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Abstract Paramos, unique and biodiverse ecosystems found solely in the high mountain regions of the tropics, are under threat. Despite their crucial role as primary water sources and significant carbon repositories in Colombia, they are deteriorating rapidly and garner less attention than other vulnerable ecosystems like the Amazon rainforest. Their fertile soil and unique climate make them prime locations for agriculture and cattle grazing, often coinciding with economically critical deposits such as coal which has led to a steady decline in paramo area. Anthropic impact was evaluated using multispectral images from Landsat and Sentinel over 37 years, on the Guerrero and Rabanal paramos in central Colombia which have experienced rapid expansion of mining and agriculture. Our analysis revealed that since 1984, the Rabanal and Guerrero paramos have lost 47.96% and 59.96% of their native vegetation respectively, replaced primarily by crops, pastures, and planted forests. We detected alterations in the spectral signatures of native vegetation near coal coking ovens, indicating a deterioration of paramo health and potential impact on ecosystem services. Consequently, human activity is reducing the extent of paramos and their efficiency as water sources and carbon sinks, potentially leading to severe regional and even global consequences.

Abstract Background The term “post-COVID-19 condition” refers to the symptomatology that appears between four to twelve weeks after Covid-19 infection. These symptoms can persist for weeks or even months, significantly diminishing the quality of life for affected individuals. The primary objective of this study was to assess the effectiveness of pulmonary rehabilitation programs and/or respiratory muscle training on respiratory sequelae in patients with post-COVID condition. Methods The literature search was conducted in the following databases: PubMed, PEDro, Embase, Cochrane, Scopus, and Web of Science. Randomized clinical trials were included in which participants were aged 18 years or older. Articles were excluded if at least one of the therapies did not involve pulmonary rehabilitation or respiratory muscle training, if the participants were COVID positive, if studies lacked results, and finally, if interventions were conducted without supervision or at home. This review only encompasses supervised non-virtual interventions. This study adheres to the PRISMA statement and has been registered in the PROSPERO database (CRD42023433843). Results The outcomes obtained in the included studies are assessed across the following variables: Exercise capacity using the 6-minute walk test, Dyspnea, fatigue, Pulmonary function, Maximum inspiratory pressure, and Quality of life. Conclusion Despite the absence of a specific treatment at present, it was evident from this review that a well-structured pulmonary rehabilitation program that incorporates both aerobic and muscular strength exercises along with techniques and inspiratory muscle exercises was the most effective form of treatment.

Abstract Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1 +AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1 +AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50–91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1 +AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1 +AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1 +AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.

Abstract Background Vertebral infections, including vertebral osteomyelitis, septic physitis, and discospondylitis, are rarely reported in goats, and when reported, have been largely limited to necropsy case reports. Objective Describe clinical findings and outcome in goats with vertebral infections evaluated by computed tomography (CT). Animals Five goats with vertebral osteomyelitis, septic physitis, and discospondylitis evaluated by CT. Methods Retrospective case series. Results The most common presenting complaints were progressive weakness, paresis and recumbency. Three goats were tetraparetic and 2 goats had pelvic limb paraparesis. Clinicopathologic findings included leukocytosis, mature neutrophilia, and hyperfibrinogenemia. The most common vertebrae affected were C7‐T1. All 5 goats had discospondylitis with or without vertebral osteomyelitis and septic physitis. Computed tomographic evidence of spinal cord compression was present in 4/5 goats. Medical management (antimicrobials, physical therapy, analgesia, supportive care) was attempted in 4 goats, and 1 goat was euthanized at the time of diagnosis. All 4 goats that were treated regained ambulatory ability and survived to hospital discharge. Conclusions and Clinical Importance Despite severity of CT imaging findings, goats with discospondylitis, septic physitis, and vertebral osteomyelitis can successfully return to ambulatory function. Additional studies are required to determine ideal treatment regimens.

Abstract Background This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson’s or Spearman’s coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. Results Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. Conclusions This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. Trial registration ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

Abstract Background The proliferation antigen Ki-67 has been widely used in clinical settings for cancer staging for many years, but investigations on its biological functions have lagged. Recently, Ki-67 has been shown to regulate both the composition of the chromosome periphery and chromosome behaviour in mitosis as well as to play a role in heterochromatin organisation and gene transcription. However, how the different roles for Ki-67 across the cell cycle are regulated and coordinated remain poorly understood. The progress towards understanding Ki-67 function have been limited by the tools available to deplete the protein, coupled to its abundance and fluctuation during the cell cycle. Results Here, we use a doxycycline-inducible E3 ligase together with an auxin-inducible degron tag to achieve a rapid, acute and homogeneous degradation of Ki-67 in HCT116 cells. This system, coupled with APEX2 proteomics and phospho-proteomics approaches, allows us to show that Ki-67 plays a role during DNA replication. In its absence, DNA replication is severely delayed, the replication machinery is unloaded, causing DNA damage that is not sensed by the canonical pathways and dependent on HUWE1 ligase. This leads to defects in replication and sister chromatids cohesion, but it also triggers an interferon response mediated by the cGAS/STING pathway in all the cell lines tested. Conclusions We unveil a new function of Ki-67 in DNA replication and genome maintenance that is independent of its previously known role in mitosis and gene regulation.

Radon (222Rn) is a naturally occurring gas that represents a health threat due to its causal relationship with lung cancer. Despite its potential health impacts, several regions have not conducted studies, mainly due to data scarcity and/or economic constraints. This study aims to bridge the baseline information gap by building an interactive dashboard (http://ircmodelingdashboard.eu.pythonanywhere.com/, last access: 17 April 2024) that uses inferential statistical methods to estimate the spatial distribution of indoor radon concentration (IRC) for a target area. We demonstrate the functionality of the dashboard by modeling IRC in the city of Bogotá, Colombia, using 30 in situ measurements. IRC measured was the highest reported in the country, with a geometric mean of 91±14 Bq m−3 and a maximum concentration of 407 Bq m−3. In 57 % of the residences, RC exceeded the WHO's recommendation of 100 Bq m−3. A prediction map for houses registered in Bogotá's cadaster was built in the dashboard by using a log-linear regression model fitted with the in situ measurements, together with meteorological, geologic and building-specific variables. The model showed a cross-validation root mean squared error of 57 Bq m−3. Furthermore, the model showed that the age of the house presented a statistically significant positive association with RC. According to the model, IRC measured in houses built before 1980 presents a statistically significant increase of 72 % compared to IRC of those built after 1980 (p value = 0.045). The prediction map exhibited higher IRC in older buildings most likely related to cracks in the structure that could enhance gas migration in older houses. This study highlights the importance of expanding 222Rn studies in countries with a lack of baseline values and provides a cost-effective alternative that could help deal with the scarcity of IRC data and get a better understanding of place-specific variables that affect IRC spatial distribution.

Abstract Background Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann’s procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P

Abstract The heterogeneity inherent in today’s biotherapeutics, especially as a result of heavy glycosylation, can affect a molecule’s safety and efficacy. Characterizing this heterogeneity is crucial for drug development and quality assessment, but existing methods are limited in their ability to analyze intact glycoproteins or other heterogeneous biotherapeutics. Here, we present an approach to the molecular assessment of biotherapeutics that uses proton-transfer charge-reduction with gas-phase fractionation to analyze intact heterogeneous and/or glycosylated proteins by mass spectrometry. The method provides a detailed landscape of the intact molecular weights present in biotherapeutic protein preparations in a single experiment. For glycoproteins in particular, the method may offer insights into glycan composition when coupled with a suitable bioinformatic strategy. We tested the approach on various biotherapeutic molecules, including Fc-fusion, VHH-fusion, and peptide-bound MHC class II complexes to demonstrate efficacy in measuring the proteoform-level diversity of biotherapeutics. Notably, we inferred the glycoform distribution for hundreds of molecular weights for the eight-times glycosylated fusion drug IL22-Fc, enabling correlations between glycoform sub-populations and the drug’s pharmacological properties. Our method is broadly applicable and provides a powerful tool to assess the molecular heterogeneity of emerging biotherapeutics.

Abstract Background Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians’ understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. Methods Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. Results In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. Limitations The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. Conclusion Some ADOS items may better capture the signs that are most associated with clinicians’ implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.

Cancer is the top leading cause of death among Latino people. Lack of health insurance is a significant contributor to inadequate cancer detection and treatment. Despite healthcare policy expansions such as the Affordable Care Act, Latino people persistently maintain the highest uninsured rate among any ethnic and racial group in the US, especially among Latino individuals who are immigrants or part of a mixed immigration status household. Recognizing that immigration status is a critical factor in the ability of Latino community members to seek health insurance and access healthcare services, a few US states and the District of Columbia have implemented policies that have expanded coverage to children and adults regardless of immigration status. Expansion of Medicaid eligibility regardless of immigration status may significantly benefit Latino communities, however the facilitators and barriers to enrolling in these programs need to be evaluated to ensure reach and achieve health equity across the cancer control continuum for all Latinos.

Purpose: In France, radiation oncologists are predominantly men with only 44 % of women. Many studies have highlighted gender disparities in medicine. The main objective of our study was to assess the impact of discriminations on radiation oncologists’ career. Materials and methods: An anonymous online questionnaire, adapted from the one used by the ESMO W4O group, was sent to all radiation oncologists in France between March and June 2022. It included questions related to professional experience, gender, socio-ethnicity, sexual orientation, and personal life. Results: Among the 999 radiation oncologists and 168 residents in France, 225 questionnaires were collected (19.2 %). Among the respondents, 60 % were women and 25 % were residents. The mean age was 39.2 years (range: 25–78). The career satisfaction rate was 92 %, with no gender difference. Gender was considered to have a negative impact on the career development by 65 % of women. Social origin was an obstacle to career development for 37 % of all the respondents, and ethnic origin for 25 %. Sixty two percent of women reported having experienced inappropriate behavior or sexual harassment in their workplace, 38 % felt that having a child had “extremely“ or ”very“ much impacted their career versus 8.5 % of men (p

Objective: To describe telemedicine use patterns and understand clinic’s approaches to shifting care delivery during the COVID-19 pandemic. Methods: We used electronic health record data from 203 community health centers across 13 states between 01/01/2019 and 6/31/2021 to describe trends in telemedicine visit rates over time. Qualitative data were collected from 13 of those community health centers to understand factors influencing adoption and implementation of telemedicine. Results: Most clinics in our sample were in urban areas (n = 176) and served a majority of uninsured and publicly insured patients (12.8% and 44.4%, respectively) across racial and ethnic minority groups (16.6% Black and 29.3% Hispanic). During our analysis period there was a 791% increase in telemedicine visits from before the pandemic (.06% pre- vs 47.5% during). A latent class growth analysis was used to examine differences in patterns of adoption of telemedicine across the 203 CHCs. The model resulted in 6 clusters representing various levels of telemedicine adoption. A mixed methods approach streamlined these clusters into 4 final groups. Clinics that reported rapid adoption of telemedicine attributed this change to leadership prioritization of telemedicine, robust quality improvement processes (eg, using PDSA processes), and emphasis on training and technology support. Conclusions: In response to the COVID-19 pandemic, telemedicine adoption rates varied across clinics. Our study highlight that organizational factors contributed to the clinic’s ability to rapidly uptake and use telemedicine services throughout the pandemic. These approaches could inform future non-pandemic practice change and care delivery.

Abstract Ratios of glycerol dialkyl glycerol tetraethers (GDGT), which are membrane lipids of bacteria and archaea, are at the base of several paleoenvironmental proxies. They are frequently applied to soils as well as lake‐ and marine sediments to generate records of past temperature and soil pH. To derive meaningful environmental information from these reconstructions, high analytical reproducibility is required. Based on submitted results by 39 laboratories from across the world, which employ a diverse range of analytical and quantification methods, we explored the reproducibility of brGDGT‐based proxies (MBT′5ME, IR, and #ringstetra) measured on four soil samples and four soil lipid extracts. Correct identification and integration of 5‐ and 6‐methyl brGDGTs is a prerequisite for the robust calculation of proxy values, but this can be challenging as indicated by the large inter‐interlaboratory variation. The exclusion of statistical outliers improves the reproducibility, where the remaining uncertainty translates into a temperature offset from median proxy values of 0.3–0.9°C and a pH offset of 0.05–0.3. There is no apparent systematic impact of the extraction method and sample preparation steps on the brGDGT ratios. Although reported GDGT concentrations are generally consistent within laboratories, they vary greatly between laboratories. This large variability in brGDGT quantification may relate to variations in ionization efficiency or specific mass spectrometer settings possibly impacting the response of brGDGTs masses relative to that of the internal standard used. While ratio values of GDGT are generally comparable, quantities can currently not be compared between laboratories.

IntroductionCancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management.ObjectivesThe main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS).Materials and methodsA population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations.ResultsCC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS.ConclusionsUsing clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

Abstract Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Abstract There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic.

Abstract Background Transitions from sexual to asexual reproduction are common in eukaryotes, but the underlying mechanisms remain poorly known. The pea aphid—Acyrthosiphon pisum—exhibits reproductive polymorphism, with cyclical parthenogenetic and obligate parthenogenetic lineages, offering an opportunity to decipher the genetic basis of sex loss. Previous work on this species identified a single 840 kb region controlling reproductive polymorphism and carrying 32 genes. With the aim of identifying the gene(s) responsible for sex loss and the resulting consequences on the genetic programs controlling sexual or asexual embryogenesis, we compared the transcriptomic response to photoperiod shortening—the main sex-inducing cue—of a sexual and an obligate asexual lineage of the pea aphid, focusing on heads (where the photoperiodic cue is detected) and embryos (the final target of the cue). Results Our analyses revealed that four genes (one expressed in the head, and three in the embryos) of the region responded differently to photoperiod in the two lineages. We also found that the downstream genetic programs expressed during embryonic development of a future sexual female encompass ∼1600 genes, among which miRNAs, piRNAs and histone modification pathways are overrepresented. These genes mainly co-localize in two genomic regions enriched in transposable elements (TEs). Conclusions Our results suggest that the causal polymorphism(s) in the 840 kb region somehow impair downstream epigenetic and post-transcriptional regulations in obligate asexual lineages, thereby sustaining asexual reproduction.

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.

The purpose of this study was to analyze the relationships between cybervictimization in social networks, problematic smartphone use, aggressive behaviors, and prosocial altruistic tendencies in young adults. The sample consisted of 601 young adults (mean age = 19.96 years; SD = 2.27; 69.1% female) who were administered online assessments of experiences of humiliation on networks, problematic smartphone use, prosocial altruistic tendencies, and aggressiveness. Results indicated significant indirect effects of cyber victimization on aggressiveness and prosocial altruistic tendencies through problematic smartphone use. Problematic cell phone use explained the relationships between online humiliation and aggressive and prosocial altruistic behaviors. The results confirmed the positive relationship between cybervictimization and problematic cell phone use, consistent with previous research. However, the negative relationship between cybervictimization and altruistic prosocial tendencies was not corroborated. The findings emphasize the need to promote actions that foster social connectedness and interdependence among young individuals to develop their identity within the community.

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.

IntroductionRare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability.MethodsIn a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability.ResultsBottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD.DiscussionOur findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Objective To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients.Methods Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3).Results Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p

Introduction Autism spectrum disorders (ASD) is a neurodevelopmental disorder with an estimated lifetime prevalence of at least 1%. Some studies suggest that approximately 60% of children with ASD show emotional dysregulation and 44-86% sleeping disorders. Studies suggest that cognitive behavioral therapy and animal-assisted therapy AAT can be an intervention strategy to promote emotional and behavioral dysregulation and sleep disturbances. Objectives The purpose of this study was to investigate the effect of a therapy program assisted with dogs (AAT) together with cognitive behavioral therapy (CBT) on behavioral and emotional regulation and sleep disorders in children diagnosed with ASD. Methods The sample was composed of 24 children between 7 and 10 years old diagnosed with ASD randomized into two groups (CGT group (control group) and AAT + CBT group (experimental group). Inclusion criteria: communication level of simple sentences, mild-moderate difficulties in behavioral and emotional regulation and sleep disturbances. Exclusion criteria: intellectual disability, children with specific dogs phobia. Assessment included ADOS-2, WISC-V, CGAS. dysregulation profile of Achenbach scale and Sleep Disturbance Scale for Children-Bruni. A program of 12 sessions (weekly one-hour sessions) focusing emotional and behavioral regulation and sleep disturbance was designed (Behavior Emotional Sleep Treatment Program. A pre-post evaluation was performed. Results Participants were 20 boys and 2 girls (2 participants dropped out), with a mean age of 9. Regarding the socio-demographic and clinical characteristics, no significant differences has been observed between both groups in the global functioning measured with the Children’s Global Assessment scale (CGAS) (p=0.832), nor in the cognitive capacity (QI ) neither in reference to the associated comorbidities (p=0.103) nor in the variable prescription pharmacological treatment (p= 0.142). In emotional self-regulation, a significant improvement in emotional regulation difficulties was observed after treatment in both groups (experimental group: p=0.014; control group: p=0.012). However, the comparison between the pre-post intervention results between groups, regarding the emotional regulation variable, a greater improvement is observed in the experimental group (p=0.013). Significant improvements were also observed in sleep disorders (Bruni scale total score and in the sleep conciliation and maintenance difficulties scale) in both groups. Conclusions To conclude, although this is a pilot study with a small sample size and further research is needed, results suggest that a therapy program assisted with therapy dogs and CBT have positive effects on emotional dysregulation and sleep disturbances in children with ASD and offers a possible intervention strategy. Disclosure of Interest None Declared

Machine learning (ML) approaches could expand the usefulness and application of implementation science methods in clinical medicine and public health settings. The aim of this viewpoint is to introduce a roadmap for applying ML techniques to address implementation science questions, such as predicting what will work best, for whom, under what circumstances, and with what predicted level of support, and what and when adaptation or deimplementation are needed. We describe how ML approaches could be used and discuss challenges that implementation scientists and methodologists will need to consider when using ML throughout the stages of implementation.

Summary: Background: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. Methods: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid β-amyloid (Aβ)42 and Aβ40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaβeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aβ-negative and Aβ-positive individuals. Findings: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aβ-positive and 194 as Aβ-negative. In Aβ-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22–16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25–29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aβ-negative individuals (3·52% [0·072–4·17]) on PACC, although path coefficients were not significantly different from those in the Aβ-positive group. Interpretation: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aβ-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. Funding: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. Translation: For the Spanish translation of the abstract see Supplementary Materials section.

The Matterhorn, a famous mountain in the Swiss Alps is a well characterized geomorphosite, presenting both an important scientific interest and aesthetic, cultural and economic values in Switzerland. The main scientific issues concerning the Matterhorn are its place in the tectonic history of the Alps, the carving of a residual pyramid by glacial erosion and the effects of melting of high mountain permafrost on mountaineering. To answer those questions, two “tools” were used, the field work and the bibliographic investigations. The Matterhorn played, from its first ascent in 1865 until today, a very special role in the history of mountaineering, and its remarkable shape has become iconic in Switzerland. As a consequence, the Matterhorn can be analyzed through four time scales:(1) the deep time of tectonics during the Cenozoic era, which saw the thrusting and piling up of the “Pennine nappes,” due to the collision between African and European plates; (2) the Quaternary period of glacial erosion, which carved the Matterhorn into its distinctive pyramidal peak shape;(3) the Anthropocene time of the thawing of high mountain permafrost; and (4) the era of humans or mountaineering, which spans over than 150 years, from the first ascent in 1865 to the recent achievements of modern mountaineering.

Abstract We examine the impact of spin effects on the nonequilibrium transport properties of a nanowire hosting Majorana zero-energy modes at its ends, coupled to a quantum dot junction with ferromagnetic leads. Using the real-time diagrammatic technique, we determine the current, differential conductance and current cross-correlations in the nonlinear response regime. We also explore transport in different magnetic configurations of the system, which can be quantified by the tunnel magnetoresistance. We show that the presence of Majorana quasiparticles gives rise to unique features in all spin-resolved transport characteristics, in particular, to zero-bias anomaly, negative differential conductance, negative tunnel magnetoresistance, and it is also reflected in the current cross-correlations. Moreover, we study the dependence of the zero-bias anomaly on various system parameters and demonstrate its dependence on the magnetic configuration of the system as well as on the degree of spin polarization in the leads. A highly nontrivial behavior is also found for the tunnel magnetoresistance, which exhibits regions of enhanced or negative values—new features resulting from the coupling to Majorana wire.

Abstract Background In case of locally advanced and/or non-metastatic unresectable esophageal cancer, definitive chemoradiotherapy (CRT) delivering 50 Gy in 25 daily fractions in combination with platinum-based regimen remains the standard of care resulting in a 2-year disease-free survival of 25% which deserves to be associated with new systemic strategies. In recent years, several immune checkpoint inhibitors (anti-PD1/anti-PD-L1, anti-Program-Death 1/anti-Program-Death ligand 1) have been approved for the treatment of various solid malignancies including metastatic esophageal cancer. As such, we hypothesized that the addition of an anti-PD-L1 to CRT would provide clinical benefit for patients with locally advanced oesophageal cancer. To assess the efficacy of the anti-PD-L1 durvalumab in combination with CRT and then as maintenance therapy we designed the randomized phase II ARION (Association of Radiochemotherapy with Immunotherapy in unresectable Oesophageal carciNoma- UCGI 33/PRODIGE 67). Methods ARION is a multicenter, open-label, randomized, comparative phase II trial. Patients are randomly assigned in a 1:1 ratio in each arm with a stratification according to tumor stage, histology and centre. Experimental arm relies on CRT with 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles and durvalumab starting with CRT for a total of 12 infusions. Standard arm is CRT alone. Use of Intensity Modulated radiotherapy is mandatory. The primary endpoint is to increase progression-free survival at 12 months from 50 to 68% (HR = 0.55) (power 90%; one-sided alpha-risk, 10%). Progression will be defined with central external review of imaging. Ancillary studies are planned PD-L1 Combined Positivity Score on carcinoma cells and stromal immune cells of diagnostic biopsy specimen will be correlated to disease free survival. The study of gut microbiota will aim to determine if baseline intestinal bacteria correlates with tumor response. Proteomic analysis on blood samples will compare long-term responder after CRT with durvalumab to non-responder to identify biomarkers. Conclusion Results of the present study will be of great importance to evaluate the impact of immunotherapy in combination with CRT and decipher immune response in this unmet need clinical situation. Trial registration ClinicalTrials.gov, NCT: 03777813.Trial registration date: 5th December 2018.

Abstract Background Rapid and accurate pathogen identification is required for disease management. Compared to sequencing entire genomes, targeted sequencing may be used to direct sequencing resources to genes of interest for microbe identification and mitigate the low resolution that single-locus molecular identification provides. This work describes a broad-spectrum fungal identification tool developed to focus high-throughput Nanopore sequencing on genes commonly employed for disease diagnostics and phylogenetic inference. Results Orthologs of targeted genes were extracted from 386 reference genomes of fungal species spanning six phyla to identify homologous regions that were used to design the baits used for enrichment. To reduce the cost of producing probes without diminishing the phylogenetic power, DNA sequences were first clustered, and then consensus sequences within each cluster were identified to produce 26,000 probes that targeted 114 genes. To test the efficacy of our probes, we applied the technique to three species representing Ascomycota and Basidiomycota fungi. The efficiency of enrichment, quantified as mean target coverage over the mean genome-wide coverage, ranged from 200 to 300. Furthermore, enrichment of long reads increased the depth of coverage across the targeted genes and into non-coding flanking sequence. The assemblies generated from enriched samples provided well-resolved phylogenetic trees for taxonomic assignment and molecular identification. Conclusions Our work provides data to support the utility of targeted Nanopore sequencing for fungal identification and provides a platform that may be extended for use with other phytopathogens.

Triple negative breast cancers (TNBCs) represent 15–20% of all breast cancers and are associated with higher recurrence and distant metastasis rate. Standard of care for early stage TNBC is anthracyclines combined with cyclophosphamide (AC) followed by taxanes, in the neo‐adjuvant or adjuvant setting. This work aimed to identify predictive biomarkers of AC response in patient‐derived xenograft (PDX) models of TNBC and to validate them in the clinical setting. By gene and protein expression analysis of 39 PDX with different responses to AC, we found that high expression of HORMAD1 was associated with better response to AC. Both gene and protein expression were associated with promoter hypomethylation. In a cohort of 526 breast cancer patients, HORMAD1 was overexpressed in 71% of TNBC. In a second cohort of 186 TNBC patients treated with AC, HORMAD1 expression was associated with longer metastasis‐free survival (MFS). In summary, HORMAD1 overexpression was predictive of an improved response to AC in PDX and is an independent prognostic factor in TNBC patients treated with AC.

The combination of chemotherapy and targeted therapy has been validated in non-small-cell lung cancer (NSCLC) patients with EGFR mutations. We therefore investigated whether this type of combined approach could be more widely used by targeting other genetic alterations present in NSCLC. PDXs were generated from patients with NSCLC adenocarcinomas (ADCs) and squamous-cell carcinomas (SCCs). Targeted NGS analyses identified various molecular abnormalities in the MAPK and PI3K pathways and in the cell cycle process in our PDX panel. The antitumor efficacy of targeted therapies alone or in combination with chemotherapy was then tested in vivo. We observed that trametinib, BKM120, AZD2014 and palbociclib increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a non-insignificant or slight improvement in ADCs. Furthermore, we observed high efficacy of trametinib in KRAS-, HRAS- and NRAS-mutated tumors (ADCs and SCCs), suggesting that the MEK inhibitor may be useful in a wider population of NSCLC patients, not just those with KRAS-mutated ADCs. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLCs, and particularly in SCCs, to offer patients a more effective combination of chemotherapy and targeted therapy.

Diet is the only treatment for celiac disease (CeD), and good adherence to a gluten-free diet (GFD) is the only way to ensure complete remission and to prevent complications. Limited education about the disease and a GFD is an attributing factor to inadequate adherence. Thus, our aim was to assess the current knowledge about a GFD and the clinical monitoring of adherence to the diet among CeD people and HCPs. Specific questionnaires were designed and distributed to assess the knowledge of CeD people (Q1 questionnaire) (n = 2437) and to analyze the follow-up of the disease from the perspective of patients (Q2 questionnaire) (n = 1294) and HCPs (Q3 questionnaire) (n = 346). Two-thirds of HCPs specialized in pediatric care, while one-third did so in adult care. In CeD people, general questions regarding food classification and cross-contamination are well understood. When patients have doubts, 51.4% reported using the Internet and social networks. Thus, it is crucial that resources like social media are reliable and provide valuable information. Q3 revealed the lack of time to follow up the diet after diagnosis (48% of HCPs allocate < 15 min), the interest in further training, and the need for a professional specialized in diets within the healthcare system. In conclusion, it is essential to enhance nutritional education to increase awareness of a GFD.

Background: The usefulness of thiopurines has been poorly explored in pouchitis and other pouch disorders. Objective: To evaluate the effectiveness and safety of azathioprine as maintenance therapy in inflammatory pouch disorders. Design: This was a retrospective and multicentre study. Methods: We included patients diagnosed with inflammatory pouch disorders treated with azathioprine in monotherapy. Effectiveness was evaluated at 1 year and in the long term based on normalization of stool frequency, absence of pain, faecal urgency or fistula discharge (clinical remission), or any improvement in these symptoms (clinical response). Endoscopic response was evaluated using the Pouchitis Disease Activity Index (PDAI). Results: In all, 63 patients were included [54% males; median age, 49 (28–77) years]. The therapy was used to treat pouchitis ( n = 37) or Crohn’s disease of the pouch ( n = 26). The rate of clinical response, remission and non-response at 12 months were 52%, 30% and 18%, respectively. After a median follow-up of 23 months (interquartile range 11–55), 19 patients (30%) were in clinical remission, and 45 (66%) stopped therapy. Endoscopic changes were evaluated in 19 cases. PDAI score decreased from 3 (range 2–4) to 1 (range 0–3). In all, 21 patients (33%) presented adverse events and 16 (25%) needed to stop therapy. Conclusion: Azathioprine may be effective in the long term for the treatment of inflammatory pouch disorders and could be included as a therapeutic option.

Aims: Children of parents with substance use and/or other mental health (SU/MH) diagnoses are at increased risk for health problems. It is unknown whether these children benefit from receiving primary care at the same clinic as their parents. Thus, among children of parents with >1 SU/MH diagnosis, we examined the association of parent-child clinic concordance with rates of well-child checks (WCCs) and childhood vaccinations. Design: Retrospective cohort study using electronic health record (EHR) data from the OCHIN network of community health organizations (CHOs), 2010-2018. Setting: 280 CHOs across 17 states. Participants/Cases: 41,413 parents with >1 SU/MH diagnosis, linked to 65,417 children aged 0 to 17 years, each with >1 visit to an OCHIN clinic during the study period. Measurements: Dependent variables: rates of WCCs during (1) the first 15 months of life, and (2) ages 3 to 17 years; vaccine completeness (3) by the age of 2, and (4) before the age of 18. Estimates were attained using generalized estimating equations Poisson or logistic regression. Findings: Among children utilizing the same clinic as their parent versus children using a different clinic (reference group), we observed greater WCC rates in the first 15 months of life [adjusted rate ratio (aRR) = 1.06; 95% confidence interval (CI) = 1.02-1.10]; no difference in WCC rates in ages 3 to 17; higher odds for vaccine completion before age 2 [adjusted odds ratio (aOR) = 1.12; 95% CI = 1.03-1.21]; and lower odds for vaccine completion before age 18 (aOR = 0.88; 95% CI = 0.81-0.95). Conclusion: Among children whose parents have at least one SU/MH diagnosis, parent-child clinic concordance was associated with greater rates of WCCs and higher odds of completed vaccinations for children in the youngest age groups, but not the older children. This suggests the need for greater emphasis on family-oriented healthcare for young children of parents with SU/MH diagnoses; this may be less important for older children.

IntroductionAttention Deficit Hyperactivity Disorder (ADHD) has a global mean prevalence of 5%. Cognitive Training (CT) and Mindfulness-Based Interventions (MBIs) have shown promising results in managing ADHD symptoms, but they are not its Treatment-As-Usual (TAU). The NeuroMind Study aims to evaluate the preliminary effectiveness and feasibility of three interventions: Mindfulness for Health (M4H), CT using the NeuronUP® platform (CT), and a combination of both, Mindfulness Cognitive Training (MCT). There is empirical evidence supporting the effectiveness of the M4H and NeuronUP® platform; however, this study explores for the first time the effectiveness of MCT and CT, as well as the integration of M4H into TAU. The objectives of this 5-month Randomized Controlled Trial (RCT) are: (1) To analyze the preliminary effectiveness and feasibility of M4H, CT or a combination of both (MCT) added to TAU for children with ADHD; (2) To evaluate the role of psychological process variables (mindfulness and emotional regulation) as mediators of 5-month follow-up clinical outcomes; (3) To preliminarily explore whether specific sociodemographic and clinical characteristics can predict the short-and medium-term clinical response to the specific treatments.Methods and analysisParticipants will be 120 children (7 to 12 years) with ADHD recruited at Child and Adolescent Mental Health Service (CAMHS) Sant Joan de Déu Terres de Lleida (Spain) randomly allocated to one of the four study arms: TAU vs. TAU + CT vs. TAU + M4H vs. TAU + MCT. An assessment to collect ADHD symptoms, Executive Functions (EF), comorbid symptoms and global functioning will be conducted pre-intervention, post-intervention (2 months after baseline) and at the 5-month follow-up. Linear mixed models and mediational models will be computed.DiscussionIf the preliminary effectiveness and feasibility of the MCT are demonstrated, this study could be a preliminary basis to do a full RCT with a larger sample to definitively validate the intervention. The MCT could be applied in clinical practice if it is definitively validated.Clinical trial registration:ClinicalTrials.gov, identifier, NCT05937347. https://clinicaltrials.gov/study/NCT05937347?locStr=Spain&country=Spain&cond=ADHD&intr=Mindfulness&rank=1.

Contact tracing played a crucial role in minimizing the onward dissemination of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in the recent pandemic. Previous studies had also shown the effectiveness of preventive measures such as mask-wearing, physical distancing, and exposure duration in reducing SARS-CoV-2 transmission. However, there is still a lack of understanding regarding the impact of various exposure settings on the spread of SARS-CoV-2 within the community, as well as the most effective preventive measures, considering the preventive measures adherence in different daily scenarios. We aimed to evaluate the effect of individual protective measures and exposure settings on the community transmission of SARS-CoV-2. Additionally, we aimed to investigate the interaction between different exposure settings and preventive measures in relation to such SARS-CoV-2 transmission. Routine SARS-CoV-2 contact tracing information was supplemented with additional data on individual measures and exposure settings collected from index patients and their close contacts. We used a case-control study design, where close contacts with a positive test for SARS-CoV-2 were classified as cases, and those with negative results classified as controls. We used the data collected from the case-control study to construct a Bayesian network (BN). BNs enable predictions for new scenarios when hypothetical information is introduced, making them particularly valuable in epidemiological studies. Our results showed that ventilation and time of exposure were the main factors for SARS-CoV-2 transmission. In long time exposure, ventilation was the most effective factor in reducing SARS-CoV-2, while masks and physical distance had on the other hand a minimal effect in this ventilation spaces. However, face masks and physical distance did reduce the risk in enclosed and unventilated spaces. Distance did not reduce the risk of infection when close contacts wore a mask. Home exposure presented a higher risk of SARS-CoV-2 transmission, and any preventive measures posed a similar risk across all exposure settings analyzed. Bayesian network analysis can assist decision-makers in refining public health campaigns, prioritizing resources for individuals at higher risk, and offering personalized guidance on specific protective measures tailored to different settings or environments.

Background: Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC) but little is known when it is used as the second anti-TNF. Objectives: To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients. Design: Retrospective observational study. Methods: Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially). Results: Overall, 473 UC patients were included (330 IVi and 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4% in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission. Conclusion: The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy.

BackgroundDuring the SARS-CoV-2 pandemic, nurses of primary health care has been an important role in Spain. Even so, the data obtained in the tracing have been scarcely used to investigate the possible mechanisms of transmission. Few studies focused on community transmission, evaluating the effectiveness of individual protective measures and exposure environment. The main aim of the study was to evaluate the association between individual protective measures and SARS-CoV-2 transmission in the community and to compare secondary attack rates in different exposure settings.MethodsA case–control study from contact tracing of SARS-CoV-2 index patients. COVID-19 contact tracing was led by nurses at the COVID-19 Coordinating Centre in Majorca (Spain). During the systematic tracing, additional information for this study was collected from the index patient (social-demographic variables, symptoms, the number of close contacts). And also, the following variables from their close contacts: contact place, ventilation characteristics mask-wearing, type of mask, duration of contact, shortest distance, case-contact relationship, household members, and handwashing, the test result for SARS-CoV-2 diagnostic. Close contacts with a positive test for SARS-CoV-2 were classified as “cases” and those negative as “controls.”ResultsA total of 1,778 close contacts from 463 index patients were identified. No significant differences were observed between the sexes but between age groups. Overall Secondary Attack Rate (SAR) was 24.0% (95% CI: 22.0–26.0%), 36.9% (95% CI: 33.2–40.6%) in closed spaces without ventilation and 50.7% (95% CI: 45.6–55.8%) in exposure time > 24 h. A total of 49.2% of infections occurred among household members. Multivariate logistic regression analysis showed that open-air setting (OR 0.43, 95% CI: 0.27–0.71), exposure for less than 1 h (OR 0.19, 95% CI: 0.11–0.32), and wearing a mask (OR 0.49, 95% CI: 0.28–0.85) had a protective effect transmission of SARS-CoV-2 in the community.ConclusionVentilation of the space, mask-wearing and shorter exposure time were associated with a lower risk of transmission in the community. The data obtained allowed an assessment of community transmission mechanisms and could have helped to improve and streamline tracing by identifying close contacts at higher risk.

Abstract Background The evaluation of health status by cardiopulmonary exercise test (CPET) has shown increasing interest in the paediatric population. Our group recently established reference Z-score values for paediatric cycle ergometer VO2max, applicable to normal and extreme weights, from a cohort of 1141 healthy children. There are currently no validated reference values for the other CPET parameters in the paediatric population. This study aimed to establish, from the same cohort, reference Z-score values for the main paediatric cycle ergometer CPET parameters, apart from VO2max. Results In this cross-sectional study, 909 healthy children aged 5–18 years old underwent a CPET. Linear, quadratic, and polynomial mathematical regression equations were applied to identify the best CPET parameters Z-scores, according to anthropometric parameters (sex, age, height, weight, and BMI). This study provided Z-scores for maximal CPET parameters (heart rate, respiratory exchange ratio, workload, and oxygen pulse), submaximal CPET parameters (ventilatory anaerobic threshold, VE/VCO2 slope, and oxygen uptake efficiency slope), and maximum ventilatory CPET parameters (tidal volume, respiratory rate, breathing reserve, and ventilatory equivalent for CO2 and O2). Conclusions This study defined paediatric reference Z-score values for the main cycle ergometer CPET parameters, in addition to the existing reference values for VO2max, applicable to children of normal and extreme weights. Providing Z-scores for CPET parameters in the paediatric population should be useful in the follow-up of children with various chronic diseases. Thus, new paediatric research fields are opening up, such as prognostic studies and clinical trials using cardiopulmonary fitness outcomes. Trial registration NCT04876209—Registered 6 May 2021—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04876209 .

El uso de simuladores en los procesos educativos ha tomado fuerza en los últimos años, y se han convertido en herramientas que apoyan al mejoramiento de capacidades y competencias genéricas de los estudiantes, como son: la comunicación asertiva, gestión del tiempo y de la información, trabajo en equipo, técnicas de análisis, entre otras, pero se hace necesario indagar si otros aspectos pueden influir en el momento del uso y aplicación de los simuladores empresariales, así como en los resultados obtenidos. El enfoque utilizado en esta investigación es de tipo cuantitativo-explicativo y de tiempo sincrónico y utiliza como fuente de información la base de datos del simulador de juegos de negocios Company Game, tomando la información de 1.197 registros. El objetivo del estudio es identificar la existencia de variables que influyan en el desempeño de los equipos en el juego de simuladores de negocios, tales como la formación académica, el contexto y el entrenamiento. Los resultados del modelo de regresión logística y el modelo de ecuaciones no paramétricas (PLS-SEM), muestran que el tiempo de dedicación y la cantidad de consultas de páginas asociadas al juego de simulación son los determinantes que explican la variación en los resultados del ranking, brindando una mejor comprensión a las personas interesadas en los procesos de construcción del conocimiento, mediadas por métodos de aprendizaje electrónico que buscan un fortalecimiento en las competencias genéricas.

Abstract Background Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression

Abstract Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

Topology optimization is currently enjoying renewed interest thanks to the recent development of 3D printing techniques, which offer the possibility of producing these new complex designs. One of the difficulties encountered in manufacturing topologically optimized magnetostatic structures is that they are not necessarily mechanically stable. In order to take this mechanical constraint into account, we have developed a SIMP-based topology optimization algorithm which relies on numerical simulations of both the mechanical deformation and the magnetostatic behavior of the structure. Two variants are described in this paper, respectively taking into account the compliance or the von Mises constraint. By comparing the designs obtained with those from magnetostatic optimization alone, our approach proves effective in obtaining efficient and robust designs.

Tourism plays an important part in soft power as a public diplomacy tool that, alongside destination branding, aims to reinforce the image of a place to attract visitors, with the ensuing multiplier effect on its economy. Both destination branding and public diplomacy seek the common goal of generating a positive reputation and image of the place, although they pursue different interests. On the one hand, destination branding aims at attracting tourists with an eminently economic objective in mind; while, on the other hand, public diplomacy seeks to promote national interests (economic, social, political), and advance foreign policy goals. Destination branding and public diplomacy can be regarded as two faces of the same coin, as together they leverage a country’s equity in soft power. Japan has furthered its economic, social, and political goals by projecting the image of a technologically advanced country boasting a rich cultural tradition through skillful management of its soft power and its public diplomacy, that in recent times has revolved around cultural diplomacy with the “Cool Japan” strategy for the promotion of cultural industries, as well as around sports diplomacy, with the celebration of the Tokyo 2020 Olympic Games, which owing to the COVID pandemic became an example of failed destination branding, that nevertheless did not obscure their success in terms of sports diplomacy.

Para la economía cubana el turismo representa un sector estratégico; por ello, ha aprobado un conjunto de medidas para su incentivo, entre las que se destaca la reparación de habitaciones e instalaciones hoteleras a través de las inversiones lo que garantiza el incremento de la satisfacción de los visitantes a la Isla. En este sentido, se ha comprobado que una de las deficiencias que afectan este bienestar radica en la falta de integración entre los procesos de Ama de Llaves (limpieza de habitaciones) y de Servicios Técnicos. Por tanto, el objetivo de este trabajo es diseñar un procedimiento para la integración de ambos procesos en un hotel cubano. El modelo escogido está basado en el Análisis Modal de Fallos y Efectos (AMFE), que tiene en cuenta la gestión de riesgos, sus efectos y sus causas; para determinar los índices de severidad, ocurrencia y detección. Calcular, así, el número de prioridad de riesgo y, con este valor, establecer un orden en la gestión de sus riesgos. La aplicación estableció un orden a las causas de uno de sus modos de fallos (riesgos), según el número de prioridad de riesgo y severidad.

Abstract Artificial intelligence (AI) is transforming the field of medical imaging and has the potential to bring medicine from the era of ‘sick-care’ to the era of healthcare and prevention. The development of AI requires access to large, complete, and harmonized real-world datasets, representative of the population, and disease diversity. However, to date, efforts are fragmented, based on single–institution, size-limited, and annotation-limited datasets. Available public datasets (e.g., The Cancer Imaging Archive, TCIA, USA) are limited in scope, making model generalizability really difficult. In this direction, five European Union projects are currently working on the development of big data infrastructures that will enable European, ethically and General Data Protection Regulation-compliant, quality-controlled, cancer-related, medical imaging platforms, in which both large-scale data and AI algorithms will coexist. The vision is to create sustainable AI cloud-based platforms for the development, implementation, verification, and validation of trustable, usable, and reliable AI models for addressing specific unmet needs regarding cancer care provision. In this paper, we present an overview of the development efforts highlighting challenges and approaches selected providing valuable feedback to future attempts in the area. Key points • Artificial intelligence models for health imaging require access to large amounts of harmonized imaging data and metadata. • Main infrastructures adopted either collect centrally anonymized data or enable access to pseudonymized distributed data. • Developing a common data model for storing all relevant information is a challenge. • Trust of data providers in data sharing initiatives is essential. • An online European Union meta-tool-repository is a necessity minimizing effort duplication for the various projects in the area.