SARS-CoV-2 E protein interacts with BRD2 and BRD4 SEED domains and alters transcription in a different way than BET inhibition.

Bromodomain and extra-terminal (BET) proteins are relevant chromatin adaptors involved in the transcriptional control of thousands of genes. Two tandem N-terminal bromodomains are essential for chromatin attachment through acetyl-histone recognition. Recently, the BET proteins members BRD2 and BRD4 were found to interact with the SARS-CoV-2 envelope (E) protein, raising the question of whether the interaction constitutes a virus hijacking mechanism for transcription alteration in the host cell. To shed light on this question, we have compared the transcriptome of cells overexpressing E with that of cells treated with the BET inhibitor JQ1. Notably, E overexpression leads to a strong upregulation of natural immunity- and interferon response-related genes. However, BET inhibition results in the downregulation of most of these genes, indicating that these two conditions, far from causing a significant overlap of the altered transcriptomes, course with quite different outputs. Concerning the interaction of E protein with BET members, and differing from previous reports indicating that it occurs through BET bromodomains, we find that it relies on SEED and SEED-like domains, BET regions rich in Ser, Asp, and Glu residues. By taking advantage of this specific interaction, we have been able to direct selective degradation of E protein through a PROTAC system involving a dTAG-SEED fusion, highlighting the possible therapeutic use of this peptide for targeted degradation of a viral essential protein.

SpadaHC: a database to improve the classification of variants in hereditary cancer genes in the Spanish population.

Accurate classification of genetic variants is crucial for clinical decision-making in hereditary cancer. In Spain, genetic diagnostic laboratories have traditionally approached this task independently due to the lack of a dedicated resource. Here we present SpadaHC, a web-based database for sharing variants in hereditary cancer genes in the Spanish population. SpadaHC is implemented using a three-tier architecture consisting of a relational database, a web tool and a bioinformatics pipeline. Contributing laboratories can share variant classifications and variants from individuals in Variant Calling Format (VCF) format. The platform supports open and restricted access, flexible dataset submissions, automatic pseudo-anonymization, VCF quality control, variant normalization and liftover between genome builds. Users can flexibly explore and search data, receive automatic discrepancy notifications and access SpadaHC population frequencies based on many criteria. In February 2024, SpadaHC included 18 laboratory members, storing 1.17 million variants from 4306 patients and 16 343 laboratory classifications. In the first analysis of the shared data, we identified 84 genetic variants with clinically relevant discrepancies in their classifications and addressed them through a three-phase resolution strategy. This work highlights the importance of data sharing to promote consistency in variant classifications among laboratories, so patients and family members can benefit from more accurate clinical management. Database URL: https://spadahc.ciberisciii.es/.

Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Risk in Chronic Musculoskeletal Pain.

BACKGROUND: It is unknown whether growth differentiation factor 15 (GDF-15) is associated with chronic musculoskeletal pain (CMP) and whether or not its association with incident cardiovascular disease (CVD) changes according to CMP status. METHODS: In total, 1 957 randomly selected adults aged ≥65 years without prior CVD were followed up between 2015 and 2023. CMP was classified according to its intensity, frequency, and interference with daily activities. The association between GDF-15 levels and CMP was assessed using linear models with progressive inclusion of potential confounders, whereas the association between GDF-15 and CVD risk was evaluated with Cox proportional hazard models with similar adjustment and interaction terms between GDF-15 and CMP. The incremental predictive performance of GDF-15 over standard predictors was evaluated using discrimination and risk reclassification metrics. RESULTS: GDF-15 concentrations were 6.90% (95% confidence interval [CI]: 2.56; 11.25) higher in individuals with CMP, and up to 8.89% (4.07; 15.71) and 15.79% (8.43; 23.16) higher in those with ≥3 CMP locations and interfering pain. These increased levels were influenced by a higher prevalence of cardiometabolic risk factors, functional impairments, depressive symptoms, and greater levels of inflammation in individuals with CMP. In fully adjusted models, a twofold increase in GDF-15 was associated with a 1.49 increased risk (95% CI: 1.08; 2.05) of a CVD event in individuals with CMP, but not among those without CMP (1.02 [0.77; 1.35]); p-interaction 0.041. Adding GDF-15 to models including the Framingham Risk Score improved predictive performance among individuals with CMP. CONCLUSIONS: We provide evidence that GDF-15 could serve as a biomarker to assess CMP, as well as to predict CVD incidence in individuals with CMP.

Efficacy and safety of bempedoic acid in acute coronary syndrome. Design of the clinical trial ES-BempeDACS.

INTRODUCTION AND OBJECTIVES: Only about 1 out of every 3 patients with acute myocardial infarction (AMI) achieve low-density lipoprotein cholesterol (LDL-C) values <55mg/dL in the first year. The present study aims to evaluate the impact of early intensive therapy on lipid control after an AMI. METHODS: An independent, prospective, pragmatic, controlled, randomized, open-label, evaluator-blinded clinical trial (PROBE design) will analyze the efficacy and safety of an oral lipid-lowering triple therapy: high-potency statin+bempedoic acid (BA) 180mg+ezetimibe (EZ) 10mg versus current European-based guidelines (high-potency statin±EZ 10mg), in AMI patients. LDL-C will be determined within the first 48hours. Patients with LDL-C ≥ 115mg/dL (without previous statin therapy), ≥ 100mg/dL (with previous low-potency or high-potency statin therapy at submaximal dose), or ≥ 70mg/dL (with previous high-potency statin therapy at high dose) will be randomly assigned 1:1 between 24 and 72hours post-AMI to the BA/EZ combination or to statin±EZ, without BA. The primary endpoint is the proportion of patients reaching LDL-C <55mg/dL at 8 weeks after treatment. RESULTS: The results of this study will provide novel information for post-AMI LDL-C control by evaluating the usefulness of an early intensive lipid-lowering strategy based on triple oral therapy. CONCLUSIONS: Early intensive lipid-lowering triple oral therapy vs the treatment recommended by current clinical practice guidelines could facilitate the achievement of optimal LDL-C levels in the first 2 months after AMI (a high-risk period). IDENTIFICATION NUMBER: EudraCT 2021-006550-31.

The Impact of High Levels of Compensatory Exercise on Treatment Outcomes in Threshold and Subthreshold Bulimia Nervosa.

Bulimia nervosa (BN) and other specific feeding or eating disorders with subthreshold BN symptoms (OSFED-BN) are characterized by recurrent binge eating episodes accompanied by compensatory behaviors, including excessive exercise. We aimed to examine the role of compensatory exercise on several clinical disorder-related variables and the treatment outcomes. The sample included 478 patients diagnosed with either BN or OSFED-BN admitted for a 16-week eating disorder-specific treatment program. A battery of questionnaires was administered to evaluate eating and general psychopathology, and personality traits. Other clinical disorder-related data, including levels of compensatory exercise, were assessed through a semi-structured clinical interview. Between-group comparisons of compensatory exercise levels were analyzed, as a predictive model of risk of poor treatment outcomes. Path analysis was conducted using structural equation models to estimate the direct and indirect effects between the main variables. Higher levels of self-reported compensatory exercise were associated with greater eating psychopathology, general psychopathology, and more dysfunctional personality traits and were a predictor of poor treatment outcomes. Additionally, these levels achieved a mediating role in several paths contributing to a higher likelihood of a poor outcome. Further research is required to determine how psychotherapeutic approaches can be optimized to adequately include adaptive exercise for these patients.

Store-and-forward teledermatology in a Spanish health area significantly increases access to dermatology expertise.

INTRODUCTION: Teledermatology is the practice of dermatology through communication technologies. The aim of this study is to analyze its implementation in a Spanish health area during its first two years. METHODS: Cross-sectional descriptive study. It included interconsultations between dermatologists and family physicians in the Salamanca Health Area (Spain) after the implementation of the non-face-to-face modality over a period of two consecutive years. A total of 25,424 consultations were performed (20,912 face-to-face and 4,512 non-face-to-face); 1000 were selected by random sampling, half of each modality. MAIN MEASURES: referral rate, response time and resolution time, type of pathology, diagnostic concordance, and quality of consultation. RESULTS: The annual referral rate was 42.9/1000 inhabitants (35.3 face-to-face and 7.6 non-face- to-face). The rate of face-to-face referrals was higher in urban areas (37.1) and the rate of non- face-to-face referrals in rural areas (10.4). The response time for non-face-to-face consultations was 2.4 ± 12.7 days and 56 ± 34.8 days for face-to-face consultations (p < 0.001). The resolution rate for non-face-to-face consultations was 44%. Diagnostic concordance, assessed by the kappa index, was 0.527 for face-to-face consultations and 0.564 for non-face-to-face consultations. Greater compliance with the quality criteria in the non-attendance consultations. CONCLUSIONS: Teledermatology appears to be an efficient tool in the resolution of dermatological problems, with a rapid, effective, and higher quality response for attention to skin pathologies. REGISTRY: ClinicalTrials.gov Identifier: NCT05625295. Registered on 21 November 2022 ( https://clinicaltrials.gov/ct2/show/ NCT05625295).

Biomarkers of frailty.

Several biomarkers have been proposed to identify frailty, a multisystemic age-related syndrome. However, the complex pathophysiology and the absence of a consensus on a comprehensive and universal definition make it challenging to pinpoint a singular biomarker or set of biomarkers that conclusively characterize frailty. This review delves into the main laboratory biomarkers, placing special emphasis on those associated with various pathways closely tied to the frailty condition, such as inflammation, oxidative stress, mitochondrial dysfunction, metabolic and endocrine alterations and microRNA. Additionally, we provide a summary of different clinical biomarkers encompassing different tools that have been proposed to assess frailty. We further address various imaging biomarkers such as Dual Energy X-ray Absorptiometry, Bioelectrical Impedance analysis, Computed Tomography and Magnetic Resonance Imaging, Ultrasound and D3 Creatine dilution. Intervention to treat frailty, including non-pharmacological ones, especially those involving physical exercise and nutrition, and pharmacological interventions, that include those targeting specific mechanisms such as myostatin inhibitors, insulin sensitizer metformin and with special relevance for hormonal treatments are mentioned. We further address the levels of different biomarkers in monitoring the potential positive effects of some of these interventions. Despite the availability of numerous biomarkers, their performance and usefulness in the clinical arena are far from being satisfactory. Considering the multicausality of frailty, there is an increasing need to assess the role of sets of biomarkers and the combination between laboratory, clinical and image biomarkers, in terms of sensitivity, specificity and predictive values for the diagnosis and prognosis of the different outcomes of frailty to improve detection and monitoring of older people with frailty or at risk of developing it, being this a need in the everyday clinical practice.

Histoplasma capsulatum tenosynovitis: An unusual presentation in a kidney transplant recipient.

Histoplasmosis is an expected endemic mycosis in solid organ transplant recipients and occurs as a primary infection, reactivation, or, rarely, acquired from an infected allograft. Reactivation is favored by maintenance immunosuppression or anti-rejection therapy, which facilitates the appearance of disseminated forms as well as unusual presentations. We present the case of a 66-year-old woman with isolated tenosynovitis due to Histoplasma capsulatum 25 years after a kidney transplant.

Naphthoquinone Derivatives from Angustimassarina populi CF-097565 Display Anti-Tumour Activity in 3D Cultures of Breast Cancer Cells.

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus Angustimassarina populi CF-097565. Bioassay-guided fractionation of this extract led to the identification and isolation of herbarin (1), 1-hydroxydehydroherbarin (4) plus other three naphthoquinone derivatives of which 3 and 5 are new natural products and 2 is herein described from a natural source for the first time. Four of these compounds (1, 3, 4 and 5) confirmed a specific cytotoxic effect against the human breast cancer cell line MCF-7. To evaluate the therapeutic potential of the compounds isolated, their efficacy was validated in 3D cultures, a cancer model of higher functionality. Additionally, an in-depth study was carried out to test the effect of the compounds in terms of cell mortality, sphere disaggregation, shrinkage, and morphology. The cell profile of the compounds was also compared to that of known cytotoxic compounds with the aim to distinguish the drug mode of action (MoA). The profiles of 1, 3 and 4 showed more biosimilarity between them, different to 5, and even more different to other known cytotoxic agents, suggesting an alternative MoA responsible for their cytotoxicity in 3D cultures.

Prognostic effect of systematic geriatric assessment on patients with acute heart failure.

AIMS: Frailty and dependence are frequent in patients admitted for acute heart failure (AHF), but their prognostic significance is unknown, especially in young adults. We aimed to study in adults admitted for AHF, regardless of age, the effect of frailty and dependence on the incidence of mortality and a combined event of mortality, readmissions for AHF, and visits to the emergency room (ER) for AHF at 1 and 6 months. METHODS AND RESULTS: We designed a prospective cohort study by including all the patients with AHF admitted in our Cardiology Department from July 2020 through May 2021. A multidimensional geriatric assessment was performed during the admission. We clinically followed up the patients 6 months after discharge. We enrolled 202 patients. The mean age was 73 ± 12.32 years, and 100 (49.5%) of the patients were elderly (>75 years). Just 78 patients (38.6%) were women, and 100 (49.5%) had previous HF. Frailty (FRAIL ≥ 3) was observed in 68 (33.7%) patients (mean FRAIL score: 1.88 ± 1.48). Dependence (Barthel < 100) was observed in 65 (32.2%) patients (mean Barthel index: 94.38 ± 11.21). Frailty and dependence showed a significant association with both prognostic events at 1 and 6 months. In the multivariable analysis, frailty was associated with higher mortality at 1 month [hazard ratio (HR) 12.61, 95% confidence interval (CI) 1.57-101.47, P = 0.017] but not at 6 months (HR 2.25, 95% CI 0.61-8.26, P = 0.224) or with the combined endpoint at neither 1 month (HR 1.64, 95% CI 0.54-5.03, P = 0.384) nor 6 months (HR 1.35, 95% CI 0.75-2.46, P = 0.320). Dependence was related to higher mortality at 1 month (HR 13.04, 95% CI 1.62-104.75, P = 0.016) and 6 months (HR 7.18, 95% CI 1.99-25.86, P = 0.003) and to higher incidence of the combined event at 1 month (HR 5.93, 95% CI 1.63-21.50, P = 0.007) and 6 months (HR 2.62, 95% CI 1.49-4.61, P = 0.001). CONCLUSIONS: In AHF patients, frailty and dependence implied a worse prognosis, rising mortality, readmissions, and ER visits for AHF.

Invasive pulmonary aspergillosis following human metapneumovirus infection in solid-organ transplant recipients: Another virus to add to the list.

There is increasing recognition that respiratory viral infections such as influenza, respiratory syncytial virus, parainfluenza virus, adenovirus, and SARS-CoV-2 can promote the development of invasive fungal pulmonary coinfections, particularly invasive aspergillosis, both in immunocompetent and immunocompromised patients. To date, there are no case reports exploring the role of human metapneumovirus as a risk factor for fungal coinfection. Below, we describe the case of a 63-year-old woman who received a kidney transplant and developed invasive pulmonary aspergillosis after a human metapneumovirus infection and discuss the possible phenomena that could favor this association.

Validation of the 10-Item Unilateral Vocal Fold Paralysis-Handicap Index quality of life questionnaire.

OBJECTIVES: To validate and test the reliability of the 10-Item Unilateral Vocal Fold Paralysis-Voice Handicap Index (UVFP-HI-10) quality of life (QoL) questionnaire for patients with UVFP. DESIGN: Prospective describe study based on perceptive surveys. PARTICIPANTS: We recruited 61 patients with UVFP and 53 healthy individuals comprised the control group. MAIN OUTCOME MEASURES: Both the patients and controls completed the UVFP-HI-10 questionnaire. A statistical analysis was performed to assess the internal consistency and validity of the survey. In addition, maximum phonation time (MPT) was used to objectively measure patient QoL. RESULTS: Internal consistency was high (α = .914) and the correlation with MPT was significant (rs = -0.722). The estimated marginal mean in the discriminant validity study was around seven times higher in the UVFP group compared to the controls. The UVFP-HI-10 cut-off value was more than 0.9 and the sensitivity and specificity were more than 0.8. CONCLUSIONS: The UVFP-HI-10 is a self-administered patient-reported outcome questionnaire with a high reliability and excellent criterion-based validity. This questionnaire can be used to evaluate specific clinical complaints (e.g., vocalisation, swallowing, and breathing) in terms of their impact on QoL in patients with UVFP. Thus, its use is appropriate as a basic assessment tool as part of a specific UVFP treatment protocol.

How to assess eating disorder severity in males?The DSM-5 severity index versus severity based on drive for thinness.

Using a male eating disorder (ED) sample, this study assessed the clinical utility of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) severity indices for males with anorexia nervosa (AN) and bulimia nervosa (BN) and compared it to an alternative transdiagnostic severity categorisation based on drive for thinness (DT). The participants included 143 males with an ED (60 [42.0%] AN and 83 [58.0%] BN) diagnosis, who were classified using these two severity classifications. The different severity categories were then compared based on ED symptoms, general psychopathology, and personality traits. Our results revealed that the DSM-5 "mild" and DT "low" severity categories were most prevalent in the AN and BN male patients. Clinically significant findings were strongest for the DT categorisation for both AN and BN. The current findings provide initial support for an alternative transdiagnostic DT severity classification for males that may be more clinically meaningful than the DSM-5 severity indices.

Identifying keystone connectivity spots under climate change: Implications to conservation and management of riparian systems.

Climate change has intensified the effects of habitat fragmentation in many ecosystems, particularly exacerbated in riparian habitats. Therefore, there is an urgent need to identify keystone connectivity spots to ensure long-term conservation and sustainable management of riparian systems as they play a crucial role for landscape connectivity. This paper aims to identify critical areas for connectivity under two contrasting climate change scenarios (RCP 4.5 and RCP 8.5 models) for the years 2030, 2050 and 2100 and to group these critical areas by similar connectivity in keystone spots for sustainable management. A set of analyses comprising climate analysis, drainage network analysis, configuration of potential riparian habitats, riparian habitat connectivity, data clustering, and statistical analysis within a Spanish river basin (NW Spain) were applied. The node and link connectivity would be reduced under the two climate change scenarios (≈2.5 % and 4.4 % reduction, respectively), intensifying riparian habitat fragmentation. Furthermore, 51 different clusters (critical areas) were obtained and classified in five classes (keystone spots) with similar connectivity across the different scenarios of climate change. Each keystone spot obtained by hierarchical classification was associated with one or more climate scenarios. One of these keystone spots was especially susceptible to the worst climate change scenario. Key riparian connectivity spots will be crucial for the management and restoration of highly threatened riparian systems and to ensure long-term biodiversity conservation.

Factors influencing xerostomia and oral health-related quality of life in polymedicated patients.

OBJECTIVES: To evaluate whether the severity of xerostomia in older polymedicated patients impacts oral health-related quality of life (OHRQoL). BACKGROUND: Medication-associated xerostomia is common in older people. Xerostomia may impair OHRQoL. MATERIALS AND METHODS: This cross-sectional study included older hypertensive patients from two health centres. We assessed the severity of xerostomia and OHRQoL using the Xerostomia Inventory (XI) tool, and the Oral Health Impact Profile-14 (OHIP-14) instrument, respectively. We measured unstimulated (UWS) and stimulated (SWS) salivary flows. Univariate and multiple linear regression analyses evaluated the associations of XI and OHIP-14 and different explanatory variables. RESULTS: Of the 218 patients enrolled, 51.8% had xerostomia, and 38.1% and 27.5% suffered from UWS and SWS hyposalivation, respectively. Patients with xerostomia, UWS, and SWS hyposalivation scored significantly higher on the XI. However, only those with xerostomia or UWS hyposalivation had significantly higher OHIP-14 scores. A moderate correlation was observed between XI and OHIP-14 scores. The multiple regression model showed that factors with the greatest impact on XI were the patient's complaint of xerostomia, UWS flow rate, age and sex. However, only the XI score was significantly associated with the OHIP-14 score. CONCLUSION: Xerostomia has a negative impact on OHRQoL in older polymedicated patients, but this impact is less than in other types of xerostomia. Longitudinal studies are needed to determine whether changes in the detected explanatory variables influence XI and OHIP scores in these patients.

Impulsivity and compulsivity in gambling disorder and bulimic spectrum eating disorders: Analysis of neuropsychological profiles and sex differences.

BACKGROUND: Gambling disorder (GD) and bulimic spectrum eating disorders (BSDs) not only share numerous psychopathological, neurobiological, and comorbidity features but also are distinguished by the presence of inappropriate behaviours related to impulsivity and compulsivity. This study aimed to emphasise the differences and similarities in the main impulsivity and compulsivity features between GD and BSD patients, and to analyse the potential influence of sex in these domains. METHODS: Using self-reported and neurocognitive measures, we assessed different impulsive-compulsive components in a sample of 218 female and male patients (59 with BSD and 159 with GD) and 150 healthy controls. RESULTS: We observed that GD and BSDs exhibited elevated levels of impulsivity and compulsivity in all the dimensions compared to healthy controls. Moreover, these disorders showed differences in several personality traits, such as high novelty seeking in GD, and low persistence and high harm avoidance in BSDs. In addition, patients with BSDs also displayed a trend towards greater impulsive choice than GD patients. Regarding sex effects, GD women presented higher overall impulsivity and compulsivity than GD men. Nevertheless, no sex differences were found in BSDs. CONCLUSIONS: Clinical interventions should consider these deficits to enhance their effectiveness, including adjunctive treatment to target these difficulties. Our findings also provide support to the relevance of sex in GD, which should also be considered in clinical interventions.