Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. FUNDING: Adaptimmune.

Molecular Insights of Cholestasis in MDR2 Knockout Murine Liver Organoids.

MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.

Validation of an early vascular aging construct model for comprehensive cardiovascular risk assessment using external risk indicators for improved clinical utility: data from the EVasCu study.

BACKGROUND: Cardiovascular diseases (CVDs) remain a major global health concern, necessitating advanced risk assessment beyond traditional factors. Early vascular aging (EVA), characterized by accelerated vascular changes, has gained importance in cardiovascular risk assessment. METHODS: The EVasCu study in Spain examined 390 healthy participants using noninvasive measurements. A construct of four variables (Pulse Pressure, Pulse Wave Velocity, Glycated Hemoglobin, Advanced Glycation End Products) was used for clustering. K-means clustering with principal component analysis revealed two clusters, healthy vascular aging (HVA) and early vascular aging (EVA). External validation variables included sociodemographic, adiposity, glycemic, inflammatory, lipid profile, vascular, and blood pressure factors. RESULTS: EVA cluster participants were older and exhibited higher adiposity, poorer glycemic control, dyslipidemia, altered vascular properties, and higher blood pressure. Significant differences were observed for age, smoking status, body mass index, waist circumference, fat percentage, glucose, insulin, C-reactive protein, diabetes prevalence, lipid profiles, arterial stiffness, and blood pressure levels. These findings demonstrate the association between traditional cardiovascular risk factors and EVA. CONCLUSIONS: This study validates a clustering model for EVA and highlights its association with established risk factors. EVA assessment can be integrated into clinical practice, allowing early intervention and personalized cardiovascular risk management.

Non-invasive skin autofluorescence as a screening method for diabetic retinopathy.

Diabetic retinopathy (DR) is a public health problem and a common cause of blindness. It is diagnosed by fundus examination; however, this is a costly and time-consuming method. Non-invasive skin autofluorescence (SAF) may be an accessible, fast and simple alternative for screening and early diagnosis of DR. The aim of this study was to evaluate the accuracy of SAF as a screening method for DR. A systematic search of MEDLINE, Scopus, and Web of Science databases was performed. Random effects models for sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio (dOR) value and 95% CIs were used to calculate test accuracy. In addition, hierarchical summary receiver operating characteristic curves (HSROC) were used to summarise the overall test performance. Four studies were included in the meta-analysis. Pooled sensitivity and specificity were 0.79 (95% CI 0.72-0.88; I2  = 0.0%) and 0.54 (95% CI 0.32-0.92; I2  = 97.0%), respectively. The dOR value for the diagnosis of DR using SAF was 5.11 (95% CI 1.81-14.48: I2  = 85.9%). The PRL was 2.17 (95% CI 0.62-7.64) and the NRL was 0.27 (95% CI 0.07-1.03). Heterogeneity was not relevant in sensitivity and considerable in specificity. The 95% confidence region of the HSROC included all studies. SAF as a screening test for DR shows sufficient accuracy for its use in clinical settings. SAF may be an appropriate method for DR screening, and further research is needed to recommend it as a diagnostic method.

Transarterial Embolization for Adhesive Capsulitis of the Shoulder: Midterm Outcomes on Function and Pain Relief.

PURPOSE: To determine the safety and potential effectiveness of transarterial embolization for adhesive capsulitis of the shoulder. MATERIALS AND METHODS: This prospective study analyzed consecutive adult patients with adhesive capsulitis referred for embolization between January 2018 and May 2023 after a poor response to treatment (symptoms and limitation of motion in ≥2 axes; ≤120° flexion, ≤50° external rotation and/or internal rotation with the shoulder abducted 90°) persisting for >3 months after having completed ≥6 weeks of analgesics and physical therapy. Different types of pain and mobility were measured before embolization and 1, 3, and 6 months after embolization. Overall upper limb function (Quick Disabilities of Arm, Shoulder, and Hand) and patient satisfaction were measured before and 6 months after embolization. Long-term follow-up comprised telephone interviews and clinical history reviews. RESULTS: A total of 20 patients (12 [60%] women; median age, 50.7; interquartile ranges [IQR], 45‒55 years) were included; 6 (30%) had diabetes and 15 (75%) were off work. Median duration of symptoms before embolization was 39.4 weeks (IQR, 28‒49 weeks), and median duration of rehabilitation therapy was 12.8 weeks (IQR, 8‒16 weeks). Six months after embolization, significant improvements were observed in nocturnal pain (P = .003), pain on moving (P = .001), external rotation (P < .001), internal rotation (P < .001), active flexion (P < .001), passive flexion (P = .03), active abduction (P < .001), passive abduction (P < .001), and overall function (P < .001). Despite objective improvements, patient satisfaction was nearly unchanged. Only 1 patient experienced a mild adverse event. CONCLUSION: Transarterial embolization is safe and potentially effective in treating adhesive capsulitis of the shoulder refractory to conventional treatment. Clinical improvements were maintained in the mid to long term.

Monocyte distribution width (MDW): study of reference values in blood donors.

OBJECTIVES: Monocyte distribution width (MDW) is a new biomarker used as an early indicator of sepsis (ESId). It is often aids in the identification of patients who may develop sepsis. This study aims to establish the MDW reference interval (RI) within the healthy population of blood donors using EDTA-K2 as anticoagulant. Many hospitals use this biomarker as a means of identifying patients who present to the hospital with sepsis. METHODS: A total of 274 samples obtained from healthy donors were analyzed. MDW measurements were taken within 2 h post-extraction. The RI was estimated using various statistical methodologies, including the recommended CLSI EP28-A3c guideline, non-parametric and robust methods, along with the Harrell-Davis bootstrap method applied to the entire sample. RESULTS: The RI estimated through non-parametric method was 14.77 CI90 % (14.36-14.97)-21.13 CI90 % (20.89-21.68); RI using the robust method was 15.64-19.05 and RI using the Harrell-Davis bootstrap method was 14.73 CI90 % (14.53-14.92)-21.14 CI90 % (20.88-21.40). CONCLUSIONS: Based on clinical applicability, we recommend utilizing the RI derived from the non-parametric method, aligning with the CLSI recommendations. Furthermore, we consider that our results can be taken as a reference in other laboratories that serve a population similar to our study cohort.

Prevalence and genotypic associations of epilepsy in Prader-Willi Syndrome: A systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and other mutations, in the population with Prader-Willi syndrome (PWS). METHODS: A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted. Studies estimating the prevalence of seizures, epilepsy and febrile seizures in the PWS population were included. Meta-analyses of the prevalence of epilepsy and febrile seizures and their association with genotype using the prevalence ratio (PR) were performed. RESULTS: Fifteen studies were included. The prevalence of epilepsy was 0.11 (0.07, 0.15), similar to the prevalence of febrile seizures, with a prevalence of 0.09 (0.05, 0.13). The comparison "deletion vs. UPD" had a PR of 2.03 (0.90, 4.57) and 3.76 (1.54, 9.18) for epilepsy and febrile seizures. CONCLUSIONS: The prevalence of seizure disorders in PWS is higher than in the general population. In addition, deletions in 15q11-q13 may be associated with a higher risk of seizure disorders. Therefore, active screening for seizure disorders in PWS should improve the lives of these people. In addition, genotype could be used to stratify risk, even for epilepsy, although more studies or larger sample sizes are needed.

Steps per day and health-related quality of life in schoolchildren: the mediator role of cardiorespiratory fitness.

To analyse the relationship between steps per day and health-related quality of life (HRQoL) and cardiorespiratory fitness (CRF) and to examine whether the relationship between steps per day and HRQoL is mediated by CRF in schoolchildren. This was a cross-sectional study including 501 schoolchildren (aged 9-12 years, 47% girls), from Cuenca, Spain. Steps per day were measured using the Xiaomi Mi Band 3 Smart Bracelet, HRQoL was estimated by the KIDSCREEN-27 questionnaire, and CRF was assessed using the 20-m shuttle run test. Analysis of covariance and multivariate analysis of covariance models showed that children with a higher mean number of steps per day (> 9000 steps/day) had better HRQoL (global score, and physical and psychological well-being) and higher CRF levels than their peers with a lower number of steps per day (p < 0.05); however, these differences were no longer significant when controlling for sex, age, mother's education level, and CRF (p > 0.05). Linear regression models estimated that each 1000-step increment was associated with better CRF (ß = 0.350; 95% CI, 0.192 to 0.508). In addition, the relationship between steps per day and HRQoL was mediated by CRF (p < 0.05).    Conclusion: Steps per day are a good metric to estimate daily physical activity because of its positive relationship with CRF. Moreover, those children taking more than 9000 steps per day are associated with higher levels of physical and psychological well-being. Finally, a substantial part of the improvement in HRQoL achieved through the increase in physical activity (steps per day) is mediated by CRF. What is Known: • Physical activity is known to have a positive impact on health-related quality of life in children. Steps per day are commonly used as a measure of physical activity. • Cardiorespiratory fitness is a recognized indicator of overall health in youth. What is New: • Increments of steps per day were associated with better CRF, with a nonlinear association after approximately 9000 steps/day. • Schoolchildren with > 9000 steps/ day showed better HRQoL.

Overview of the participation of community health workers in primary health care in 6 Latin American countries and a proposal for their integration into the health system: a qualitative study.

BACKGROUND: According to some health programmes, implementing primary health care through community health workers (CHWs) facilitates the connection between community and health services in Latin America. However, these are isolated processes that face different obstacles and would benefit from an overview of the corresponding health policies and programmes. OBJECTIVE: To provide an overview of CHW participation in 6 Latin American countries. METHODS: This exploratory qualitative study was based on 3 sources of information: a literature review, a review of public health policy documents, and interviews with experts who have led CHW programmes in 6 Latin American countries. RESULTS: The role of CHWs in Latin America and some advances in public health policies in the region were evidenced. However, limitations arising from variable implementation of the WHO guidelines on health programmes with CHWs were also apparent. CONCLUSIONS: CHWs contribute to the primary healthcare processes in the 6 Latin American countries studied in versatile and comprehensive ways. However, they constitute an underutilized human resource because they must provide various services that are not always relevant in different work contexts. Therefore, we propose a classification of the CHW profile, using the level of access to healthcare services of the population they serve as the main differentiator. This way, CHWs will not have to provide a wide range of services but only those most relevant to the specific needs of each community.

Association of daily steps on lipid and glycaemic profiles in children: The mediator role of cardiorespiratory fitness.

AIM: To analyse, in schoolchildren, the relationship between daily steps with metabolic parameters; and to examine whether this association is mediated by cardiorespiratory-fitness (CRF). METHODS: A cross-sectional analysis of baseline data from a feasibility trial was performed in children from two primary schools in Cuenca, Spain. Daily steps were measured using the Xiaomi MI Band 3. Lipid and glycaemic profiles were analysed from blood samples. CRF was assessed using the 20-m shuttle run test. ANCOVA models were used to test the mean differences by daily steps quartiles. Mediation analyses were conducted to examine whether CRF mediates the association between daily steps and lipid and glycaemic parameters. RESULTS: A total of 159 schoolchildren (aged 9-12 years, 53% female) were included in the analysis. Schoolchildren in the highest daily steps quartiles (>10 000 steps) showed significantly lower triglycerides and insulin levels (p = 0.004 and 0.002, respectively). This association did not remain after controlling for CRF. In mediation analyses, a significant indirect effect was observed through CRF in the relationship between daily steps with triglycerides and insulin. CONCLUSION: Children who daily accumulate more than 10 000 steps have better lipid and metabolic profile, and CRF mediated their relationship in schoolchildren.

Exploring the Relationship Between Instagram Use and Self-Criticism, Self-Compassion, and Body Dissatisfaction in the Spanish Population: Observational Study.

BACKGROUND: The widespread use of online social networks, particularly among the younger demographic, has catalyzed a growing interest in exploring their influence on users' psychological well-being. Instagram (Meta), a visually oriented platform, has garnered significant attention. Prior research has consistently indicated that Instagram usage correlates with heightened levels of perfectionism, body dissatisfaction, and diminished self-esteem. Perfectionism is closely linked to self-criticism, which entails an intense self-scrutiny and is often associated with various psychopathologies. Conversely, self-compassion has been linked to reduced levels of perfectionism and stress, while fostering greater positive affect and overall life satisfaction. OBJECTIVE: This study investigates the relationship between Instagram usage (time of use and content exposure) and users' levels of self-compassion, self-criticism, and body dissatisfaction. METHODS: This study comprised 1051 adult participants aged between 18 and 50 years, either native to Spain or residing in the country for at least a decade. Each participant completed a tailored questionnaire on Instagram usage, along with abbreviated versions of the Self-Compassion Scale, the Body Shape Questionnaire, and the Depressive Experiences Questionnaire, spanning from January 23 to February 25, 2022. RESULTS: A positive correlation was observed between daily Instagram usage and self-criticism scores. Participants of all age groups who spent over 3 hours per day on Instagram exhibited higher self-criticism scores than users who spent less than 1 hour or between 1 and 3 hours per day. Contrary to previous findings, no significant relationship was detected between Instagram usage time and levels of self-compassion or body dissatisfaction. Furthermore, content centered around physical appearance exhibited a positive correlation with self-criticism and body dissatisfaction scores. Among younger participants (aged 18-35 years), those who primarily viewed beauty or fashion content reported higher self-criticism scores than those consuming science-related content. However, this association was not significant for participants aged 35-50 years. Conversely, individuals who predominantly engaged with sports or fitness or family or friends content exhibited higher levels of body dissatisfaction than those focusing on science-related content. No significant associations were observed between self-compassion scores and daily Instagram usage or most-viewed content categories. CONCLUSIONS: The findings of this study underscore the considerable impact of Instagram usage on self-criticism and body dissatisfaction-2 variables known to influence users' psychological well-being and be associated with various symptoms and psychological disorders.

Apolar Extracts of St. John's Wort Alleviate the Effects of ß-Amyloid Toxicity in Early Alzheimer's Disease.

Hypericum perforatum (St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral ß-amyloid (Aß) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aß were analyzed using biochemical analyses. Our study confirms that the scCO2H. perforatum formulation shows better biological activity against Aß-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aß (-27% and -25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.

IgG4-related disease mimicking a liver abscess.

IgG4-related disease (IGRD) is a complex medical condition affecting multiple organs, including the liver. The condition is characterized by excessive production of IgG4 antibodies, leading to chronic inflammation and tissue damage. We present a case of a 37-year-old man with a history of chronic pancreatitis was diagnosed with a liver mass. Initial treatment included piperacillin and tazobactam, but the patient's condition worsened. An ultrasound-guided biopsy revealed increased IgG4 positive cells, leading to the diagnosis of an inflammatory pseudotumor associated with IGRD. The patient was treated with prednisone taper therapy, and the liver mass resolved after six months of corticoid treatment.

A meta-analysis of the prevalence of neuropsychiatric disorders and their association with disease onset in myotonic dystrophy.

There is a high prevalence of neuropsychiatric disorders in myotonic dystrophy types 1 and 2 (DM1 and DM2), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in DM1, and depression and anxiety in both DMs. The aim of this systematic review and meta-analysis was to estimate the prevalence of ASD, ADHD, depression and anxiety in the population with DM, and their association with disease onset. A systematic search of Medline, Scopus, Web of Science, and the Cochrane Library was conducted from inception to November 2023. Observational studies estimating the prevalence of these disorders in DM1 or DM2 were included. A meta-analysis of the prevalence of these disorders and an association study with disease onset by prevalence ratio meta-analysis were performed. Thirty-eight studies were included. In DM1, the prevalence of ASD was 14%, with congenital onset being 79% more common than juvenile onset, while the prevalence of ADHD was 21%, with no difference between congenital and juvenile onset, and the prevalence of depression and anxiety were 14% and 16%. Depression was more common in the adult onset. Finally, the prevalence of depression in DM2 was 16%. A higher prevalence of neuropsychiatric disorders is observed in individuals with DM1 and DM2 than in the general population. Therefore, actively screening for congenital and juvenile neurodevelopmental disorders in DM1 and emotional disorders in DM1 and DM2 may improve the quality of life of those affected.

Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice.

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous group of early onset and progressive neurodegenerative disorders, characterized by degeneration in the frontal and temporal lobes, which causes deterioration in cognition, personality, social behavior and language. Around 45% of the cases are characterized by the presence of aggregates of the RNA-binding protein TDP-43. METHODS: In this study, we have used a murine model of FTD that overexpresses this protein exclusively in the forebrain (under the control of the CaMKIIα promoter) for several biochemical, histological and pharmacological studies focused on the endocannabinoid system. RESULTS: These mice exhibited at postnatal day 90 (PND90) important cognitive deficits, signs of emotional impairment and disinhibited social behaviour, which were, in most of cases, maintained during the first year of life of these animals. Motor activity was apparently normal, but FTD mice exhibited higher mortality. Their MRI imaging analysis and their ex-vivo histopathological evaluation proved changes compatible with atrophy (loss of specific groups of pyramidal neurons: Ctip2- and NeuN-positive cells) and inflammatory events (astroglial and microglial reactivities) in both cortical (medial prefrontal cortex) and subcortical (hippocampus) structures at PND90 and also at PND365. The analysis of the endocannabinoid system in these mice proved a decrease in the hydrolysing enzyme FAAH in the prefrontal cortex and the hippocampus, with an increase in the synthesizing enzyme NAPE-PLD only in the hippocampus, responses that were accompanied by modest elevations in anandamide and related N-acylethanolamines. The potentiation of these elevated levels of anandamide after the pharmacological inactivation of FAAH with URB597 resulted in a general improvement in behaviour, in particular in cognitive deterioration, associated with the preservation of pyramidal neurons of the medial prefrontal cortex and the CA1 layer of the hippocampus, and with the reduction of gliosis in both structures. CONCLUSIONS: Our data confirmed the potential of elevating the endocannabinoid tone as a therapy against TDP-43-induced neuropathology in FTD, limiting glial reactivity, preserving neuronal integrity and improving cognitive, emotional and social deficits.

Hydroxynitrile lyase defends Arabidopsis against Tetranychus urticae.

Plant-pest interactions involve multifaceted processes encompassing a complex crosstalk of pathways, molecules, and regulators aimed at overcoming defenses developed by each interacting organism. Among plant defensive compounds against phytophagous arthropods, cyanide-derived products are toxic molecules that directly target pest physiology. Here, we identified the Arabidopsis (Arabidopsis thaliana) gene encoding hydroxynitrile lyase (AtHNL, At5g10300) as one gene induced in response to spider mite (Tetranychus urticae) infestation. AtHNL catalyzes the reversible interconversion between cyanohydrins and derived carbonyl compounds with free cyanide. AtHNL loss- and gain-of-function Arabidopsis plants showed that specific activity of AtHNL using mandelonitrile as substrate was higher in the overexpressing lines than in wild-type (WT) and mutant lines. Concomitantly, mandelonitrile accumulated at higher levels in mutant lines than in WT plants and was significantly reduced in the AtHNL overexpressing lines. After mite infestation, mandelonitrile content increased in WT and overexpressing plants but not in mutant lines, while hydrogen cyanide (HCN) accumulated in the three infested Arabidopsis genotypes. Feeding bioassays demonstrated that the AtHNL gene participated in Arabidopsis defense against T. urticae. The reduced leaf damage detected in the AtHNL overexpressing lines reflected the mite's reduced ability to feed on leaves, which consequently restricted mite fecundity. In turn, mites upregulated TuCAS1 encoding ß-cyanoalanine synthase to avoid the respiratory damage produced by HCN. This detoxification effect was functionally demonstrated by reduced mite fecundity observed when dsRNA-TuCAS-treated mites fed on WT plants and hnl1 mutant lines. These findings add more players in the Arabidopsis-T. urticae interplay to overcome mutual defenses.

Early vascular aging as an index of cardiovascular risk in healthy adults: confirmatory factor analysis from the EVasCu study.

BACKGROUND: The concept of early vascular aging (EVA) represents a potentially beneficial model for future research into the pathophysiological mechanisms underlying the early manifestations of cardiovascular disease. For this reason, the aims of this study were to verify by confirmatory factor analysis the concept of EVA on a single factor based on vascular, clinical and biochemical parameters in a healthy adult population and to develop a statistical model to estimate the EVA index from variables collected in a dataset to classify patients into different cardiovascular risk groups: healthy vascular aging (HVA) and EVA. METHODS: The EVasCu study, a cross-sectional study, was based on data obtained from 390 healthy adults. To examine the construct validity of a single-factor model to measure accelerated vascular aging, different models including vascular, clinical and biochemical parameters were examined. In addition, unsupervised clustering techniques (using both K-means and hierarchical methods) were used to identify groups of patients sharing similar characteristics in terms of the analysed variables to classify patients into different cardiovascular risk groups: HVA and EVA. RESULTS: Our data show that a single-factor model including pulse pressure, glycated hemoglobin A1c, pulse wave velocity and advanced glycation end products shows the best construct validity for the EVA index. The optimal value of the risk groups to separate patients is K = 2 (HVA and EVA). CONCLUSIONS: The EVA index proved to be an adequate model to classify patients into different cardiovascular risk groups, which could be valuable in guiding future preventive and therapeutic interventions.

Old poisons, new signaling molecules: the case of hydrogen cyanide.

The high phenotypic plasticity developed by plants includes rapid responses and adaptations to aggressive or changing environments. To achieve this, they evolved extremely efficient mechanisms of signaling mediated by a wide range of molecules, including small signal molecules. Among them, hydrogen cyanide (HCN) has been largely ignored due to its toxic characteristics. However, not only is it present in living organisms, but it has been shown that it serves several functions in all kingdoms of life. Research using model plants has changed the traditional point of view, and it has been demonstrated that HCN plays a positive role in the plant response to pathogens independently of its toxicity. Indeed, HCN induces a response aimed at protecting the plant from pathogen attack, and the HCN is provided either exogenously (in vitro or by some cyanogenic bacteria species present in the rhizosphere) or endogenously (in reactions involving ethylene, camalexin, or other cyanide-containing compounds). The contribution of different mechanisms to HCN function, including a new post-translational modification of cysteines in proteins, namely S-cyanylation, is discussed here. This work opens up an expanding 'HCN field' of research related to plants and other organisms.

Prediction of blood volume to be processed to achieve a target number of CD34+ cells: Development, validation and implementation of a formula.

BACKGROUND AND OBJECTIVES: Calculation of blood volume (BV) to be processed to achieve the target number of CD34+ cells can be accomplished by using collection efficiency 2 (CE2) formula. Our aim was to develop a BV web formula. MATERIALS AND METHODS: We calculated CE2 from aphereses performed between January 2015 and March 2020 in allogeneic donors and patients. From May 2020 to May 2021, we validated a formula: BV = ((Target CD34+ cells in the product)/(CD34+ pre-apheresis cells × CE2)) × 100. Subsequently, we compared the outcome of the procedures carried out before formula implementation (pre-formula), when standard three total BV collection was performed. RESULTS: CE2 was assessed in 384 apheresis procedures before formula implementation. CE2 was higher in allogeneic donors than in patients (53% ± 17% vs. 48% ± 15%, p = 0.008). CE2 was higher in multiple myeloma and non-Hodgkin lymphoma than Hodgkin's lymphoma (48% ± 15%, 48% ± 15% and 42% ± 13%, respectively; p = 0.008). Our formula (available on a website: Publisheet) was prospectively used in 54 individuals. The formula was very accurate: predicted versus observed CD34 + cells/kg collected had an r-value of 0.89 (p < 0.0001). We compared their results with 78 pre-formula individuals. In the post-formula group, a greater BV was processed in patients and less BV in allogeneic donors. Among individuals under 60 years of age, it was significantly less frequent than the need for more than one apheresis in the post-formula group. CONCLUSION: Formula calculations were accurate. Formula implementation allowed the optimization of the procedures and reduced the rate of individuals in need of apheresis for more than 1 day.

Global prevalence of intellectual developmental disorder in dystrophinopathies: A systematic review and meta-analysis.

AIM: To estimate the global prevalence of intellectual developmental disorder (IDD) and the IDD prevalence-genotype association in Becker muscular dystrophy (BMD) or Duchenne muscular dystrophy (DMD) according to the affected isoforms of the DMD gene: Dp427, Dp140, Dp71. METHOD: Systematic searches in MEDLINE, Scopus, Web of Science, and the Cochrane Library were conducted from inception of each database to March 2022. Observational studies that determined the prevalence of IDD in the population with BMD or DMD were included. Meta-analyses of IDD prevalence and prevalence ratios of the IDD-genotype association were conducted. RESULTS: Forty-nine studies were included. The prevalence of IDD in BMD was 8.0% (95% confidence interval 5.0-11.0), and in DMD it was 22.0% (18.0-27.0). Meta-analyses of IDD-genotype association showed a deleterious association between IDD and the number of isoforms affected in DMD, with a prevalence ratio = 0.43 (0.28-0.64) and 0.17 (0.09-0.34) for Dp140+ /Dp71+ versus Dp140- /Dp71+ and Dp140+ /Dp71+ versus Dp140- /Dp71- comparisons respectively. However, in BMD, there was no association for Dp140+ /Dp71+ versus Dp140- /Dp71+ . INTERPRETATION: There is a high prevalence of IDD in BMD and DMD. Moreover, the number of isoforms affected is strongly and negatively associated with the prevalence of IDD in DMD. WHAT THIS PAPER ADDS: The global prevalence of intellectual developmental disorder (IDD) was 8% in Becker muscular dystrophy and 22% in Duchenne muscular dystrophy (DMD). The global prevalence of IDD in DMD was 12%, 29%, and 84% in participants with Dp427- /Dp140+ /Dp71+ , Dp427- /Dp140- /Dp71+ , and Dp427- /Dp140- /Dp71- genotypes respectively. In DMD, 12% and 22% of participants had abnormal performance IQ and verbal IQ values respectively.