Prediction of Alzheimer's disease dementia with MRI beyond the short-term: Implications for the design of predictive models

Magnetic resonance imaging (MRI) volumetric measures have become a standard tool for the detection of in-cipientAlzheimer'sDisease(AD)dementiainmildcognitiveimpairment(MCI).Focusedonprovidinganearlierand more accurate diagnosis, sophisticated MRI machine learning algorithms have been developed over therecentyears,mostofthemlearningtheirnon-diseasepatternsfromMCIthatremainedstableover2–3years.Inthis work, we analyzed whether these stable MCI over short-term periods are actually appropriate trainingexamples of non-disease patterns. To this aim, we compared the diagnosis of MCI patients at 2 and 5years offollow-up and investigated its impact on the predictive performance of baseline volumetric MRI measures pri-marily involved in AD, i.e., hippocampal and entorhinal cortex volumes. Predictive power was evaluated interms ofthe areaunder the ROCcurve(AUC), sensitivity,andspecificity inatrialsample of248 MCIpatientsfollowed-up over 5years. We further compared the sensitivity in those MCI that converted before 2years andthose that converted after 2years. Our results indicate that 23% of the stable MCI at 2years progressed in thenextthreeyearsandthatMRIvolumetricmeasuresaregoodpredictorsofconversiontoADdementiaevenatthemid-term, showing a better specificity and AUC as follow-up time increases. The combination of hippocampusand entorhinal cortex yielded an AUC that was significantly higher for the 5-year follow-up (AUC=73% at2yearsvs.AUC=84%at5years),aswellasforspecificity(56%vs.71%).Sensitivityshowedanon-significantslightdecrease(81%vs.78%).Remarkably,theperformanceofthismodelwascomparabletomachinelearningmodels at the same follow-up times. MRI correctly identified most of the patients that converted after 2years(with sensitivity>60%), and these patients showed a similar degree of abnormalities to those that convertedbefore 2years. This implies that most of the MCI patients that remained stable over short periods and subse-quentlyprogressedtoADdementiahadevidentatrophiesatbaseline.Therefore,machinelearningmodelsthatuse these patients to learn non-disease patterns are including an important fraction of patients with evidentpathological changes related to the disease, something that might result in reduced performance and lack ofbiological interpretability.This work was partially supported by the project PI16/01416(ISCIIIco-fundedFEDER) and RYC-2015/17430 (RamónyCajal,Pablo Aguiar). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI)(National Institutes of Health Grant U01AG024904) and DODADNI (Department of Defense award number W81XWH-12-2-0012)S

y-QUIT: Smoking Prevalence, Engagement, and Effectiveness of an Individualized Smoking Cessation Intervention in Youth With Severe Mental Illness

Introduction: Young people with psychosis are six times more likely to be tobacco smokers than their gender- and age-matched peers. Smoking is a major contributor to the 15-year reduced life expectancy among people experiencing severe mental illness (SMI). There is a lack of evidence-supported interventions for smoking cessation among young people with SMI.Material and Methods: The study comprised two phases and aimed to assess (i) the prevalence of smoking among a community sample of young people with psychotic illness or at high risk of developing psychosis; (ii) the proportion who engaged in the intervention; (iii) the proportion who achieved smoking cessation; and (iv) secondary smoking-related outcomes. In phase one, prevalence of smoking was assessed among young people with psychotic illness or at high risk of developing psychosis attending a community-based youth mental health service between 16/5/2017 and 16/11/2017. In phase two, over a 1-year period, individuals identified as smokers were invited to participate in a 12-week tailored smoking cessation intervention program that included pharmacological treatment, motivational interviewing, and behavioral change techniques. Those unwilling to participate in a full intervention were offered a brief intervention. Participants of the full intervention were assessed at baseline and at week 12 endpoint on: daily cigarettes smoked (self-report), exhaled CO, nicotine dependence, readiness to quit, and confidence to quit.Results: In phase one, smoking prevalence was 48.2% (53 of 110) among clients of the youth mental health service. Smokers were significantly more likely to be male (X2 = 6.41 p = 0.009). During phase two, 41 of 61 eligible clients engaged in a smoking cessation intervention (67.2%). Effectiveness: twenty-one clients participated in a full intervention (34.4%), of whom three (14.3%) received a brief intervention initially and during engagement converted to full intervention. Twenty participants (32.8%) received a brief intervention only. Ten participants in the full intervention (47.6%) and five in the brief intervention (25%) dropped out. Six (28.6% of full intervention) reported smoking cessation verified by CO monitoring. Participants who completed the full intervention (n = 9) reduced number of cigarettes smoked, nicotine dependence, and exhaled CO, while readiness to quit and confidence to quit increased. Pharmacotherapy was predominantly combination NRT (n = 18; 85.7%), varenicline (4.8%), oral NRT only (4.8%), or none (4.8%). No adverse events were reported.Conclusion: This pilot real-world study demonstrates that both screening for smoking and offering an effective smoking cessation intervention are achievable in youth experiencing or at risk of psychosis

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Omicron SARS-CoV-2 infection management and outcomes in patients with hematologic disease and recipients of cell therapy

IntroductionScarce real-life data exists for COVID-19 management in hematologic disease (HD) patients in the Omicron era.PurposeTo assess the current clinical management and outcome of SARS-CoV-2 infection diagnosed, identify the risk factors for severe outcomes according to the HD characteristics and cell therapy procedures in a real-world setting.MethodsA retrospective observational registry led by the Spanish Transplant Group (GETH-TC) with 692 consecutive patients with HD from December 2021 to May 2023 was analyzed.ResultsNearly one-third of patients (31%) remained untreated and presented low COVID-19-related mortality (0.9%). Nirmatrelvir/ritonavir was used mainly in mild COVID-19 cases in the outpatient setting (32%) with a low mortality (1%), while treatment with remdesivir was preferentially administered in moderate-to-severe SARS-CoV-2 infection cases during hospitalization (35%) with a mortality rate of 8.6%. The hospital admission rate was 23%, while 18% developed pneumonia. COVID-19-related mortality in admitted patients was 14%. Older age, autologous hematopoietic stem cell transplantation (SCT), chimeric antigen receptor T-cell therapy, corticosteroids and incomplete vaccination were factors independently associated with COVID-19 severity and significantly related with higher rates of hospital admission and pneumonia. Incomplete vaccination status, treatment with prior anti-CD20 monoclonal antibodies, and comorbid cardiomyopathy were identified as independent risk factors for COVID-19 mortality.ConclusionsThe results support that, albeit to a lower extent, COVID-19 in the Omicron era remains a significant problem in HD patients. Complete vaccination (3 doses) should be prioritized in these immunocompromised patients. The identified risk factors may help to improve COVID-19 management to decrease the rate of severe disease, ICU admissions and mortality

Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients

Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.Peer reviewe

How do presenters engage with their audience? Speakers’ multimodal interpersonal behaviour in research dissemination talks

Speakers in research dissemination talks are challenged with the need to connect with an audience that does not necessarily share their knowledge and expertise. This communicative situation can be particularly challenging for speakers using English both as a foreign language and for academic purposes. This study combines multimodal and ethnographic methods to explore how speakers of dissemination talks engage with their public. It focuses on four presenters’ use and combination of language, paralanguage, kinesics, proxemics and gaze during intensive moments of engagement. The results show that these interpersonal rich points consist of dense multimodal ensembles that serve to shorten the distance between presenters and their audiences. The findings suggest that a skilful orchestration of modes can be greatly beneficial to achieve the desired level of audience engagement. Therefore, developing speakers’ multimodal communicative competence should be a priority in English for specific and academic purposes (ESP/EAP) training

Podredumbres postcosecha por Phacidiopycnis en frutos de pepita

El Alto Valle de Río Negro es una de las principales zonas productoras de frutales de pepita de la Argentina. El almacenamiento frigorífico postcosecha es frecuentemente utilizado para la exportación y/o comercialización a contraestación. Frecuentemente, durante este período, se producen pérdidas por patógenos como Botrytis cinerea, Alternaria spp., Cladosporium spp, Penicillium expansum. De carácter esporádico, con cierta frecuencia de aparición, en diferentes cultivares de peras y manzanas se han detectado durante los últimos 10 años, podredumbres con sintomatología característica de Phacidiopycnis ssp. (teleomorfo de Potebniamyces spp.). La problemática fue detectada con baja incidencia durante la corta conservación en pera William’s (2012 y 2013), y mediana-larga conservación en manzana Granny Smith (2019), pera Beurré d’Anjou (2021) y en Packham’s Triumph (2022). Con el objetivo de establecer las características del patógeno, desde frutos de pera de Packham’s Triumph con 7 meses de almacenamiento, con síntomas principalmente asociados a pedúnculos y signos, se llevaron a cabo aislamientos en agar papa dextrosa acidificado (APD-A), a partir de los cuales se realizó la identificación molecular y pruebas de patogenicidad en los cultivares de pera más importantes para la región. Los aislados obtenidos en APD-A incubados a 7, 14 y 21 días con un régimen de luz 12:12 horas, se caracterizaron macro y micromorfológicamente, y se los identificó molecularmente a través del secuenciamiento del fragmento ITS1-ITS4. Las pruebas de patogenicidad se realizaron con inoculación de frutos de los cultivares Beurre d’Anjou, Packham’s Triumph y William’s a partir de suspensiones de conidios en pedúnculo, cáliz y heridas en la zona ecuatorial, e incubación 7 días a 20°C y 30 días a 0°C más 7 a 20°C (góndola). Desde los síntomas de los frutos inoculados se realizaron re-aislamientos, con los cuales se cumplimentaron los Postulados de Koch. Las características macro-microscópicas respondieron a las características descriptas para el género Phacidiopycnis. Las secuencias de ITS de los aislados confirmaron la identidad del patógeno, con una similaridad de 99-100% con la secuencia de Potebniamyces pyri (anamorfo Phacidiopycnis pyri) CBS:322.63. Las secuencias fueron depositadas en el GenBank (accesos: OQ280987.1, OQ280986.1, OQ280985.1). En lo que respecta a las pruebas de patogenicidad, tanto a los 7 días 20°C, como luego de 30 días a 0°C más 7 a 20°C, los aislados resultaron patogénicos a partir de las inoculaciones de pedúnculo y heridas de frutos de todos los cultivares, mientras que de cáliz sólo en William’s y d’Anjou. De acuerdo con nuestros estudios, Phacidiopycnis en la región, es un patógeno que hasta el momento aparece en baja frecuencia, pero afectando a todos los cultivares de pera de importancia. Estudios epidemiológicos son necesarios para conocer las fuentes de inoculo, momentos de infección y condiciones ambientales predisponentes para la ocurrencia de la podredumbre.Facultad de Ciencias Agrarias y Forestale

Analysis of demographic, psychological and cultural aspects associated with the practice of sexting in Mexican and Spanish adolescents

Sexting is an increasingly frequent phenomenon among adolescents, and it involves risky behaviors such as sextortion or even grooming. This study aims to analyze demographic, psychological, and cultural variables that may explain the nature of this phenomenon. The sample consisted of 471 adolescents from 12 to 18 years old from two countries, Spain and Mexico, with dissimilar levels of gender inequality. Results highlight important differences in sexting behavior between the two countries. We have found higher levels of sexting behaviors in Mexican adolescents (41.5 %) than in Spanish adolescents (24.6 %) as well as an earlier start in Mexican adolescents. Moreover, adolescents in Mexico engage in sexting more frequently. There are no differences, however, in age showing a growing pattern in the two countries, nor in gender, self-esteem or impulsivity. These results are interpreted from a cultural perspective and highlight the importance of studying the phenomenon of sexting within the framework of cultural influences, especially sexism. Considering cultural factors is necessary, in order to implement differential preventive strategies according to each culture. Prevention in countries with high inequality, such as Mexico, should be earlier