Primers episodis psicòtics, cànnabis, factors d'estrès, gènere i ètnia

L’esquizofrènia és una malaltia complexa que s’origina per una alteració del neurodesenvolupament causada per la interacció de factors genètics i ambientals al llarg de les diferents etapes de la vida . El primer episodi psicòtic succeeix en èpoques primerenques, entre la adolescència i l’adultesa jove. La probabilitat de patir un episodi psicòtic per tant, té a veure amb la interacció de la vulnerabilitat genètica individual i els diferents factors ambientals. L’ estrès és un dels principals factors ambientals implicats en la etiologia de la psicosi dins el model diàtesis–estrès i per tant te especial rellevància la seva relació amb mesures de l’eix hipotàlem-hipòfisi-adrenal (HHA). En el nostre estudi hem volgut també centrar-nos en un dels principals riscos ambientals evitables , que és el consum del cànnabis i veure la seva interacció amb factors estressants com son el trauma a la infància i els esdeveniments vitals estressants en pacients amb psicosi d’inici control comparats amb grup control. Posteriorment em valorat l’efecte d’aquests factors ambientals sobre mesures biològiques de l’eix HHA. Per continuar hem explorat l’efecte del cànnabis i del gènere en les variables clíniques de pacients ingressats per un Primer Episodi Psicòtic ( PEP), així com les diferencies en raons de consum de cànnabis entre homes i dones. Finalment hem explorat si existien diferències en prevalença de consum de cànnabis, esdeveniments estressants i també en les variables clíniques principals entre PEPs immigrants d’origen marroquí i PEPs població autòctona. En conjunt aquests tesi posa en evidencia que existeix un efecte acumulatiu i un efecte dosi-resposta dels factors de risc ambientals estudiats en el risc de psicosi , essent el trauma a la infància el factor de risc més important. Alhora , el consum de cànnabis es va associar amb una alteració en les mesures de l’eix HHA però sense diferencies entre pacients i controls. Vàrem trobar diferencies de gènere en les raons de consum de cànnabis i una interacció de gènere i cànnabis en el funcionament. Finalment , no vàrem trobar diferencies en la prevalença de esdeveniments estressants entre PEPs d’origen marroquí i PEPs de població autòctona i una menor tendència a consumir cànnabis en aquesta població i un pitjor funcionament.La esquizofrenia es una enfermedad compleja que se origina por una alteración del neurodesarrollo causada por la interacción de factores genéticos y ambientales a lo largo de las diferentes etapas de la vida. El primer episodio psicótico sucede en épocas tempranas, entre la adolescencia o los adultos jóvenes. La probabilidad de sufrir un primer episodio psicótico tiene que ver con la interacción de la vulnerabilidad genética individual y los factores ambientales. El estrés es uno de los principales factores implicados en la etiología de las psicosis dentro del modelo diátesis-estrés y por tanto tiene especial relevancia la relación de las medidas del eje hipotálamo-hipofisario-adrenal. En nuestro estudio hemos querido centrarnos también en unos de los principales riesgos ambientales evitables, que es el consumo de cannabis. Y ver su interacción con los factores estresantes como son el trauma infantil y los acontecimientos vitales estresantes en pacientes con psicosis de inicio reciente comparados con controles. Posteriormente hemos valorado el efecto de estos factores ambientales sobre las medidas del eje hipotálamo-hipofisario-adrenal. Para continuar hemos explorado las características clínicas de los pacientes de origen marroquí versus la población autóctona, siempre en una muestra de primeros episodios y observando el uso de cannabis. Y para finalizar, las diferencias de género, el consumo de cannabis y las razones para continuar el consumo. En conjunto, nuestro estudio muestra que el principal factor de riesgo para desarrollar una psicosis es el maltrato infantil (de los factores que hemos estudiado), potenciándose junto al consumo de cánnabis que incrementa el riesgo. En cambio, no hemos encontrado relación con el cortisol en los primeros episodios que consumían cannabis. Y en nuestros pacientes marroquíes que tienden más a ser hombres, a llevar más tratamiento inyectable y a consumir menos cannabis que la población autóctona. En cuanto al género, No hemos encontrado diferencias clínicas en el consumo de cánnabis, salvo mayor consumo para relajarse y mayor GAF al alta en mujeres.The aetiology of schizophrenia is multi-factorial, consisting of interactions between genetic vulnerability and environmental risk factors. Schizophrenia is considerer as an illness of the neurodevelopment. The probability of suffering a first psychosis episode is an interaction between the genetic vulnerability and the environmental factors. According to the model of diathesis-stress, stress is one of the most important risk factors i the aetiology of schizophrenia, given relevance to obtain the measures of the hypothalamic-pituitary-adrenal axis function. In our study we want to study one of the most avoidable environmental risk, cannabis use. Cannabis is the third most common drug of dependence in the world, after tobacco and alcohol. There is now strong evidence that cannabis use is a risk factor for the development of psychosis. And determine whether the risk of psychosis depends on the severity of exposure to childhood trauma, recent life events and cannabis use and to determine whether there is an interaction and/or a cumulative effect among these environmental factors. In conclusion, our study provides evidence for a cumulative and a dose–response effect of environmental factors in the development of early psychosis. We did not find a relationship between HPA axis and first episodes. We find that our Moroccan patients tend to be male and tend to have LAI prescription more than native population. Considering gender, female show more "relax” as reason of use and a higher GAF at discharge

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice

The Multiplanet System TOI-421: A Warm Neptune and a Super Puffy Mini-Neptune Transiting a G9 V Star in a Visual Binary

We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations—comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echellé Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution Échelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements—and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P_b = 5.19672 ± 0.00049 days, a mass of M_b = 7.17 ± 0.66 M⊕, and a radius of R_b = 2.68^(+0.19)_(-0.18) R⊕, whereas the outer warm Neptune, TOI-421 c, has a period of Pc = 16.06819 ± 0.00035 days, a mass of M_c = 16.42^(+1.06)_(-1.04) M⊕, a radius of R_c = 5.09^(+0.16)_(-0.15) R⊕ and a density of ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³. With its characteristics, the outer planet (ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Lyα transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Lessons learned from recruiting into a longitudinal remote measurement study in Major Depressive Disorder

The use of remote measurement technologies (RMTs) across mobile health (mHealth) studies is becoming popular, given their potential for providing rich data on symptom change and indicators of future state in recurrent conditions such as major depressive disorder (MDD). Understanding recruitment into RMT research is fundamental for improving historically small sample sizes, reducing loss of statistical power, and ultimately producing results worthy of clinical implementation. There is a need for the standardisation of best practices for successful recruitment into RMT research. The current paper reviews lessons learned from recruitment into the Remote Assessment of Disease and Relapse- Major Depressive Disorder (RADAR-MDD) study, a large-scale, multi-site prospective cohort study using RMT to explore the clinical course of people with depression across the UK, Netherlands, and Spain. More specifically, the paper reflects on key experiences from the UK site and consolidates these into four key recruitment strategies, alongside a review of barriers to recruitment. Finally, the strategies and barriers outlined are combined into a model of lessons learned. This work provides a foundation for future RMT study design, recruitment and evaluation