ELM-the Eukaryotic Linear Motif resource-2024 update.

Short Linear Motifs (SLiMs) are the smallest structural and functional components of modular eukaryotic proteins. They are also the most abundant, especially when considering post-translational modifications. As well as being found throughout the cell as part of regulatory processes, SLiMs are extensively mimicked by intracellular pathogens. At the heart of the Eukaryotic Linear Motif (ELM) Resource is a representative (not comprehensive) database. The ELM entries are created by a growing community of skilled annotators and provide an introduction to linear motif functionality for biomedical researchers. The 2024 ELM update includes 346 novel motif instances in areas ranging from innate immunity to both protein and RNA degradation systems. In total, 39 classes of newly annotated motifs have been added, and another 17 existing entries have been updated in the database. The 2024 ELM release now includes 356 motif classes incorporating 4283 individual motif instances manually curated from 4274 scientific publications and including >700 links to experimentally determined 3D structures. In a recent development, the InterPro protein module resource now also includes ELM data. ELM is available at: http://elm.eu.org.

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

Intravenous Golimumab in Children With Polyarticular-Course Juvenile Idiopathic Arthritis: Long-Term Extension of an Open-Label, Phase III Study.

OBJECTIVE: To report pharmacokinetics (PK), immunogenicity, clinical effect, and safety of intravenous (IV) golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in A Study to Evaluate the Pharmacokinetics, Efficacy and Safety of Intravenous Golimumab in Pediatric Participants With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy (GO-VIVA)'s open-label, long-term extension (LTE) through week 252. METHODS: GO-VIVA participants who continued IV golimumab (80 mg/m2 every 8 weeks) after week 52 were included. PK and safety were assessed through week 244 (last dose) and week 252, respectively, and clinical response through week 116. Clinical outcomes included JIA-American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Binary outcomes used nonresponder imputation, and other descriptive analyses used observed data. RESULTS: Of 112/127 (88.2%) participants entering the LTE, 69 completed the week 252 visit. Median steady-state trough golimumab concentrations were generally maintained from week 52 through week 244 (range 0.3-0.6 µg/mL). Antigolimumab antibody rates were consistent through week 52 (39.2% [49/125]) and week 244 (44.8% [56/125]). Week 52 JIA-ACR 30/50/70/90 response rates (75.6% [96/127], 74% [94/127], 65.4% [83/127], and 48.8% [62/127], respectively) were generally maintained through week 116 (72.4% [92/127], 71.7% [91/127], 63.8% [81/127], and 50.4% [64/127], respectively), when the median cJADAS10 was 1.6 and 56.7% (72/127) of participants achieved cJADAS10 ≤ 5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through week 252 were 7.7 and 3.9, respectively. CONCLUSION: GO-VIVA LTE participants experienced adequate PK exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest IV golimumab treatment provided durable clinical response through week 116, with an acceptable risk-benefit profile.

Analysis of the circumstances associated with death and predictors of mortality in Spanish adults with Down syndrome, 1997-2014.

OBJECTIVES: Characterise the circumstances associated with death during admission of adults with Down syndrome (DS) and to identify predictors of mortality. PATIENTS AND METHODS: Observational study based on data on all emergent admissions of adults with DS to hospitals of the Spanish National Health System between 1997 and 2014. We analysed epidemiological and clinical variables. RESULTS: We analysed admissions of 11,594 adults with DS, mean age 47 years. 1715 patients died (15%), being the highest mortality (35%) in individuals aged 50-59. A past medical history of cerebrovascular disease (aOR 2.95 [2.30-3.77]) or cancer (aOR 2.79 [2.07-3.75]), gross aspiration's admission (aOR 2.59 [2.20-3.04]), immobility (aOR 2.31 [1.46-3-62]), and readmission within 30 days (aOR 2.43 [2.06-2.86]) were identified as predictors of mortality. CONCLUSIONS: Adults with DS have a high in-hospital mortality rate. The main predictors of death were cerebrovascular disease, cancer, early readmission, and conditions commonly associated with advanced dementia.

Multivariate reference and tolerance regions based on conditional transformation models: Application to glycemic markers.

The reference interval is the most widely used medical decision-making, constituting a central tool in determining whether an individual is healthy or not. When the results of several continuous diagnostic tests are available for the same patient, their clinical interpretation is more reliable if a multivariate reference region (MVR) is available rather than multiple univariate reference intervals. MVRs, defined as regions containing 95% of the results of healthy subjects, extend the concept of the reference interval to the multivariate setting. However, they are rarely used in clinical practice owing to difficulties associated with their interpretability and the restrictions inherent to the assumption of a Gaussian distribution. Further statistical research is thus needed to make MVRs more applicable and easier for physicians to interpret. Since the joint distribution of diagnostic test results may well change with patient characteristics independent of disease status, MVRs adjusted for covariates are desirable. The present work introduces a novel formulation for MVRs based on multivariate conditional transformation models (MCTMs). Additionally, we take into account the estimation uncertainty of such MVRs by means of tolerance regions. These conditional MVRs imply no parametric restriction on the response, and potentially nonlinear continuous covariate effects can be estimated. MCTMs allow the estimation of the effects of covariates on the joint distribution of multivariate response variables and on these variables' marginal distributions, via the use of most likely transformation estimation. Our contributions proved reliable when tested with simulated data and for a real data application with two glycemic markers.

What brings adults with Down syndrome to the hospital? A retrospective review of a Spanish cohort between 1997 and 2014.

OBJECTIVES: To describe the clinical and epidemiological characteristics of adult patients with Down syndrome admitted to Spanish hospitals between 1997 and 2014. Secondary goals were to study trend changes over time, and to analyse differences between patients admitted to medical and surgical departments. PATIENTS AND METHODS: Retrospective observational study on data collected from the Minimum Basic Dataset (MBDS, Conjunto Mínimo Básico de Datos [CMBD]) of admissions of adults with Down syndrome to hospitals belonging to the Spanish National Health System from 1 January 1997 through 31 December 2014. We analysed epidemiological and clinical variables. RESULTS: We analysed 28,716 admissions of 16,874 adult patients with Down syndrome. Men accounted for 58.2% of the sample, and the mean age on admission was 41 ± 13 years, with an 11-year increase in mean age during the study period. Admissions among persons with Down syndrome increased by 5% during the study period, with a noticeable rise in admissions of older adults and to medical departments. Almost one-third of patients (31.8%) were admitted more than once. Age-adjusted mortality was 15.7%. The most common comorbid conditions were chronic obstructive pulmonary disease (25%), hypothyroidism (18.6%), and epilepsy (14.3%). The departments with the highest numbers of admissions were internal medicine (26.3%), pulmonary medicine (6.9%), and general surgery (5.25%). CONCLUSION: Hospital admissions among Spanish adults with Down syndrome have increased in recent decades, especially in older patients. We identified substantial differences between patients admitted to medical and surgical departments.

Modeling conditional reference regions: Application to glycemic markers.

Many clinical decisions are taken based on the results of continuous diagnostic tests. Usually, only the results of one single test is taken into consideration, the interpretation of which requires a reference range for the healthy population. However, the use of two different tests, can be necessary in the diagnosis of certain diseases. This obliges a bivariate reference region be available for their interpretation. It should also be remembered that reference regions may depend on patient variables (eg, age and sex) independent of the suspected disease. However, few proposals have been made regarding the statistical modeling of such reference regions, and those put forward have always assumed a Gaussian distribution, which can be rather restrictive. The present work describes a new statistical method that allows such reference regions to be estimated with no insistence on the results being normally distributed. The proposed method is based on a bivariate location-scale model that provides probabilistic regions covering a specific percentage of the bivariate data, dependent on certain covariates. The reference region is estimated nonparametrically and the nonlinear effects of continuous covariates via polynomial kernel smoothers in additive models. The bivariate model is estimated using a backfitting algorithm, and the optimal smoothing parameters of the kernel smoothers selected by cross-validation. The model performed satisfactorily in simulation studies under the assumption of non-Gaussian conditions. Finally, the proposed methodology was found to be useful in estimating a reference region for two continuous diagnostic tests for diabetes (fasting plasma glucose and glycated hemoglobin), taking into account the age of the patient.

Demographic, clinical, and functional determinants of antithrombotic treatment in patients with nonvalvular atrial fibrillation.

BACKGROUND: This study assessed the sociodemographic, functional, and clinical determinants of antithrombotic treatment in patients with nonvalvular atrial fibrillation (NVAF) attended in the internal medicine setting. METHODS: A multicenter, cross-sectional study was conducted in NVAF patients who attended internal medicine departments for either a routine visit (outpatients) or hospitalization (inpatients). RESULTS: A total of 961 patients were evaluated. Their antithrombotic management included: no treatment (4.7%), vitamin K antagonists (VKAs) (59.6%), direct oral anticoagulants (DOACs) (21.6%), antiplatelets (6.6%), and antiplatelets plus anticoagulants (7.5%). Permanent NVAF and congestive heart failure were associated with preferential use of oral anticoagulation over antiplatelets, while intermediate-to high-mortality risk according to the PROFUND index was associated with a higher likelihood of using antiplatelet therapy instead of oral anticoagulation. Longer disease duration and institutionalization were identified as determinants of VKA use over DOACs. Female gender, higher education, and having suffered a stroke determined a preferential use of DOACs. CONCLUSIONS: This real-world study showed that most elderly NVAF patients received oral anticoagulation, mainly VKAs, while DOACs remained underused. Antiplatelets were still offered to a proportion of patients. Longer duration of NVAF and institutionalization were identified as determinants of VKA use over DOACs. A poor prognosis according to the PROFUND index was identified as a factor preventing the use of oral anticoagulation.

Volumetric BMD by 3D-DXA and Trabecular Bone Score in Adults With Down Syndrome.

Adults with Down syndrome (DS) have lower bone mineral density (BMD) than the general population. The objective of our study was to describe bone mineral status in DS population through volumetric BMD (vBMD) and trabecular bone score (TBS). Retrospective study of 297 subjects recruited from the Adult DS Outpatient Clinic of a tertiary care hospital in Spain, who underwent a bone densitometry for clinical purposes between January 2010 and June 2015. vBMD determination and TBS analysis on conventional DXA (Hologic QDR 4500) densitometer were performed in this cohort. The mean (±SD) age of our population was 34.3 (±10.9) years; 51% were women. Trabecular vBMD at total hip and femoral neck was lower in males than in females (191.7 ± 48.4 mg/cm3 vs 206.9 ± 46.7 mg/cm3, p = 0.007, and 250.5 ± 70.1 mg/cm3 vs 275.7 ± 66.2 mg/cm3, p = 0.002, respectively). Trabecular and cortical vBMD decreased with age, but age decline in trabecular vBMD was more pronounced in males. Likewise, lumbar TBS declined with age being normal in 63%, low in 29% and very low in 8% of subjects with DS, without differences between sexes. TBS showed a positive correlation (r = 0.37; p < 0.001, Kappa index= 0.275) with conventional DXA lumbar Z-score. vBMD at the hip showed lower values in DS subjects than in the general population, especially in males. Moreover, TBS was also lower at lumbar spine. Therefore, both assessments could be used as complementary tools to areal BMD (Z-score) to assess bone status in DS subjects.

Impact of the Covid-19 pandemic on perinatal mental health (Riseup-PPD-COVID-19): protocol for an international prospective cohort study.

BACKGROUND: Corona Virus Disease 19 (COVID-19) is a new pandemic, declared a public health emergency by the World Health Organization, which could have negative consequences for pregnant and postpartum women. The scarce evidence published to date suggests that perinatal mental health has deteriorated since the COVID-19 outbreak. However, the few studies published so far have some limitations, such as a cross-sectional design and the omission of important factors for the understanding of perinatal mental health, including governmental restriction measures and healthcare practices implemented at the maternity hospitals. Within the Riseup-PPD COST Action, a study is underway to assess the impact of COVID-19 in perinatal mental health. The primary objectives are to (1) evaluate changes in perinatal mental health outcomes; and (2) determine the risk and protective factors for perinatal mental health during the COVID-19 pandemic. Additionally, we will compare the results between the countries participating in the study. METHODS: This is an international prospective cohort study, with a baseline and three follow-up assessments over a six-month period. It is being carried out in 11 European countries (Albania, Bulgaria, Cyprus, France, Greece, Israel, Malta, Portugal, Spain, Turkey, and the United Kingdom), Argentina, Brazil and Chile. The sample consists of adult pregnant and postpartum women (with infants up to 6 months of age). The assessment includes measures on COVID-19 epidemiology and public health measures (Oxford COVID-19 Government Response Tracker dataset), Coronavirus Perinatal Experiences (COPE questionnaires), psychological distress (BSI-18), depression (EPDS), anxiety (GAD-7) and post-traumatic stress symptoms (PTSD checklist for DSM-V). DISCUSSION: This study will provide important information for understanding the impact of the COVID-19 pandemic on perinatal mental health and well-being, including the identification of potential risk and protective factors by implementing predictive models using machine learning techniques. The findings will help policymakers develop suitable guidelines and prevention strategies for perinatal mental health and contribute to designing tailored mental health interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04595123 .