Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis.

Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to the de novo synthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus.IMPORTANCE An appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis.

The initial age-associated decline in early T-cell progenitors reflects fewer pre-thymic progenitors and altered signals in the bone marrow and thymus microenvironments.

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre-thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre-thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age-associated thymus involution.

Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program.

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies. SIGNIFICANCE: New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities. See related commentary by Stieg et al., p. 1046. See related article by Choe et al., p. 1250. This article is highlighted in the In This Issue feature, p. 1027.

Lung Cancer Screening: Survival in an Extensive Early Detection Program in Spain (I-ELCAP). / Cribado de cáncer de pulmón: Supervivencia en un amplio programa de detección precoz en España (I-ELCAP).

INTRODUCTION: Lung cancer (LC) is usually diagnosed at advanced stages with only a 12% 5-year survival. Trials as NLST and NELSON show a mortality decrease, which justifies implementation of lung cancer screening in risk population. Our objective was to show survival results of the largest LC screening program in Spain with low dosage computed tomography (LDCT). METHODS: Clinical records from International Early Lung Cancer Detection Program (IELCAP) at Valencia, Spain were analysed. This program recruited volunteers, ever-smokers aged 40-80 years, since 2008. Results are compared to those from other similar sizeable programs. RESULTS: A total of 8278 participants were screened with at least two-rounds until November 2020. A mean of 6 annual screening rounds were performed. We detected 239 tumours along 12-year follow-up. Adenocarcinoma was the most common histology, being 61.3% at stage I. The lung cancer prevalence and incidence proportion was 1.5% and 1.4%, respectively with an annual detection rate of 0.17. One-year survival and 10-year survival were 90% and 80.1%, respectively. Adherence was 96.84%. CONCLUSION: Largest lung cancer screening in Spain shows that survival is improved when is performed in multidisciplinary team experienced in management of LC, and is comparable to similar screening programs.

Linguistic Competence in Early Childhood Education as a Predictor of Verbal Naming Speed.

BACKGROUND: This study determined the predictive value of linguistic competence in children in Early Childhood Education for verbal naming speed. METHOD: The participants were 86 pupils in the second Early Childhood Education cycle. They were evaluated with WPPSI-IV Wechsler Preschool & Primary Scale of Intelligence (Verbal Comprehension, VC) and Vocabulary Acquisition, VA; Childish Vocabulary Test (Vavel) and the Rapid and Automatic Naming Test. RESULTS: Children who had high scores in the Verbal Comprehension Index and Vocabulary Acquisition spent less time doing the verbal naming task. Linguistic competence predicted verbal naming speed, with Vavel having the strongest correlation. CONCLUSIONS: Linguistic competence of children in Early Childhood Education allows us to predict their aptitude for verbal naming. Lexical-semantic knowledge was linguistic competence dimension with the highest predictive value for the Verbal Naming Task. Automatic Naming and Verbal Comprehension depend on the same cerebral area, Wernicke's area.

Lung Cancer Screening: Use of Low-Dose Computed Tomography. / Diagnóstico precoz del cáncer de pulmón: utilidad de la tomografía computarizada de baja dosis de radiación.

INTRODUCTION: The prognosis of lung cancer (LC) correlates directly with the stage of the disease at the time of diagnosis. MATERIAL AND METHODS: We performed low-dose CT (LDCT) in asymptomatic individuals ≥50years old, smokers or former smokers of ≥10 pack-years, with no history of cancer. We followed an evaluation algorithm, according to the size and morphology of the nodules. The appropriate treatment for the LC diagnosis was given and patients were followed up for 5years. RESULTS: We studied 4,951 individuals (65.4% males) with an average age of 56.89±5.26years; 550 presented nodules. Of the 3,891 nodules detected, 692 (19.57%) were considered positive, and 38 tumors (36LC) were identified. In the annual follow-up, nodules were found in 224 subjects, 288 (7.91%) of which were positive (13LC). In 80%, the study was performed with LDCT, and biopsy was indicated in 5.8% (baseline) and in 7.6% (annual) of the positive nodules. Prevalence was 0.89 and incidence was 0.1%. The sensitivity, specificity, PPV and NPV in the baseline study were 92.31, 89.54, 6.55 and 99.93%, respectively, and in the annual study, they were 76.92, 95.7, 4.52 and 99.94%, respectively. A total of 52 tumors were detected (49LC), 25 (52.08%) in stageI. The 5-year overall survival rate for LC was 58.5% and cancer-specific survival was 67.1% (75.8% in surgical patients). CONCLUSION: LDCT integrated into an elaborate nodule detection and evaluation program is a useful tool for diagnosing early-stage LC.

[Contribution of exhaled nitric oxide measurements to abbreviated bronchial challenge test protocols]. / Aportaciones del óxido nítrico exhalado a los procedimientos abreviados de las pruebas de provocación bronquial.

OBJECTIVE: The bronchial challenge test is commonly used to diagnose asthma but it is a tedious, time-consuming procedure. Although in recent years, several shortened methods have been proposed, it has been shown that they can give rise to exaggerated bronchoconstriction. The aims of the present study were a) to determine the frequency of exaggerated bronchoconstriction in patients with asthma following the application of a shortened bronchial challenge test, and b) to determine if the fraction of exhaled nitric oxide (FENO) can be used to predict the onset of exaggerated bronchoconstriction. PATIENTS AND METHODS: We performed a prospective study of 210 patients with asthma in whom FENO levels were measured in accordance with the abbreviated protocol recommended by the European Respiratory Society (ERS). Exaggerated bronchoconstriction was defined as a decrease of more than 20% in forced expiratory volume in 1 second after the first challenge, after a skipped dose, or after administration of saline. A receiver operating characteristic (ROC) curve was generated to determine the best FENO cutoff value for predicting exaggerated bronchoconstriction. The pretest probability of developing exaggerated bronchoconstriction was also calculated using Bayes' theorem. RESULTS: The frequency of exaggerated bronchoconstriction in our series was 30%. Patients who developed exaggerated bronchoconstriction had significantly higher FENO levels than those who did not (32.6 vs 16.2 parts per billion [ppb]). The chosen FENO cutoff of 19.5 ppb had a sensitivity of 80%, a specificity of 77%, and a negative predictive value of 88%. The area under the ROC curve was 0.83 (95% confidence interval, 0.77-0.89). CONCLUSIONS: The abbreviated bronchial challenge test recommended by the ERS led to exaggerated bronchoconstriction in 30% of the patients studied. FENO measurements could possibly be used to identify patients at increased risk of exaggerated bronchoconstriction. The shortened challenge test can be performed safely in individuals with a FENO of <19.5 ppb.

[Acute intermittent porphyria and chronic transaminase elevation]. / Porfiria aguda intermitente y elevación crónica de las transaminasas.

Acute intermittent porphyria is an autosomal dominant inherited disorder resulting from a deficiency of porphobilinogen deaminase activity, the third enzyme in the heme biosynthesis pathway. This disease is uncommon, although the prevalence is higher in asymptomatic heterozygotic carriers; however, this prevalence is difficult to establish because of the absence of symptoms. Although acute intermittent porphyria is a multisystemic disease, its most common form of presentation is abdominal pain and neurological or mental symptoms, which can sometimes be due to precipitating factors such as reduced energy intake, smoking, alcohol, some drugs, and stress. Diagnosis can be made by testing urinary porphobilinogen levels, with subsequent measurement of enzyme activity and DNA testing. Treatment is based on prevention of porphyria attacks by avoiding precipitating factors and early administration of intravenous glucose or hemin therapy. We present the case of a patient diagnosed with acute intermittent porphyria based on study of chronic mild alanine aminotransferase (ALT) elevation.

Murine cytomegalovirus M72 promotes acute virus replication in vivo and is a substrate of the TRiC/CCT complex.

Betaherpesvirus dUTPase homologs are core herpesvirus proteins, but little is known about their role during infection. Human cytomegalovirus (HCMV) UL72 and murine cytomegalovirus (MCMV) M72 have been designated dUTPase homologs, and previous studies indicate UL72 is dispensable for replication and enzymatically inactive. Here, we report the initial characterization of MCMV M72. M72 does not possess dUTPase activity, and is expressed as a leaky-late gene product with multiple protein isoforms. Importantly, M72 augments MCMV replication in vitro and during the early stage of acute infection in vivo. We identify and confirm interaction of M72 with the eukaryotic chaperonin tailless complex protein -1 (TCP-1) ring complex (TRiC) or chaperonin containing tailless complex polypeptide 1 (CCT). Accumulating biochemical evidence indicates M72 forms homo-oligomers and is a substrate of TRiC/CCT. Taken together, we provide the first evidence of M72's contribution to viral pathogenesis, and identify a novel interaction with the TRiC/CCT complex.

The HIDEA School-Based Screening Scale for Teachers to Detect ADHD Markers in Elementary Students.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with academic difficulties both short- and long-term. The aim of the study was to provide a new brief ADHD screening scale that could be easily used by teachers and educational professionals in elementary schools. METHOD: Participants were teachers of 158 children with a prior diagnosis of ADHD and 169 children without a diagnosis of ADHD. An initial pool of 38 items was generated from ADHD symptoms of both DSM-5 and CIE-10 criteria, as well from Conners 3, EDAH, SDQ and ADHD-RS-IV scales. RESULTS: A 5-item model showed the best fit (c2 = 7.04; d.f. = 5; p = .218; RMSEA = .035; CFI = .999; TLI = .999). The HIDEA total score was highly correlated with both ADHD-IN (r = .93; p<.001) and ADHD-HY (r = .87; p<.001). The ROC curve for the HIDEA total score gave an AUC value of .998 (95%, CI = [.994, 1.000]). HIDEA scale showed a good sensitivity (97%) and very good specificity (3%). CONCLUSION: The HIDEA scale has shown adequate psychometric properties. It is potentially useful for screening ADHD in elementary grade as part of a preventive strategies in school settings.

[Orthogeriatrics: The First multicentre regional register of hip fractures in Castilla y León (Spain)]. / Ortogeriatría: primer registro multicéntrico autonómico de fracturas de cadera en Castilla y León (España).

OBJECTIVE: The objective of this study is to describe the characteristics of the patients with hip fracture admitted to the Public Hospitals of Castilla y León during three monthly periods (November 2014, and October and November 2015). MATERIAL AND METHOD: The Castilla y León orthogeriatrics work group created a common register to collect data on hip fractures. The study included patients 75 years-old and over hospitalised with hip fractures in the 13 public hospitals in the community during November 2014, and October and November 2015. A multicentre, prospective, and observational study was conducted, in which clinical, functional, and social variables, as well as in-hospital mortality, were collected. RESULTS: The analysis included data from a total of 776 patients with a mean age of 86 (±6) years. The surgical delay was 4±2.8 days, and the mean hospital stay was 10±4.7 days. The anaesthesia risk was ASA 3±0.6. Around two-thirds (66.5%) of the patients had medical complications while in hospital, and 55.5% required a transfusion. In-hospital mortality was 4.6%. The mean pre-surgical stay was related to the overall stay: P<.001. CONCLUSIONS: Hip fracture registers are an essential tool for evaluating the process and for improving the treatment quality of these patients. This is the first multicentre register of hip fracture in the elderly created in a Spanish region, and could be a good precedent reference for a future national register.

Differentiation of benign and malignant lung lesions: Dual-Energy Computed Tomography findings.

PURPOSE: To determine whether parameters generated by Dual-Energy Computed Tomography (DECT) can distinguish malignant from benign lung lesions. METHODS: A prospective review of 125 patients with 126 lung lesions (23 benign and 103 malignant) who underwent lung DECT during arterial phase. All lesions were confirmed by tissue sampling. A radiologist semi-automatically contoured lesions and placed regions of interest (ROIs) in paravertebral muscle (PVM) for normalization. Variables related to absorption in Hounsfield units (HU), effective atomic number (Zeff), iodine concentration (ρI) and spectral CT curves were assessed. Receiver operating characteristic (ROC) curves were generated to calculate sensitivity and specificity as predictors of malignancy. Multivariate logistic regression analysis was performed. RESULTS: Reproducibility of measures normalized with PVM was poor. Bivariate analysis showed minimum Zeff and normalized mean Zeff to be statistically significant (p=0.001), with area under the curve (AUC) values: 0.66 (CI 95% 0.54-0.80) and 0.72 (CI 95%, 0.60-0.84), respectively. Logistic regression models showed no differences between raw and normalized measurements. In both models, minimum HU (OR: 0.9) and size (OR: 0.1) were predictive of benign lesions. CONCLUSIONS: A quantitative approach to DECT using raw measurements is simpler than logistic regression models. Normalization to PVM was not clinically reliable due to its poor reproducibility. Further studies are needed to confirm our findings.

[Orthogeriatric activity in public hospitals of Castilla y León: description and review of the literature]. / Actividad ortogeriátrica en los hospitales públicos de Castilla y León: descripción y revisión de la literatura.

The benefits of the collaboration between orthopaedics and geriatrics in the management and care of elderly patients admitted with hip fracture have been widely demonstrated. A questionnaire was sent to all hospital geriatricians of Castilla y León in order to determine the characteristics this collaboration between orthopaedics and geriatrics in the public hospitals of Castilla y León. They were asked about the type of collaboration with orthopaedics in the care of the elderly patient admitted with hip fracture and details of the treatment of the complications. Most of the hospitals maintain a high level of orthogeriatric collaboration with geriatricians, and the geriatrician attends to most of the medical complications of these patients. The average hospital stay is 10 days, with a surgical delay of 3 days. Management of the most frequent clinical problems in hospitals of Castilla y León are detailed in this article, comparing them with the latest articles and current recommendations from clinical practice guides.