome sequencing revealed very rare variants in the type I IFN pathway in 31.6% of the patients, which was similar to controls. Analyses of cryopreserved leukocytes did not indicate any defect in plasmacytoid dendritic cell sensing of TLR7 and TLR9 agonists in patients carrying variants in these pathways. However, lymphocyte STAT phosphorylation and protein upregulation upon IFN-α stimulation revealed three possible cases of impaired type I IFN signaling in carriers of rare variants. Together, our results suggest a strategy of functional screening followed by genome analyses and biochemical validation to uncover undiagnosed causes of critical COVID-19.
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COVID-19 , Interferon Tipo I , Humanos , Adulto Jovem , COVID-19/genética , Interferon-alfa , Transdução de Sinais , AutoanticorposRESUMO
The global decline of freshwater mussels and their crucial ecological services highlight the need to understand their phylogeny, phylogeography and patterns of genetic diversity to guide conservation efforts. Such knowledge is urgently needed for Unio crassus, a highly imperilled species originally widespread throughout Europe and southwest Asia. Recent studies have resurrected several species from synonymy based on mitochondrial data, revealing U. crassus to be a complex of cryptic species. To address long-standing taxonomic uncertainties hindering effective conservation, we integrate morphometric, phylogenetic, and phylogeographic analyses to examine species diversity within the U. crassus complex across its entire range. Phylogenetic analyses were performed using cytochrome c oxidase subunit I (815 specimens from 182 populations) and, for selected specimens, whole mitogenome sequences and Anchored Hybrid Enrichment (AHE) data on â¼ 600 nuclear loci. Mito-nuclear discordance was detected, consistent with mitochondrial DNA gene flow between some species during the Pliocene and Pleistocene. Fossil-calibrated phylogenies based on AHE data support a Mediterranean origin for the U. crassus complex in the Early Miocene. The results of our integrative approach support 12 species in the group: the previously recognised Unio bruguierianus, Unio carneus, Unio crassus, Unio damascensis, Unio ionicus, Unio sesirmensis, and Unio tumidiformis, and the reinstatement of five nominal taxa: Unio desectusstat. rev., Unio gontieriistat. rev., Unio mardinensisstat. rev., Unio nanusstat. rev., and Unio vicariusstat. rev. Morphometric analyses of shell contours reveal important morphospace overlaps among these species, highlighting cryptic, but geographically structured, diversity. The distribution, taxonomy, phylogeography, and conservation of each species are succinctly described.
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Unio , Animais , Filogenia , Filogeografia , Unio/genética , Europa (Continente) , DNA Mitocondrial/genética , Variação GenéticaRESUMO
The crises of climate change and biodiversity loss are interlinked and must be addressed jointly. A proposed solution for reducing reliance on fossil fuels, and thus mitigating climate change, is the transition from conventional combustion-engine to electric vehicles. This transition currently requires additional mineral resources, such as nickel and cobalt used in car batteries, presently obtained from land-based mines. Most options to meet this demand are associated with some biodiversity loss. One proposal is to mine the deep seabed, a vast, relatively pristine and mostly unexplored region of our planet. Few comparisons of environmental impacts of solely expanding land-based mining versus extending mining to the deep seabed for the additional resources exist and for biodiversity only qualitative. Here, we present a framework that facilitates a holistic comparison of relative ecosystem impacts by mining, using empirical data from relevant environmental metrics. This framework (Environmental Impact Wheel) includes a suite of physicochemical and biological components, rather than a few selected metrics, surrogates, or proxies. It is modified from the "recovery wheel" presented in the International Standards for the Practice of Ecological Restoration to address impacts rather than recovery. The wheel includes six attributes (physical condition, community composition, structural diversity, ecosystem function, external exchanges and absence of threats). Each has 3-5 sub attributes, in turn measured with several indicators. The framework includes five steps: (1) identifying geographic scope; (2) identifying relevant spatiotemporal scales; (3) selecting relevant indicators for each sub-attribute; (4) aggregating changes in indicators to scores; and (5) generating Environmental Impact Wheels for targeted comparisons. To move forward comparisons of land-based with deep seabed mining, thresholds of the indicators that reflect the range in severity of environmental impacts are needed. Indicators should be based on clearly articulated environmental goals, with objectives and targets that are specific, measurable, achievable, relevant, and time bound.
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Mineração , Biodiversidade , Ecossistema , Meio Ambiente , Conservação dos Recursos Naturais , Mudança ClimáticaRESUMO
BACKGROUND: Atipamezole, an α-2 adrenergic receptor antagonist, reverses the α-2 agonist anesthetic effects. There is a dearth of information on the physiological effects of these drugs in cynomolgus macaques (Macaca fascicularis). We assessed atipamezole's physiologic effects. We hypothesized atipamezole administration would alter anesthetic parameters. METHODS: Five cynomolgus macaques were sedated with ketamine/dexmedetomidine intramuscularly, followed 45 min later with atipamezole (0.5 mg/kg). Anesthetic parameters (heart rate, blood pressure [systolic (SAP), diastolic (DAP), and mean (MAP) blood pressure], body temperature, respiratory rate, and %SpO2) were monitored prior to and every 10 min (through 60 min) post atipamezole injection. RESULTS: While heart rate was significantly increased for 60 min; SAP, DAP, MAP, and temperature were significantly decreased at 10 min. CONCLUSIONS: This study indicates subcutaneous atipamezole results in increased heart rate and transient blood pressure decrease. These findings are clinically important to ensure anesthetist awareness to properly support and treat patients as needed.
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Anestésicos , Ketamina , Animais , Macaca fascicularis , Imidazóis/farmacologia , Ketamina/farmacologia , Anestésicos/farmacologia , Frequência CardíacaRESUMO
Optimal performance lies at intermediate autonomic arousal, but no previous research has examined whether the emergence of endogenous control associates with changes in children's up-regulation from hypo-arousal, as well as down-regulation from hyper-arousal. We used wearables to take day-long recordings from N = 58, 12-month-olds (60% white/58% female); and, in the same infants, we measured self-regulation in the lab with a still-face paradigm. Overall, our findings suggest that infants who showed more self-regulatory behaviors in the lab were more likely to actively change their behaviors in home settings moment-by-moment "on the fly" following changes in autonomic arousal, and that these changes result in up- as well as down-regulation. Implications for the role of atypical self-regulation in later psychopathology are discussed.
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INTRODUCTION: Mental health conditions (MHC) among adolescents in low- and middle-income countries, including South Africa, are estimated to be high. Adaptive emotion regulation (ER) skills can protect against MHC among adolescents. In South Africa, there is limited adolescent mental health prevalence data as well as little understanding of the associations between MHC and ER among adolescents. This study aimed to address these gaps by describing the psychosocial characteristics of older South African adolescents from low-income settings as well as investigating associations between depression and anxiety symptoms and ER. METHODS: We selected 12 schools in collaboration with two NGOs. Learners aged 15-18-years were recruited to complete a tablet-based survey. ER, depression, anxiety, and other psychosocial measures were included. Two multiple linear regression models were used to determine associations between depression symptoms, anxiety symptoms, other psychosocial factors, and ER. RESULTS: Of the 733 participants from 12 Western Cape schools, 417 (56.90%) screened at risk for clinically significant anxiety symptoms, 423 (57.70%) participants for depression symptoms, 229 (31.40%) participants for PTSD symptoms and 263 (35.90%) for risky alcohol use. Depression and anxiety scores were found to be significantly positively correlated with ER difficulties and adolescents struggled most with identifying and utilizing adaptive ER strategies. The adjusted linear regression model reported that female gender, clinically significant depressive, anxiety, post-traumatic stress symptoms and risky-alcohol use were all significantly associated with poorer ER scores, while self-esteem was significantly associated with better ER scores. CONCLUSION: These findings contribute to the South African adolescent mental health literature and to the research gap on the links between depression and anxiety and ER. Future research should consider further exploration of the relationships between psychosocial factors and ER to inform the urgent development and testing of appropriate adolescent interventions in this setting.
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Ansiedade , Depressão , Regulação Emocional , Pobreza , Humanos , Adolescente , África do Sul/epidemiologia , Feminino , Masculino , Depressão/psicologia , Depressão/epidemiologia , Ansiedade/psicologia , Ansiedade/epidemiologia , Pobreza/psicologiaRESUMO
Lower urinary tract symptoms due to benign prostatic hyperplasia (BPH) are common in older patients assigned male sex at birth, regardless of gender identity, and treatment of these symptoms is therefore common in primary care practice. In 2021, the American Urological Association published guidelines for management of BPH. They recommend using a standardized scoring system such as the International Prostate Symptom Score to help establish a diagnosis and to monitor the efficacy of interventions, α-blockers as the first-choice pharmacotherapy option, and 5α-reductase inhibitors for patients with prostate size estimated to be at least 30 cc. Tadalafil is another option regardless of erectile dysfunction. Combination therapies with α-blockers and 5α-reductase inhibitors, anticholinergic agents, or ß3-agonists are effective options. A surgical referral is warranted if the BPH results in chronic kidney disease, refractory urinary retention, or recurrent urinary tract infections; if there is concern for bladder or prostate cancer; or if symptoms do not respond to medical therapy. In this article, a general internal medicine physician and a urologist discuss the treatment options and how they would apply their recommendations to a patient who wishes to learn more about his options.
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Hiperplasia Prostática , Visitas de Preceptoria , Feminino , Recém-Nascido , Humanos , Masculino , Idoso , Hiperplasia Prostática/complicações , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/tratamento farmacológico , Quimioterapia Combinada , Identidade de Gênero , Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Oxirredutases/uso terapêutico , Resultado do TratamentoRESUMO
Quantum diffusion is a major topic in condensed-matter physics, and the Caldeira-Leggett model has been one of the most successful approaches to study this phenomenon. Here, we generalize this model by coupling the bath to the system through a Liouville fractional derivative. The Liouville fractional Langevin equation is then derived in the classical regime, without imposing a non-Ohmic macroscopic spectral function for the bath. By investigating the short- and long-time behavior of the mean squared displacement, we show that this model is able to describe a large variety of anomalous diffusion. Indeed, we find ballistic, sub-ballistic, and super-ballistic behavior for short times, whereas for long times, we find saturation and sub- and super-diffusion.
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OBJECTIVES: To determine the association between smoking and tooth loss in individuals aged 18 years or more living in Brazil. METHODS: Secondary analysis of the 2019 Brazilian National Health Survey data. The outcome was self-reported tooth loss, and the main independent variable was tobacco smoking. Family income, schooling, sex and age were covariates. Multiple linear regression analysis determined the association between tobacco smoking and the number of missing teeth and then the average number of missing teeth was predicted according to smoking status. RESULTS: The mean number of missing teeth in 88,531 individuals aged 18 or more was 7.7 (95%CI: 7.6-7.8). At least one missing tooth was identified in 72.0% (95%CI: 71.4-72.6) of the population, 21.3% (95%CI: 20.9-21.7) had a non-functional dentition, 14.2% (95%CI: 13.9-14.6) had severe tooth loss and 10.3% (95%CI: 10.0-10.6) were edentulous. The adjusted regression coefficients for number of missing teeth showed that current or former smokers, individuals with low family income and schooling, older age and females exhibited higher tooth loss. Current and former smokers had 1.40 (95%CI: 1.35-1.46) and 1.13 (95%CI: 0.54-0.98) times more lost teeth than never smokers, respectively. CONCLUSIONS: Both tooth loss and smoking are common in Brazilians and are associated. Unfavorable socioeconomic status and demographic factors also predict tooth loss.
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AIMS: To determine the concentration, in comparison with the maximum residue limit (MRL), of anthelmintic marker residues in the target tissues (liver and fat) of sheep treated concurrently with two oral drenches, one containing monepantel and abamectin and the other oxfendazole and levamisole. METHODS: On day 0 of the study, 12 sheep (six male and six female; 8-9-months old) were dosed according to individual body weight determined the day prior. Zolvix Plus (dual-active oral drench containing 25 g/L monepantel and 2 g/L abamectin) was administered to all animals prior to administration of Scanda (dual-active oral drench containing 80 g/L levamisole hydrochloride and 45.3 g/L oxfendazole). Six sheep (three male and three female) were slaughtered 21 and 28 days after treatment and renal fat and liver samples were collected.Using validated methods, analyses for monepantel sulfone, abamectin, levamisole and oxfendazole (expressed as total fenbendazole sulfone following conversion of the combined concentrations of oxfendazole, fenbendazole and fenbendazole sulfone) were performed on liver samples while renal fat specimens were analysed for monepantel sulfone and abamectin residues only. Detected concentrations were compared to the established MRL in sheep for each analyte determined by the Ministry for Primary Industries. RESULTS: All residues detected in samples of liver and fat collected 21 and 28 days after treatment were below the MRL for each analyte. All liver samples collected on day 21 had detectable monepantel sulfone (mean 232 (min 110, max 388) µg/kg) and oxfendazole (mean 98.7 (min 51.3, max 165) µg/kg) residues below the MRL (5,000 and 500 µg/kg, respectively). Monepantel sulfone (mean 644 (min 242, max 1,119) µg/kg; MRL 7,000 µg/kg) residues were detected in 6/6 renal fat samples. Levamisole residues were detected in 3/6 livers (mean 40.0 (min 14.3, max 78.3) µg/kg; MRL 100 µg/kg), and abamectin residues in 1/6 livers (0.795 µg/kg; MRL 25 µg/kg) and 2/6 fat samples, (mean 0.987 (min 0.514, max 1.46) µg/kg; MRL 50 µg/kg) 21 days after treatment. CONCLUSION AND CLINICAL RELEVANCE: These results suggest that concurrent administration of Zolvix Plus and Scanda to sheep is unlikely to result in an extended residue profile for any of the active ingredients, with all analytes measured being under the approved New Zealand MRL 21 days after treatment. This work was not completed in line with guidance for establishing official residue profiles, nor is it sufficient to propose a new withholding period.
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Aminoacetonitrila/análogos & derivados , Anti-Helmínticos , Benzimidazóis , Ivermectina/análogos & derivados , Doenças dos Ovinos , Animais , Masculino , Feminino , Ovinos , Levamisol/uso terapêutico , Fenbendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Sulfonas/uso terapêutico , Doenças dos Ovinos/tratamento farmacológicoRESUMO
AIM/HYPOTHESIS: This study aimed to investigate the safety and efficacy of treatment with allogeneic Wharton's jelly-derived mesenchymal stromal cells (MSCs) in recent-onset type 1 diabetes. METHODS: A combined Phase I/II trial, composed of a dose escalation followed by a randomised double-blind placebo-controlled study in parallel design, was performed in which treatment with allogeneic MSCs produced as an advanced therapy medicinal product (ProTrans) was compared with placebo in adults with newly diagnosed type 1 diabetes. Inclusion criteria were a diagnosis of type 1 diabetes <2 years before enrolment, age 18-40 years and a fasting plasma C-peptide concentration >0.12 nmol/l. Randomisation was performed with a web-based randomisation system, with a randomisation code created prior to the start of the study. The randomisation was made in blocks, with participants randomised to ProTrans or placebo treatment. Randomisation envelopes were kept at the clinic in a locked room, with study staff opening the envelopes at the baseline visits. All participants and study personnel were blinded to group assignment. The study was conducted at Karolinska University Hospital, Stockholm, Sweden. RESULTS: Three participants were included in each dose cohort during the first part of the study. Fifteen participants were randomised in the second part of the study, with ten participants assigned to ProTrans treatment and five to placebo. All participants were analysed for the primary and secondary outcomes. No serious adverse events related to treatment were observed and, overall, few adverse events (mainly mild upper respiratory tract infections) were reported in the active treatment and placebo arms. The primary efficacy endpoint was defined as Δ-change in C-peptide AUC for a mixed meal tolerance test at 1 year following ProTrans/placebo infusion compared with baseline performance prior to treatment. C-peptide levels in placebo-treated individuals declined by 47%, whereas those in ProTrans-treated individuals declined by only 10% (p<0.05). Similarly, insulin requirements increased in placebo-treated individuals by a median of 10 U/day, whereas insulin needs of ProTrans-treated individuals did not change over the follow-up period of 12 months (p<0.05). CONCLUSIONS/INTERPRETATION: This study suggests that allogeneic Wharton's jelly-derived MSCs (ProTrans) is a safe treatment for recent-onset type 1 diabetes, with the potential to preserve beta cell function. TRIAL REGISTRATION: ClinicalTrials.gov NCT03406585 FUNDING: The sponsor of the clinical trial is NextCell Pharma AB, Stockholm, Sweden.
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COVID-19 , Diabetes Mellitus Tipo 1 , Células-Tronco Mesenquimais , Adulto , Humanos , Adolescente , Adulto Jovem , Diabetes Mellitus Tipo 1/tratamento farmacológico , SARS-CoV-2 , Insulina/uso terapêutico , Peptídeo C , Resultado do Tratamento , Método Duplo-Cego , Cordão UmbilicalRESUMO
The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.
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Aspirina , Hemorragia , Humanos , Estados Unidos/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Hemorragia/induzido quimicamente , Austrália/epidemiologia , Método Duplo-CegoRESUMO
PURPOSE: Patients with antibody deficiencies often receive maintenance treatment with donor plasma-derived immunoglobulin (Ig) preparations to decrease the incidence and severity of infections. We have previously shown that IgG antibodies to the original SARS-CoV-2 strain were not consistently present in off-the-shelf Ig batches produced up to approximately 18 months after the first identified case of COVID-19 in the USA and that Ig batches with anti-SARS-CoV-2 IgG primarily contained vaccine-induced spike specific antibodies. This study aimed to investigate the degree of cross-reactivity between vaccine-induced anti-SARS-CoV-2 antibodies against Wuhan strain and subsequent viral variants. METHODS: Samples were collected from 74 Ig batches supplied by three different commercial manufacturers. All batches were used at the Immunodeficiency Unit at the Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until September 2022. Antibody quantity and potential to neutralize virus entry into host cells were assessed against the original SARS-CoV-2 Wuhan strain and the following nine variants: Alpha, Beta, Delta, IHU, and the Omicron BA.1, BA.1.1, BA.1 with spike mutation L452R, BA.2, and BA.3. RESULTS: Ig batches produced approximately 18 months after the SARS-CoV-2 outbreak (from around July 2021) and later consistently contained high quantities of antibodies that bind the Wuhan strain. The Ig batches had overall low reactivity to the SARS-CoV-2 nucleocapsid, which implies that plasma donor spike IgG essentially is the result of vaccination. We assessed the degree of cross-reactivity towards each virus variant by plotting the variant/Wuhan strain ratio, which was consistent regardless of production date, suggesting cross-reactivity with vaccine-induced antibodies rather than virus exposure in the plasma donor population. Viral variants that emerged later during the pandemic systematically had a lower reactivity ratio, except for the Delta and IHU variants. The Ig batches displayed markedly low neutralizing potential towards the Beta variant and all tested Omicron variants. CONCLUSION: Commercial Ig batches currently contain large quantities of SARS-CoV-2 vaccine-induced antibodies. Cross-reactivity with variant strains is evident but varies, with markedly low neutralizing potential observed against Omicron variants.
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Vacinas contra COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , Anticorpos Antivirais , Imunoglobulina G , Anticorpos NeutralizantesRESUMO
Development of targeted therapeutics to alleviate gastrointestinal (GI) inflammation and its debilitating consequences are required. In this context, the trace aminergic system may link together sex, diet and inflammation. Utilising a zebrafish larval model of GI inflammation, the current study aimed to investigate mechanisms by which excess amounts of trace amines (TAs) may influence GI health. In addition, we probed the potential role of 17ß-estradiol (E2) and its receptors, given the known female-predominance of many GI disorders. To assess GI functionality and integrity, live imaging techniques (neutral red staining) and post-mortem immunofluorescent staining of tight junction proteins (occludin and ZO-1) were analyzed respectively. In addition, behavioural assays, as an indication of overall wellbeing, as well as whole body H2O2 and prostaglandin E2 assays were performed to inform on oxidative and inflammatory status. Excess ß-phenethylamine (PEA), tryptamine (TRP) and ρ-tyramine (TYR) resulted in adverse GI and systemic effects. In this regard, clear beneficial effects of E2 to modulate the effects of PEA, TRP and TYR was evident. Moreover, agmatine displayed potential protective effects on GI epithelium and whole body oxidative status, however, potential to induce systemic inflammation suggests the importance of dosage and administration optimisation. Taken together, TYR seems like the most prominent TA to have damaging GI effects, feasibly exacerbating GI inflammation. In this context, the relative lack of E2 may provide mechanistic insights into the reported female-predominance of GI disorders. Moreover, an effective therapeutic in this context may be required to maintain GI TA load despite fluctuating E2 levels.
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Tiramina , Peixe-Zebra , Animais , Feminino , Estradiol/farmacologia , Peróxido de Hidrogênio , Inflamação/metabolismo , LarvaRESUMO
BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.
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KEY MESSAGE: Breeding target traits can be broadened to include nutritive value and plant breeder's rights traits in perennial ryegrass by using in-field regression-based spectroscopy phenotyping and genomic selection. Perennial ryegrass breeding has focused on biomass yield, but expansion into a broader set of traits is needed to benefit livestock industries whilst also providing support for intellectual property protection of cultivars. Numerous breeding objectives can be targeted simultaneously with the development of sensor-based phenomics and genomic selection (GS). Of particular interest are nutritive value (NV), which has been difficult and expensive to measure using traditional phenotyping methods, resulting in limited genetic improvement to date, and traits required to obtain varietal protection, known as plant breeder's rights (PBR) traits. In order to assess phenotyping requirements for NV improvement and potential for genetic improvement, in-field reflectance-based spectroscopy was assessed and GS evaluated in a single population for three key NV traits, captured across four timepoints. Using three prediction approaches, the possibility of targeting PBR traits using GS was evaluated for five traits recorded across three years of a breeding program. Prediction accuracy was generally low to moderate for NV traits and moderate to high for PBR traits, with heritability highly correlated with GS accuracy. NV did not show significant or consistent correlation between timepoints highlighting the need to incorporate seasonal NV into selection indexes and the value of being able to regularly monitor NV across seasons. This study has demonstrated the ability to implement GS for both NV and PBR traits in perennial ryegrass, facilitating the expansion of ryegrass breeding targets to agronomically relevant traits while ensuring necessary varietal protection is achieved.