Evaluation of the PECARN rule for traumatic brain injury applied to infants younger than 3 months and creation of a modified, age-specific rule.

Infants < 3 months with minor head trauma (MHT) are a particularly vulnerable group, though few studies have focused specifically on these patients. We aimed to evaluate the application of the PECARN prediction rule, designed for clinically important traumatic brain injury (ciTBI) in children < 2 years in infants < 3 months, and create a specific prediction rule for this population. We conducted a prospective multicenter observational study in 13 pediatric emergency departments (PEDs) in Spain. The PECARN rule was applied to all patients. A new specific prediction rule for infants < 3 months of age was created. The main outcome measures were (1) ciTBI, (2) TBI evidenced on computed tomography (CT) scan, and (3) isolated skull fracture (ISF). Telephone follow-up was conducted for all patients over the 4 weeks after the initial PED visit. Of 21,981 children with MHT, 366 (1.7%) were < 3 months old and 195 (53.3%) underwent neuroimaging, including 37 (10.1%) with CT scan. The sensitivity and negative predictive value (NPV) of the PECARN prediction rule for ciTBI were 100% (95% CI, 20.7-100) and 99.7% (95% CI, 98.4-100%), respectively. Of the 230 infants (62.8%) who met the PECARN low-risk criteria, none had ciTBI, 1 (0.4% overall, 95% CI, 0-2.4) had TBI on CT, and 2 (0.9% overall; 95% CI, 0.1-3.1) had an ISF. Among the 136 infants (37.2%) who did not meet the PECARN low-risk criteria, 1 (0.3% overall; 95% CI, 0-1.5) had ciTBI, 11 (8.1% overall; 95% CI, 4.1-14.0) had TBI on CT, and 18 (13.2% overall; 95% CI, 8-20.1) had an ISF. The sensitivity and NPV of the Spanish prediction rule for ciTBI were 100% (95% CI, 20.7-100) and 100% (95% CI, 98.4-100%), respectively. No infants in the registry developed complications during follow-up. CONCLUSION: The PECARN rule for infants < 2 years old accurately identified infants < 3 months old at low risk for ciTBI in our population, although the adapted Spanish rule presented here could be even more accurate. WHAT IS KNOWN: • Infants younger than 3 months are vulnerable to minor blunt head trauma due to their age and to difficulties in assessing the subtle symptoms and minimal physical findings detected on examination. • A low threshold for CT scan is recommended in this population. WHAT IS NEW: • PECARN rule for infants < 2 years old is an adequate tool with which to identify infants < 3 months old at low risk for clinically important traumatic brain injury. • Spanish rule could identify even more low-risk infants without overlooking important outcomes but it should be validated to confirm its predictive capacity.

Author Correction: Rapid and efficient induction of functional astrocytes from human pluripotent stem cells.

In the version of Supplementary Fig. 1 originally published with this paper, some images in panel e were accidental duplicates of images in panel b. This error has been corrected in the online integrated supplementary information and in the Supplementary Information PDF.

Epidemiology of minor blunt head trauma in infants younger than 3 months.

Specific knowledge of the features of minor head trauma in infants is necessary to develop appropriate preventive strategies and adjust clinical management in pediatric emergency departments (PEDs). The aim of this study is to describe the epidemiology of minor blunt head trauma in infants < 3 months who present to PEDs. We performed a prospective study of infants evaluated in any of 13 Spanish PEDs within 24 h of a minor head trauma (Glasgow Coma Scale scores of 14-15) between May 2017 and November 2020. Telephone follow-up was conducted for all patients over the 4 weeks after the initial PED visit. Of 1,150,255 visits recorded, 21,981 children (1.9%) sustained a head injury, 386 of whom (0.03%) were under 3 months old. Among the 369 patients who met the inclusion criteria (0.03%), 206 (56.3%) were male. The main causes of trauma were fall-related (298; 80.8%), either from furniture (138/298; 46.3%), strollers (92/298; 30.9%), or a caregiver's arms (61/298; 20.5%). Most infants were asymptomatic (317; 85.9%) and showed no signs of injury on physical exam (210; 56.9%). Imaging studies were performed in 195 patients (52.8%): 37 (10.0%) underwent computed tomography (CT) scan, 162 (43.9%) X-ray, and 22 (6.0%) ultrasound. A clinically important traumatic brain injury (ciTBI) occurred in 1 infant (0.3% overall; 95% CI, 0-1.5), TBI was evidenced on CT scan in 12 (3.3% overall; 95% CI, 1.7-5.7), and 20 infants had an isolated skull fracture (5.5% overall; 95% CI, 3.4-8.3). All outcomes were caused by falls onto hard surfaces. CONCLUSION:  Most head injuries in infants younger than 3 months are benign, and the rate of ciTBI is low. Prevention strategies should focus on falls onto hard surfaces from furniture, strollers, and caregivers' arms. Optimizing imaging studies should be a priority in this population. WHAT IS KNOWN: • Infants younger than 3 months are vulnerable to minor blunt head trauma due to their age and to difficulties in assessing the subtle symptoms and minimal physical findings detected on examination. • A low threshold for CT scan is recommended in this population. WHAT IS NEW: • Most cases of blunt head trauma in infants younger than 3 months have good outcomes, and the rate of clinically important traumatic brain injury is low. • Optimizing imaging studies should be a priority in this population, avoiding X-ray examinations and reducing unnecessary CT scans.

Rapid and efficient induction of functional astrocytes from human pluripotent stem cells.

The derivation of astrocytes from human pluripotent stem cells is currently slow and inefficient. We demonstrate that overexpression of the transcription factors SOX9 and NFIB in human pluripotent stem cells rapidly and efficiently yields homogeneous populations of induced astrocytes. In our study these cells exhibited molecular and functional properties resembling those of adult human astrocytes and were deemed suitable for disease modeling. Our method provides new possibilities for the study of human astrocytes in health and disease.

Use of adenosine in the treatment of supraventricular tachycardia in a pediatric emergency department.

OBJECTIVE: Supraventricular tachycardia (SVT) is the most frequent arrhythmia requiring treatment in childhood, with an estimated incidence of 1/100 to 1/250 children. The treatment of choice of the acute event is intravenous adenosine. This study aimed to determine if doses of adenosine higher than previously described are needed to successfully revert SVT in children. METHODS: This is a retrospective study of SVT cases in a tertiary hospital from January 2007 to December 2011. RESULTS: A total of 44 episodes of SVT were recorded in 26 patients. Mean age was 3.1 years. In 39 patients (89%), adenosine was administered, reverting to stable sinus rhythm in 29 episodes, which represents an effectiveness of 75%. In relation to the number of doses administered, 12 patients (30%) received a single dose, with a mean (SD) response dose of 112 (35) µg/kg; 16 (41%) received 2 doses, with a mean (SD) response dose of 188 (55) µg/kg; and 9 (24%) received 3 doses, with a mean (SD) response dose of 249 (108) µg/kg. Finally, in 2 patients (4%), 4 doses of adenosine were administered, with only 1 of them responding to a dose of 300 µg/kg. The mean (SD) dose that reverted the SVT to normal sinus rhythm was 173 (84) µg/kg, and the mean (SD) number of doses administered was 1.7 (0.8) (range, 1-4). Sixty-six percent were discharged home, without the need to be transferred to pediatric intensive care unit or pediatric ward. CONCLUSIONS: Most of the patients with SVT episodes require treatment with more than 1 dose of adenosine. Doses higher than the usually described in the guidelines are necessary to revert SVT. Most patients can be discharged home from the emergency department, without the need of hospital admission.

Temporal dynamics of TNF-mediated changes in hematopoietic stem cell function and recovery.

While tumor necrosis factor (TNF) is a critical mediator of appropriate immune response and tissue repair, its misregulation is linked to cancer, autoimmunity, bone marrow failure, and aging. Understanding the context-dependent roles of TNF is essential for elucidating normal and pathogenic conditions and to guide clinical therapy advancements. Prior studies suggested that TNF restricts the self-renewal capacity of hematopoietic stem cells (HSCs), but its long-term effect on HSCs remains unclear. Here, we demonstrate that in vivo TNF administration results in a transient exit of HSCs from quiescence, which coincides with a compromised repopulation capacity. These functional changes are; however, fully reversible even following prolonged/chronic transient exposure to TNF. Notably, antagonizing TNF signaling in transplantation recipients enhances donor HSC reconstitution. Our findings provide molecular and functional insight into HSC regulation, with implications for both acute and chronic inflammatory conditions.

COVID-19 and tourism sector stock price in Spain: medium-term relationship through dynamic regression models.

The global pandemic, coronavirus disease 2019 (COVID-19), has significantly affected tourism, especially in Spain, as it was among the first countries to be affected by the pandemic and is among the world's biggest tourist destinations. Stock market values are responding to the evolution of the pandemic, especially in the case of tourist companies. Therefore, being able to quantify this relationship allows us to predict the effect of the pandemic on shares in the tourism sector, thereby improving the response to the crisis by policymakers and investors. Accordingly, a dynamic regression model was developed to predict the behavior of shares in the Spanish tourism sector according to the evolution of the COVID-19 pandemic in the medium term. It has been confirmed that both the number of deaths and cases are good predictors of abnormal stock prices in the tourism sector.

Variability in the management of infants under 3 months with minor head injury in paediatric emergency departments.

INTRODUCTION: In the assessment of infants younger than 3 months with minor traumatic head injury (MHI), it is essential to adapt the indication of imaging tests. The Pediatric Head Injury/Trauma Algorithm (PECARN) clinical prediction rule is the most widely used to guide clinical decision making. OBJECTIVES: To analyse the variability in the performance of imaging tests in infants under 3 months with MHI in paediatric emergency departments (PEDs) and the adherence of each hospital to the recommendations of the PECARN rule. POPULATION AND METHODS: We conducted a prospective multicentre observational study in 13 paediatric emergency departments in Spain between May 2017 and November 2020. RESULTS: Of 21 981 children with MHI, 366 (1.7%) were aged less than 3 months; 195 (53.3%) underwent neuroimaging, with performance of CT scans in 37 (10.1%; interhospital range, 0%-40.0%), skull X-rays in 162 (44.3 %; range, 0%-100%) and transfontanellar ultrasound scans in 22 (6.0%; range, 0%-24.0%). The established recommendations were followed in 25.6% (10/39) of infants classified as high-risk based on PECARN criteria (range, 0%-100%); 37.1% (36/97) classified as intermediate-risk (range, 0%-100%) and 57.4% (132/230) classified as low-risk (range, 0%-100%). CONCLUSION: We found substantial variability and low adherence to the PECARN recommendations in the performance of imaging tests in infants aged less than 3 months with MHI in Spanish PEDs, mainly due to an excessive use of skull X-rays.

Oligodendrocytes in human induced pluripotent stem cell-derived cortical grafts remyelinate adult rat and human cortical neurons.

Neuronal loss and axonal demyelination underlie long-term functional impairments in patients affected by brain disorders such as ischemic stroke. Stem cell-based approaches reconstructing and remyelinating brain neural circuitry, leading to recovery, are highly warranted. Here, we demonstrate the in vitro and in vivo production of myelinating oligodendrocytes from a human induced pluripotent stem cell (iPSC)-derived long-term neuroepithelial stem (lt-NES) cell line, which also gives rise to neurons with the capacity to integrate into stroke-injured, adult rat cortical networks. Most importantly, the generated oligodendrocytes survive and form myelin-ensheathing human axons in the host tissue after grafting onto adult human cortical organotypic cultures. This lt-NES cell line is the first human stem cell source that, after intracerebral delivery, can repair both injured neural circuitries and demyelinated axons. Our findings provide supportive evidence for the potential future use of human iPSC-derived cell lines to promote effective clinical recovery following brain injuries.

Is it possible to treat nonalcoholic liver disease using a flavanol-based nutraceutical approach? Basic and clinical data.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of diseases, ranging from simple steatosis to hepatocellular carcinoma. The main factors for NAFLD are closely related to obesity, insulin resistance, intestinal microbiota alterations, hyperinsulinism, low-grade systemic inflammation, nitroxidative stress, lipid peroxidation, and mitochondrial dysfunction. Currently, the treatment of NAFLD is based on diet and exercise because, to date, there is no specific pharmacological agent, already approved, that raises the need for new therapeutic strategies. Nutraceuticals, such as polyphenols, have potential beneficial effects for health. In this article, the beneficial effects of epigallocatechin-3-gallate (EGCG) and (-)-epicatechin (EC) are discussed. EGCG is the main catechin in green tea, which has shown in various studies its potential effect preventing and treating NAFLD since it has shown antihyperlipidemic, anti-inflammatory, antifibrotic, antioxidant, and improvement of liver lipid metabolism. However, it has been found that excessive consumption may cause hepatotoxicity. EC is widely distributed in nature (fruits and vegetables). This flavanol has shown many beneficial effects, including antihypertensive, anti-inflammatory, anti-hyperglycemic, antithrombotic, and antifibrotic properties. It increases mitochondrial biogenesis, and it also has effects on the regulation of synthesis and metabolism of lipids. This flavanol is a nontoxic substance; it has been classified by the United States Food and Drug Administration as harmless. The EC-induced effects can be useful for the prevention and/or treatment of NAFLD.

Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress.

The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly, and Bmi1 expression wanes as cells differentiate. Furthermore, Bmi1 has been found to be overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have used loss-of-function models, which have established Bmi1 as an important regulator for HSC maintenance. Additionally, gain-of-function studies using retroviral and lentiviral approaches have observed increased self-renewal of Bmi1-transduced HSCs. However, the clinical and biological relevance of such studies is typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we describe how we developed a novel tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We found that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or after 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild-type recipients resulted in marked increases in the number and chimerism of HSCs. These data, in concert with previous loss-of-function studies, suggest that although endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSCs from transplantation-associated stress.

In silico evaluation of flavonoids as potential inhibitors of SARS-CoV-2 main nonstructural proteins (Nsps)-amentoflavone as a multitarget candidate.

Despite the development of vaccines against COVID-19 disease and the multiple efforts to find efficient drugs as treatment for this virus, there are too many social, political, economic, and health inconveniences to incorporate a fully accessible plan of prevention and therapy against SARS-CoV-2. In this sense, it is necessary to find nutraceutical/pharmaceutical drugs as possible COVID-19 preventives/treatments. Based on their beneficial effects, flavonoids are one of the most promising compounds. Therefore, using virtual screening, 478 flavonoids obtained from the KEGG database were evaluated against non-structural proteins Nsp1, Nsp3, Nsp5, Nsp12, and Nsp15, which are essential for the virus-host cell infection, searching for possible multitarget flavonoids. Amentoflavone, a biflavonoid found mainly in Ginkgo biloba, Lobelia chinensis, and Byrsonima intermedia, can interact and bind with the five proteins, suggesting its potential as a multitarget inhibitor. Molecular docking calculations and structural analysis (RMSD, number of H bonds, and clustering) performed from molecular dynamics simulations of the amentoflavone-protein complex support this potential. The results shown here are theoretical evidence of the probable multitarget inhibition of non-structural proteins of SARS-CoV-2 by amentoflavone, which has wide availability, low cost, no side effects, and long history of use. These results are solid evidence for future in vitro and in vivo experiments aiming to validate amentoflavone as an inhibitor of the Nsp1, 3, 5, 12, and 15 of SARS-CoV-2.

A somatic mutation in moesin drives progression into acute myeloid leukemia.

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg295Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.

The human bone marrow harbors a CD45- CD11B+ cell progenitor permitting rapid microglia-like cell derivative approaches.

Microglia, the immune sentinel of the central nervous system (CNS), are generated from yolk sac erythromyeloid progenitors that populate the developing CNS. Interestingly, a specific type of bone marrow-derived monocyte is able to express a yolk sac microglial signature and populate CNS in disease. Here we have examined human bone marrow (hBM) in an attempt to identify novel cell sources for generating microglia-like cells to use in cell-based therapies and in vitro modeling. We demonstrate that hBM stroma harbors a progenitor cell that we name stromal microglial progenitor (STR-MP). STR-MP single-cell gene analysis revealed the expression of the consensus genetic microglial signature and microglial-specific genes present in development and CNS pathologies. STR-MPs can be expanded and generate microglia-like cells in vitro, which we name stromal microglia (STR-M). STR-M cells show phagocytic ability, classically activate, and survive and phagocyte in human brain tissue. Thus, our results reveal that hBM harbors a source of microglia-like precursors that can be used in patient-centered fast derivative approaches.

Effects of (-)-epicatechin on the time course of the expression of perilipins in a diet-induced model of nonalcoholic steatohepatitis.

The existing treatments for nonalcoholic steatohepatitis (NASH) are not completely effective. The need for new alternatives without adverse effects and low cost, such as the flavonoid (-)-epicatechin (EC), which has beneficial effects on lipid metabolism and cardiovascular diseases, arises. The objective of this work was to analyze EC effects in the NASH induced by a Paigen-type diet (PD). Mice were administered with (1) normal chow and water, (2) PD + fructose 30% and (3) PD + fructose 30% + EC (1 mg/kg) per gavage during 9 weeks. At the end of each treatment, serum was collected for analysis of the biochemical profile and liver enzymes. The liver was collected for microscopic analysis and for the evaluation of the relative expression of Plin2, Plin3, CD36, adiponectin and UCP2. Results showed that EC reduced weight gain and decreased triglyceride (TG), low-density lipoprotein cholesterol, TG/high-density lipoprotein and the activity of liver enzymes (alanine aminotransferase and alkaline phosphatase), suggesting lower liver damage. The microscopic analysis showed less "balloonization" of the hepatocyte, small drops of lipids, less accumulation of collagen and infiltration of inflammatory cells as compared to nontreated group. Finally, a decrease in the expression of Plin 2 was observed. While CD36 decreased, adiponectin and UCP2 increased. In conclusion, EC improves the biochemical profile, the microscopic characteristics and protein expression. Therefore, it may be a possible therapeutic approach for NASH since it prevents the progression of the hepatic and metabolic damage induced by high-fat diets.

Effects of Cacao By-Products and a Modest Weight Loss Intervention on the Concentration of Serum Triglycerides in Overweight Subjects: Proof of Concept.

Therapeutic approaches to decrease serum triglyceride (TG) concentrations are not successful mainly due to poor adherence or adverse effects of therapies. In consequence, the search for new low-cost and safer therapeutic alternatives is mandatory. Dark chocolate and cacao have shown promising results improving lipid profiles. Recently, using cacao by-products to reduce elevated cardiometabolic risk markers in an animal model of obesity induced by a high-fat diet and fructose, we showed that TGs, low-density lipoprotein cholesterol, and the TG/high-density lipoprotein (HDL) ratio decreased, suggesting that cacao by-products improved the metabolic function of obese animals. Based on these results, as a proof of concept, a blinded placebo-controlled study was implemented to explore the effects of cacao by-products on anthropometric and biochemical variables in a group of overweight subjects participating in a program composed of reduced-calorie-diet counseling plus a simple aerobic exercise plan. The results showed that counseling induced weight and abdominal circumference reductions in both groups. TGs did not change in the control group; however, TG decreased significantly by 54.9 mg/dL (27.9%) in the experimental group. The TG/HDL cholesterol ratio changed markedly (1.5) in the experimental group. The results reported suggest the use of cacao by-products as an alternative for the treatment of hypertriglyceridemia.

Hif-1α Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML.

Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1α mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1α-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML.

Introducing olive-oil tourism as a special interest tourism.

Olive-oil tourism is an emerging tourism typology that is especially developing in the Mediterranean basin, though successful cases also exist in other regions of the world. The main motivation underlying olive-oil tourism demand is the desire to learn about and enjoy the world of olives and olive oil. The objective of this article is to characterise this new tourism typology and identify its main activities. Based on a thorough bibliographical review and an expert panel, we show that this tourism typology corresponds to special interest tourism, and derives from three types of general interest tourism (rural, nature and cultural) with connections to other specific types of tourism. Furthermore, we demonstrate its links to an increasingly broad range of activities and services, thus revealing how complex this type of tourism can be, a feature proper to so-called special interest tourism.

Obesity and Cardiovascular Risk Improvement Using Cacao By-Products in a Diet-Induced Obesity Murine Model.

In the production of chocolate, only cocoa seeds are used, generating by-products that are generally discarded, increasing the risk of environmental contamination. Given fiber, carbohydrates, proteins, and flavonoid content the use of cacao pod husks can generate nutraceutical products for human consumption. In contrast, obesity represents a major public health problem worldwide. Cacao derivatives are able to modulate overweight and lipid disorders. The objective of present work was to prepare and characterize products using cacao by-products and analyze their effects on altered cardiometabolic risk markers in an obesity model induced by high fat diet and fructose ingestion in rats. The effects of a pellet and extracts made with outer pod husk and kernel husk for 5 weeks were analyzed in an obesity rat model. The treatments significantly decreased body weight by 39%, systolic blood pressure by 27%, triglycerides by 55%, total cholesterol by 24%, low-density lipoprotein cholesterol by 37%, and the triglycerides/high-density lipoprotein ratio by 54%. Cacao by-products improved the metabolic function of obese animals, without causing secondary effects.