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Purpose – This study aims to evaluate the presence of abnormal returns due to stock splits or reverse stock splits in the Brazilian capital market context. Design/methodology/approach – The event study technique was used on data from 518 events that occurred in a 30-year period (1987–2016), comprising 167 stock splits and 351 reverse stock splits. Findings – The results revealed the occurrence of abnormal returns around the time the shares began trading stock splits or reverse stock splits at a statistical significance level of 5%. The main conclusion is that stock split and reverse stock split operations represent opportunities for extraordinary gains and may serve as a reference for investment strategies in the Brazilian stock market. Originality/value – This study innovates by including reverse stock splits, as the existing literature focuses on stock splits, and by testing two distinct “zero” dates that of the ordinary general meeting that approved the share alteration and the “ex” date of the alteration, when the shares were effectively traded, reverse split or split.

Taper equations are indispensable tools for characterizing the stem profile of trees, providing valuable insights for forest management, timber inventory, and optimal assortments allocation. The recent progress in Terrestrial Laser Scanning (TLS) has revolutionized forest inventory practices by enabling non-destructive data collection. In this study, four taper models from three different model categories were established based on point cloud data of 219 Pinus nigra trees. The taper equations fitted with TLS data were used to predict the diameter at specific stem heights and the total stem volume. The results show that among fitted models, the Max and Burkhart segmented model calibrated by the means of a mixed-effects approach provided the best estimate of the diameter at different heights and the total stem volume evaluated for different diameter at breast height (DBH) classes. In numerical terms, this model estimated the diameter and the volume with a respective overall error of 0.781 cm and 0.021 m3. The predicted profile also shows that above a relative height of 0.7, the diameter error tends to increase due to the low reliability of data collected beyond the base of the crown primarily caused by interference from branches and leaves. Nevertheless, this study shows that TLS technology presents a compelling opportunity and a promising non-destructive alternative for generating taper profiles and estimating tree volume.

In this study, we validated the "ReadFree tool", a computerised battery of 12 visual and auditory tasks developed to identify poor readers also in minority-language children (MLC). We tested the task-specific discriminant power on 142 Italian-monolingual participants (8-13 years old) divided into monolingual poor readers (N = 37) and good readers (N = 105) according to standardised Italian reading tests. The performances at the discriminant tasks of the "ReadFree tool" were entered into a classification and regression tree (CART) model to identify monolingual poor and good readers. The set of classification rules extracted from the CART model were applied to the MLC's performance and the ensuing classification was compared to the one based on standardised Italian reading tests. According to the CART model, auditory go-no/go (regular), RAN and Entrainment100bpm were the most discriminant tasks. When compared with the clinical classification, the CART model accuracy was 86% for the monolinguals and 76% for the MLC. Executive functions and timing skills turned out to have a relevant role in reading. Results of the CART model on MLC support the idea that ad hoc standardised tasks that go beyond reading are needed.

Abstract The crosstalk between the chromaffin and adrenocortical cells is essential for the endocrine activity of the adrenal glands. This interaction is also likely important for tumorigenesis and progression of adrenocortical cancer and pheochromocytoma. We developed a unique in vitro 3D model of the whole adrenal gland called Adrenoid consisting in adrenocortical carcinoma H295R and pheochromocytoma MTT cell lines. Adrenoids showed a round compact morphology with a growth rate significantly higher compared to MTT-spheroids. Confocal analysis of differential fluorescence staining of H295R and MTT cells demonstrated that H295R organized into small clusters inside Adrenoids dispersed in a core of MTT cells. Transmission electron microscopy confirmed the strict cell–cell interaction occurring between H295R and MTT cells in Adrenoids, which displayed ultrastructural features of more functional cells compared to the single cell type monolayer cultures. Adrenoid maintenance of the dual endocrine activity was demonstrated by the expression not only of cortical and chromaffin markers (steroidogenic factor 1, and chromogranin) but also by protein detection of the main enzymes involved in steroidogenesis (steroidogenic acute regulatory protein, and CYP11B1) and in catecholamine production (tyrosine hydroxylase and phenylethanolamine N-methyltransferase). Mass spectrometry detection of steroid hormones and liquid chromatography measurement of catecholamines confirmed Adrenoid functional activity. In conclusion, Adrenoids represent an innovative in vitro 3D-model that mimics the spatial and functional complexity of the adrenal gland, thus being a useful tool to investigate the crosstalk between the two endocrine components in the pathophysiology of this endocrine organ.

Biomedical applications relying on optical radiation, particularly with the advent of lasers, have experienced exponential growth in the last 20 years. Powerful optical sources are now found not only in universities, hospitals, and industries but also in beauty centers, used for tasks such as tattoo removal, and even in our homes. Despite their widespread use, managing the risks associated with lasers, particularly in non-research contexts, has not kept pace with their proliferation. While the risks associated with direct exposure to radiation to the eye and skin are relatively well understood, the hazards posed by reflected and diffuse radiation remain less characterized and monitored. Therefore, there is a critical need to assess potential eye and skin hazards in spaces where lasers and non-coherent light sources are used. This necessitates a detailed analysis of reflective surfaces, with particular emphasis on evaluating their reflectance characteristics at relevant wavelength ranges. This study investigates the reflectance and transmittance (where relevant) properties of commonly used materials in biomedical settings, including fabrics, plastics, and metals, across a broad spectrum from 250 nm (UVA) to visible light and into the infrared (IR) region up to 25 μm. Both specular (at 45° incidence) and diffuse reflectance spectra were measured using spectrophotometric techniques and used to provide a straightforward parameter to classify the specular/diffusive behavior of the different surfaces. Besides, small-angle reflectance measurements in the IR range were performed by Fourier transform infrared spectrometry. The knowledge of the material optical properties used in environments where optical radiation is employed allows for accurate assessment of associated risks. This facilitates the determination of appropriate preventive measures and the establishment of safer protocols, for both operators and, where applicable, patients and the general public. For this scope, the creation of a database of material reflective properties has been initiated.

There has been continuous progress in diabetes management over the last few decades, not least due to the widespread dissemination of continuous glucose monitoring (CGM) and automated insulin delivery systems. These technological advances have radically changed the daily lives of people living with diabetes, improving the quality of life of both children and their families. Despite this, hypoglycemia remains the primary side-effect of insulin therapy. Based on a systematic review of the available scientific evidence, this paper aims to provide evidence-based recommendations for recognizing, risk stratifying, treating, and managing patients with hypoglycemia. The objective of these recommendations is to unify the behavior of pediatric diabetologists with respect to the timely recognition and prevention of hypoglycemic episodes and the correct treatment of hypoglycemia, especially in patients using CGM or advanced hybrid closed-loop systems. All authors have long experience in the specialty and are members of the Italian Society of Pediatric Endocrinology and Diabetology. The goal of treating hypoglycemia is to raise blood glucose above 70 mg/dL (3.9 mmol/L) and to prevent further decreases. Oral glucose at a dose of 0.3 g/kg (0.1 g/kg for children using “smart pumps” or hybrid closed loop systems in automated mode) is the preferred treatment for the conscious individual with blood glucose

The increasing number of primary students with varying degrees of exposure to a family minority language requires a reflection on whether specific aspects of their daily language experience influence their learning. Indeed, Minority Language Children (MLC) often report difficulties in reading that must be better investigated to exclude neurodevelopmental conditions such as developmental dyslexia.To this aim, we developed a new instrument, the Daily Linguistic Practice Interview. It allows for collecting information about the linguistic practice and use in the family (Scale A) and extra-family context (Scale B), and about the child's linguistic preferences and habits (Scale C). The Interview further provides analogic quantitative measures of minority language active speaking with mother, father, and passive listening, in the form of clocks to paint.The relationship between these linguistic aspects and reading skills was investigated on 79 MLC aged 8 to 11 y.o.through a correlational approach and regression models. Our results show that family and extra-family language use influence accurate lexical recognition, moreover a “mother effect” broadly affects reading skills in the majority language.Our findings suggest that MLC deserve a more careful evaluation of learning disorders with ad hoc standardized tests, that incorporates information about the family language exposure.

The present study investigates third language (L3) learners' processing of Chinese subject and object relative clauses in a supportive context. Using a self-paced reading task, we tested native Italian L3 learners of Mandarin Chinese and native Chinese speakers. The results showed that the L3 learners read significantly more slowly than the native speakers in all the target regions. Also, in the head noun region, they read object relative clauses significantly more slowly compared to subject relative clauses, indicating a preference for the latter. By contrast, for the native speakers, no significant differences were observed between subject and object relative clauses in any of the target regions. The L3 learners' performance offers support for the Structural Distance Hypothesis over the Dependency Locality Theory, and the contrast between the two populations indicates that context is at play in the processing of relative clauses.

Understanding the spatial heterogeneity of forest structure is crucial for comprehending ecosystem dynamics and promoting sustainable forest management. Unmanned aerial vehicle (UAV) LiDAR technology provides a promising method to capture detailed three-dimensional (3D) information about forest canopies, aiding in management and silvicultural practices. This study investigates the heterogeneity of forest structure in broadleaf forests using UAV LiDAR data, with a particular focus on tree crown features and their different information content compared to diameters. We explored a non-conventionally used method that emphasizes crown competition by employing a nearest neighbor selection technique based on metrics derived from UAV point cloud profiles at the tree level, rather than traditional DBH (diameter at breast height) spatial arrangement. About 300 vegetation elements within 10 plots collected in a managed Beech forest were used as reference data. We demonstrate that crown-based approaches, which are feasible with UAV LiDAR data at a reasonable cost and time, significantly enhances the understanding of forest heterogeneity, adding new information content for managers. Our findings underscore the utility of UAV LiDAR in characterizing the complexity and variability of forest structure at high resolution, offering valuable insights for carbon accounting and sustainable forest management.

Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The β3-adrenoreceptor (β3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that β3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague–Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective β3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of β3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of β3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure.

Children with Developmental Language Disorder (DLD) have been shown to struggle with the acquisition of complex structures requiring structural embedding and movement of a sentential element from its original position. This study examines the production of subject and object relative clauses (RCs) by Italian children, investigating whether: i) seven-year-old children with DLD are impaired in embedding or movement operations; ii) specific factors, such as animacy of the arguments, affect the production of sentences with movement and embedding, iii) the linguistic profile of children with DLD is qualitatively different from that of typically developing (TD) children. We elicited the production of RCs with animate and inanimate arguments in 12 Italian-speaking children with DLD (mean age = 7;2) and in two TD control groups: age matched (AM) and language matched (LM). Children with DLD produced fewer RCs than either control group and made different errors, showing a slightly different developmental path. Animacy mismatch did not improve RC production in any group. Results suggest that seven-year-old children with DLD are in a transitional stage: they can use embedding but still have difficulties with movement operations, especially in object RCs. This indicates that the language competence of children with DLD improves with age, but long-distance dependencies continue to be challenging.

Introduction: Purportedly, the progression of multiple sclerosis (MS) occurs when neurodegenerative processes due to derangement of axonal bioenergetics take over the autoimmune response. However, a clear picture of the causative interrelationship between autoimmunity and axonal mitochondrial dysfunction in progressive MS (PMS) pathogenesis waits to be provided. Methods: In the present study, by adopting the NOD mouse model of PMS, we compared the pharmacological effects of the immunosuppressants dexamethasone and fingolimod with those of mTOR inhibitors rapamycin and everolimus that, in addition to immunosuppression, also regulate mitochondrial functioning. Female Non-Obese Diabetic (NOD) mice were immunized with MOG35–55 and treated with drugs to evaluate functional, immune and mitochondrial parameters during disease evolution. Results: We found that dexamethasone and fingolimod did not affect the pattern of progression as well as survival. Conversely, mTOR inhibitors rapamycin and everolimus delayed disease progression and robustly extended survival of immunized mice. The same effects were obtained when treatment was delayed by 30 days after immunization. Remarkably, dexamethasone and fingolimod prompted the same degree of immunosuppression of rapamycin within both spleen and spinal cord of mice. However, only rapamycin prompted mitochondriogenesis by increasing mitochondrial content, and expression of several mitochondrial respiratory complex subunits, thereby preventing mtDNA reduction in the spinal cords of immunized mice. These pharmacodynamic effects were not reproduced in healthy NOD mice, suggesting a disease context-dependent pharmacodynamic effect. Discussion: Data corroborate the key role of mitochondriogenesis to treatment of MS progression, and for the first time disclose the translational potential of mTOR inhibitors in PMS therapy.

In English, a sentence like "The cat didn't eat the carrot or the pepper" typically receives a "neither" interpretation; in Japanese it receives a "not this or not that" interpretation. These two interpretations are in a subset/superset relation, such that the "neither" interpretation (strong reading) asymmetrically entails the "not this or not that" interpretation (weak reading). This asymmetrical entailment raises a learnability problem. According to the Semantic Subset Principle, all language learners, regardless of the language they are exposed to, start by assigning the strong reading, since this interpretation makes such sentences true in the narrowest range of circumstances.). If the "neither" interpretation is children's initial hypothesis, then children acquiring a superset language will be able to revise their initial hypothesis on the basis of positive evidence. The aim of the present study is to test an additional account proposed by Pagliarini, Crain, Guasti (2018) as a possible explanation for the earlier convergence to the adult grammar by Italian children. The hypothesis tested here is that the presence of a lexical form such as recursive "né" that unambiguously conveys a "neither" meaning, would lead children to converge earlier to the adult grammar due to a blocking effect of the recursive "né" form in the inventory of negated disjunction forms in a language. We compared data from Italian (taken from Pagliarini, Crain, Guasti, 2018), French, Hungarian and Dutch. Dutch was tested as baseline language. French and Hungarian have -- similarly to Italian -- a lexical form that unambiguously expresses the "neither" interpretation ("ni ni" and "sem sem," respectively). Our results did not support this hypothesis however, and are discussed in the light of language-specific particularities of the syntax and semantics of negation.

The discovery of immune checkpoints (CTLA-4, PD-1, and PD-L1) and their impact on the prognosis of oncological diseases have paved the way for the development of revolutionary oncological treatments. These treatments do not combat tumors with drugs “against” cancer cells but rather support and enhance the ability of the immune system to respond directly to tumor growth by attacking the cancer cells with lymphocytes. It has now been widely demonstrated that the presence of an adequate immune response, essentially represented by the number of TILs (tumor-infiltrating lymphocytes) present in the tumor mass decisively influences the response to treatments and the prognosis of the disease. Therefore, immunotherapy is based on and cannot be carried out without the ability to increase the presence of lymphocytic cells at the tumor site, thereby limiting and nullifying certain tumor evasion mechanisms, particularly those expressed by the activity (under positive physiological conditions) of checkpoints that restrain the response against transformed cells. Immunotherapy has been in the experimental phase for decades, and its excellent results have made it a cornerstone of treatments for many oncological pathologies, especially when combined with chemotherapy and radiotherapy. Despite these successes, a significant number of patients (approximately 50%) do not respond to treatment or develop resistance early on. The microbiota, its composition, and our ability to modulate it can have a positive impact on oncological treatments, reducing side effects and increasing sensitivity and effectiveness. Numerous studies published in high-ranking journals confirm that a certain microbial balance, particularly the presence of bacteria capable of producing short-chain fatty acids (SCFAs), especially butyrate, is essential not only for reducing the side effects of chemoradiotherapy treatments but also for a better response to immune treatments and, therefore, a better prognosis. This opens up the possibility that favorable modulation of the microbiota could become an essential complementary treatment to standard oncological therapies. This brief review aims to highlight the key aspects of using precision probiotics, such as Clostridium butyricum, that produce butyrate to improve the response to immune checkpoint treatments and, thus, the prognosis of oncological diseases.

Cesarean section is considered a possible trigger of atopy and gut dysbiosis in newborns. Bifidobacteria, and specifically B. bifidum, are thought to play a central role in reducing the risk of atopy and in favoring gut eubiosis in children. Nonetheless, no trial has ever prospectively investigated the role played by this single bacterial species in preventing atopic manifestations in children born by cesarean section, and all the results published so far refer to mixtures of probiotics. We have therefore evaluated the impact of 6 months of supplementation with B. bifidum PRL2010 on the incidence, in the first year of life, of atopy, respiratory tract infections, and dyspeptic syndromes in 164 children born by cesarean (versus 249 untreated controls). The results of our multicenter, randomized, and controlled trial have shown that the probiotic supplementation significantly reduced the incidence of atopic dermatitis, upper and lower respiratory tract infections, and signs and symptoms of dyspeptic syndromes. Concerning the gut microbiota, B. bifidum supplementation significantly increased α-biodiversity and the relative values of the phyla Bacteroidota and Actinomycetota, of the genus Bacteroides, Bifidobacterium and of the species B. bifidum and reduced the relative content of Escherichia/Shigella and Haemophilus. A 6-month supplementation with B. bifidum in children born by cesarean section reduces the risk of gut dysbiosis and has a positive clinical impact that remains observable in the following 6 months of follow-up.

Intense physical exercise can be related to a significant incidence of gastrointestinal symptoms, with a prevalence documented in the literature above 80%, especially for more intense forms such as running. This is in an initial phase due to the distancing of the flow of blood from the digestive system to the skeletal muscle and thermoregulatory systems, and secondarily to sympathetic nervous activation and hormonal response with alteration of intestinal motility, transit, and nutrient absorption capacity. The sum of these effects results in a localized inflammatory process with disruption of the intestinal microbiota and, in the long term, systemic inflammation. The most frequent early symptoms include abdominal cramps, flatulence, the urge to defecate, rectal bleeding, diarrhea, nausea, vomiting, regurgitation, chest pain, heartburn, and belching. Promoting the stability of the microbiota can contribute to the maintenance of correct intestinal permeability and functionality, with better control of these symptoms. The literature documents various acute and chronic alterations of the microbiota following the practice of different types of activities. Several nutraceuticals can have functional effects on the control of inflammatory dynamics and the stability of the microbiota, exerting both nutraceutical and prebiotic effects. In particular, curcumin, green tea catechins, boswellia, berberine, and cranberry PACs can show functional characteristics in the management of these situations. This narrative review will describe its application potential.

Background: Berberine is a poorly absorbed natural alkaloid widely used as nutraceutical to counteract diarrhoea and to lower cholesterol and hyperglycaemia. It has also been reported to reduce signs and symptoms of polycystic ovary syndrome (PCOS).Objective: To explore, through a multi-centric, randomized, controlled and prospective study, the possible role played by a form berberine that is more easily absorbed (Berberine Phytosome®, BP) in 130 Pakistani women with a diagnosis of PCOS and fertility problems due to menstrual and ovary abnormalities.Results: Ninety days of supplementation with BP, administered at 550 mg x2/die, determined (i) resumption of regular menstruation in about 70% of women (versus 16% in the control group; p < 0.0001), (ii) normalization of the ovaries anatomy in more than 60% of women (versus 13% in the control group; p < 0.0001), (iii) acne improvement in 50% of women (versus 16% in the control group; p = 0.0409) and (iv) hirsutism reduction in 14% of women (versus 0% in the control group; p = 0.0152). The metabolic and the hormonal profiles of the women in the two groups did not significantly differentiate at the end of the study. BP was well-tolerated and no specific side-effects were registered. Respectively after one, two and 8 years of trying, three women supplemented with BP became and are currently pregnant.Conclusion: Our study showed the positive effects of BP supplementation in women with PCOS and confirmed the high safety profile of this nutraceutical.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT05480670

Summary: Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency. Motivation: Adrenal insufficiency is a life-threatening condition resulting from the inability to produce steroid hormones in a dose and time-dependent manner. The ability to generate cells that produce cortisol in response to adrenocorticotrophic hormone (ACTH), the main regulator of glucocorticoid production in humans, combined with the development of encapsulation and immunoprotecting technologies, will open future opportunities to treat this condition using cell-based therapies. Current protocols have demonstrated the generation of fetal-like steroid-producing cells from hPSCs. However, the resulting cells fail to secrete cortisol, the main glucocorticoid in humans. We therefore sought to develop a protocol that enables the generation of billions of cells that produce cortisol and can respond to ACTH stimulation.

Objectives: Small-sized financial institutions stand out in serving SMEs due to their comparative advantages in the use of relationship-based credit. This study explores the impact of the relationship between a small financial institution and SMEs on credit access conditions. Methodology: The research employs the ordinary least square multiple regression method (OLS) on a dataset comprising 194 loan agreements from a small financial institution, which were contracted by 43 SMEs. The dataset includes financial information and records regarding the relationship strength with the creditor from 2015 to 2019. Results: The parameters of the OLS models that measured the association between the cost of credit, credit line available and average maturity with the bank relationship profile showed statistically significant results. Conclusions: The findings suggest that the duration of the banking relationship and the number of services contracted do not significantly affect the cost of credit. However, a noteworthy association is observed between credit concentration within the small-sized bank and higher costs for clients. Additionally, the length of the banking relationship directly influences the credit line available to SMEs. Interestingly, the impact of guarantees offered on credit conditions does not justify long credit transactions. Furthermore, an inverse relationship emerges between the credit rating of SMEs and the credit term. RESUMEN Introducción: las instituciones financieras de pequeño tamaño se destacan en el servicio a las PYME por sus ventajas comparativas en el uso del crédito basado en la relación. Este artículo investiga el impacto de la relación entre una pequeña institución financiera y las PYMES en las condiciones de acceso al crédito. Metodología: la investigación emplea el método de regresión lineal múltiple de mínimos cuadrados ordinarios (OLS) en un conjunto de datos que comprende 194 contratos de préstamos de una pequeña institución financiera, contratados por 43 PYMES. El conjunto de datos incluye información financiera y registros de la fortaleza de la relación con el acreedor desde 2015 hasta 2019. Resultados: los parámetros de los modelos OLS que midieron la asociación entre el costo del crédito, la línea de crédito disponible y el plazo del crédito con el perfil de relación bancaria mostraron resultados estadísticamente significativos. Conclusión: los resultados sugieren que la duración de la relación bancaria y el número de servicios contratados no afectan significativamente el costo del crédito. Sin embargo, se observa una asociación destacable entre la concentración de crédito dentro del banco de pequeño tamaño y mayores costos para los clientes. Además, la duración de la relación bancaria influye directamente en la línea de crédito disponible para las PYMES. Así las cosas, el impacto de las garantías ofrecidas en las condiciones de crédito no justifica transacciones de crédito a largo plazo. Además, se evidencia una relación inversa entre la calificación crediticia de las PYMES y el plazo del crédito.

Abstract Digital health technology is receiving increasing attention in cardiology. The rise of accessibility of digital health tools including wearable technologies and smart phone applications used in medical practice has created a new era in healthcare. The coronavirus pandemic has provided a new impetus for changes in delivering medical assistance across the world. This Consensus document discusses the potential implementation of digital health technology in older adults, suggesting a practical approach to general cardiologists working in an ambulatory outpatient clinic, highlighting the potential benefit and challenges of digital health in older patients with, or at risk of, cardiovascular disease. Advancing age may lead to a progressive loss of independence, to frailty, and to increasing degrees of disability. In geriatric cardiology, digital health technology may serve as an additional tool both in cardiovascular prevention and treatment that may help by (i) supporting self‐caring patients with cardiovascular disease to maintain their independence and improve the management of their cardiovascular disease and (ii) improving the prevention, detection, and management of frailty and supporting collaboration with caregivers. Digital health technology has the potential to be useful for every field of cardiology, but notably in an office‐based setting with frequent contact with ambulatory older adults who may be pre‐frail or frail but who are still able to live at home. Cardiologists and other healthcare professionals should increase their digital health skills and learn how best to apply and integrate new technologies into daily practice and how to engage older people and their caregivers in a tailored programme of care.

Acute kidney injury is frequent, often fatal and can leave survivors with chronic kidney disease. Here the authors show that tubular cell polyploidy reduces early fatality sustaining residual function but promotes chronic kidney disease, which can be prevented by blocking YAP1

El maltrato infantil es toda acción que atenta contra los derechos más básicos de niñas, niños y adolescentes los cuales afectan su desarrollo físico y mental (OMS, 2020). La población infantil del sector rural es vulnerable y coexiste con problemáticas biopsicosociales, el estudio exploratorio inicial permite abordar esta temática a nivel psicológico para evaluar el impacto negativo de exposición a la violencia en los contextos casa, escuela, colegio y televisión. Participaron 36 niños, niñas y adolescentes de la parroquia Atahualpa, 18 hombres y 18 mujeres de 6 a 15 años (M=10,92; DT=2,36). Se aplicó el cuestionario exposición a la violencia CEV y al mismo tiempo se realizaron entrevistas para confirmar la información obtenida. Entre los diversos resultados se destaca que no se hallaron diferencias estadísticamente significativas en los diversos contextos de violencia evaluados, se evidenció que las mujeres presentan un rango mayor en exposición a la violencia en casa en comparación a los hombres, en este mismo contexto se obtuvo el valor más elevado con un 75%, seguido de calle con 72% indicando la necesidad de realizar un estudio más amplio que permita focalizar los posibles factores de riesgo en los niños y adolescentes.

This tutorial delves into the application of proportional odds-type ordinal logistic regression to assess the impact of incorporating both fixed and random effects when predicting the rankings of Brazilian universities in a well-established international academic assessment utilizing authentic data. In addition to offering valuable insights into the estimation of ordinal logistic models, this study underscores the significance of integrating random effects into the analysis and addresses the potential pitfalls associated with the inappropriate treatment of phenomena exhibiting categorical ordinal characteristics. Furthermore, we have made the R language code and dataset available as supplementary resources for the replication.

Reduced forms such as the pronoun "he" provide little information about their intended meaning compared to more elaborate descriptions such as "the lead singer of Coldplay." Listeners must therefore use contextual information to recover their meaning. Across languages, there appears to be a trade-off between the informativity of a form and the prominence of its referent. For example, Italian adults generally interpret informationally empty null pronouns as in the sentence "Corre" (meaning "He/She/It runs") as referring to the most prominent referent in the discourse, and more informative overt pronouns (e.g., "lui" in "Lui corre," "He runs") as referring to less prominent referents. Although children acquiring Italian are known to experience difficulties interpreting pronouns, it is unclear how they acquire this division of pragmatic labor between null and overt subject pronouns, and how this relates to the development of their cognitive capacities. Here we show that cognitive development can account for the general interpretation patterns displayed by Italian-speaking children and adults. Using experimental studies and computational simulations in a framework modeling bounded-rational behavior, we argue that null pronoun interpretation is influenced by working memory capacity and thus appears to depend on discourse context, whereas overt pronoun interpretation is influenced by processing speed, suggesting that listeners must reason about the speaker's choices. Our results demonstrate that cognitive capacities may constrain the acquisition of linguistic forms and their meanings in various ways. The novel predictions generated by the computational simulations point out several directions for future research.

Glioblastoma is the most frequent and aggressive primary brain cancer. In preclinical studies, Zika virus, a flavivirus that triggers the death of glioblastoma stem-like cells. However, the flavivirus oncolytic activity has not been demonstrated in human patients. Here we report a glioblastoma patient who received the standard of care therapy, including surgical resection, radiotherapy and temozolomide. However, shortly after the tumor mass resection, the patient was clinically diagnosed with a typical arbovirus-like infection, during a Zika virus outbreak in Brazil. Following the infection resolution, the glioblastoma regressed, and no recurrence was observed. This clinical response continues 6 years after the glioblastoma initial diagnosis.

BackgroundFibroblast growth factor 21 (FGF21) is an essential metabolic regulator that adapts to changes in nutritional status. Severe childhood undernutrition induces elevated FGF21 levels, contributing to growth hormone (GH) resistance and subsequent linear growth attenuation potentially through a direct action on chondrocytes.MethodsIn this study, we assessed expression of the components of both GH and FGF21 pathways in rare and unique human growth plates obtained from children. Moreover, we investigated the mechanistic interplay of FGF21 on GH receptor (GHR) signaling in a heterologous system.ResultsChronic FGF21 exposure increased GH-induced GHR turnover and SOCS2 expression, leading to the inhibition of STAT5 phosphorylation and IGF-1 expression. The clinical significance of FGF21 signaling through GH receptors was tested in nutritionally driven growth failure seen in very preterm (VPT) infants right after birth. VPT infants display an immediate linear growth failure after birth followed by growth catch-up. Consistent with the in vitro model data, we show that circulating FGF21 levels were elevated during deflection in linear growth compared to catch-up growth and were inversely correlated with the length velocity and circulating IGF1 levels.ConclusionsThis study further supports a central role of FGF21 in GH resistance and linear growth failure and suggests a direct action on the growth plate.

The Meaning First Approach offers a model of the relation between thought and language that includes a Generator and a Compressor. The Generator build non-linguistic thought structures and the Compressor is responsible for its articulation through three processes: structure-preserving linearization, lexification, and compression via non-articulation of concepts when licensed. One goal of this paper is to show that a range of phenomena in child language can be explained in a unified way within the Meaning First Approach by the assumption that children differ from adults with respect to compression and, specifically, that they may undercompress in production, an idea that sets a research agenda for the study of language acquisition. We focus on dependencies involving pronouns or gaps in relative clauses and wh-questions, multi-argument verbal concepts, and antonymic concepts involving negation or other opposites. We present extant evidence from the literature that children produce undercompression errors (a type of commission errors) that are predicted by the Meaning First Approach. We also summarize data that children’s comprehension ability provides evidence for the Meaning First Approach prediction that decompression should be challenging, when there is no 1-to-1 correspondence.

In English, the sentence "Mary didn't eat pizza or sushi" is assigned the "neither interpretation" (both disjuncts must be false). In Mandarin Chinese, the equivalent sentence is assigned the at least one interpretation (at least one disjunct must be false). The cross-linguistic variation in the interpretation of negative sentences with disjunction has been attributed to the Disjunction Parameter. On one value of this lexical parameter, disjunction is a Positive Polarity Item (+PPI). On the other value, disjunction is not a Positive Polarity Item (-PPI). According to the Semantic Subset Principle (SSP), all child language learners are predicted to initially assign the neither interpretation to negative disjunctive sentences, for reasons of language learnability. The present study investigates the interpretation of negative sentences with disjunction in Catalan. The findings confirm that disjunction is +PPI for adults; children show a bimodal distribution. For some children, disjunction is -PPI, as predicted by the SSP. However, some children adopt the adult +PPI value of the Disjunction Parameter. Children's level of linguistic maturity, as measured by a sentence repetition task, was correlated with their judgments about negative sentences with disjunction such that children with lower scores tended to adopt the -PPI value. To explain the relatively early parameter resetting by some Catalan-speaking children, as compared to children acquiring other languages where disjunction is +PPI, we discuss the possible "blocking effect" of an alternative lexical expression in Catalan, which unambiguously conveys the neither interpretation.

The aim of our study was to retrospectively evaluate whether the oral administration of L. crispatus (M247) could increase pregnancy and live birth rates in women undergoing assisted reproductive technology procedures. Enrolled women (N = 160) were divided into two groups: treated (N = 80) or untreated (N = 80) with the probiotic strain. The odds ratio (OR) for a treated woman to have a clinical pregnancy (CP) was 1.56. In women aged 30–40 years, M247 increased the probability of a CP in correlation with the progressive rise in BMI, reaching 47% (35% in controls) with a BMI of 35 (OR: 2.00). The CAID statistics showed that in a woman of the blastocyst subgroup, below 43 years, with a BMI over 18.6, treatment with M247 increased the chance of a CP from 28.4% to 44.5% (OR: 2.08; p < 0.05). Considering live births, the rate of the probiotic group was 12.5% versus 7.5% (OR: 1.76). Considering only the blastocyst subgroup, the treatment increased the number of live births by 200% (OR: 3.64; p = 0.05). As confirmed also by statistical indices NNT, NNH, and LHH, the use of M247 demonstrated a risk-benefit ratio to the full advantage of the benefits.

Agreement is a morphosyntactic dependency which is sensitive to the hierarchical structure of the clause and is constrained by the structural distance that separates the elements involved in this relation. In this paper we present two experiments, providing new evidence that Italian-speaking children with Developmental Language Disorder (DLD), as well as Typically Developing (TD) children, are sensitive to the same hierarchical and locality factors that characterise agreement in adult grammars. This sensitivity holds even though DLD children show accrued difficulties in more complex agreement configurations. In the first experiment, a forced-choice task was used to establish whether children are more affected in the computation of S-V agreement when an element intervenes hierarchically or linearly in the agreement relation: DLD children are more subject to attraction errors when the attractor intervenes hierarchically, indicating that DLD children discriminate between hierarchical and linear configurations. The second experiment, also conducted through a forced-choice task, shows that the computation of agreement in DLD children is more 'fragile' than in TD children (and also in children with a primary impairment in the phonological domain), in that it is more sensitive to the factors of complexity identified in Moscati and Rizzi's (2014) typology of agreement configurations. To capture the agreement pattern found in DLD children, we put forth a novel hypothesis: the Fragile Computation of Agreement Hypothesis. Its main tenet is that DLD children make use of the same grammatical operations employed by their peers, as demonstrated in Experiment 1, but difficulties increase as a function of the complexity of the agreement configuration.

In this commentary on the Special Issue, I will address the question of what memory spans measure concerning language, as language has, at least, a linear and a hierarchical dimension. I suggest that if anything what is measured has to do with the linear dimension. Then, I will discuss the welcome results on bilingual children with language problems and reflect on what it means that working memory measures seem to be more relevant for bilingual children than for monolingual ones. I will tentatively suggest that what is at stake is not memory per se, but inhibitory skills.

Different words generally have different meanings. However, some words seemingly share similar meanings. An example are null and overt pronouns in Italian, which both refer to an individual in the discourse. Is the interpretation and processing of a form affected by the existence of another form with a similar meaning? With a pupillary response study, we show that null and overt pronouns are processed differently. Specifically, null pronouns are found to be less costly to process than overt pronouns. We argue that this difference is caused by an additional reasoning step that is needed to process marked overt pronouns but not unmarked null pronouns. A comparison with data from Dutch, a language with overt but no null pronouns, demonstrates that Italian pronouns are processed differently from Dutch pronouns. These findings suggest that the processing of a marked form is influenced by alternative forms within the same language, making its processing costly.

Introduction: Derangement of axonal mitochondrial bioenergetics occurs during progressive multiple sclerosis (PMS). However, whether this is a delayed epiphenomenon or an early causative event of disease progression waits to be understood. Answering this question might further our knowledge of mechanisms underlying neurobiology of PMS and related therapy. Methods: MOG35–55-immunized NOD and PLP139–151-immunized SJL female mice were adopted as models of progressive or relapsing-remitting experimental autoimmune encephalomyelitis (EAE), respectively. Multiple parameters of mitochondrial homeostasis were analyzed in the mouse spinal cord during the early asymptomatic stage, also evaluating the effects of scavenging mitochondrial reactive oxygen species with Mito-TEMPO. Results: Almost identical lumbar spinal cord immune infiltrates consisting of Th1 cells and neutrophils without B and Th17 lymphocytes occurred early upon immunization in both mouse strains. Still, only NOD mice showed axon-restricted dysregulation of mitochondrial homeostasis, with reduced mtDNA contents and increased cristae area. Increased expression of mitochondrial respiratory complex subunits Nd2, Cox1, Atp5d, Sdha also exclusively occurred in lumbar spinal cord of NOD and not SJL mice. Accordingly, in this region genes regulating mitochondrial morphology (Opa1, Mfn1, Mfn2 and Atp5j2) and mitochondriogenesis (Pgc1α, Foxo, Hif-1α and Nrf2) were induced early upon immunization. A reduced extent of mitochondrial derangement occurred in the thoracic spinal cord. Notably, the mitochondrial radical scavenger Mito-TEMPO reduced H2O2 content and prevented both mtDNA depletion and cristae remodeling, having no effects on dysregulation of mitochondrial transcriptome. Discussion: We provide here the first evidence that axonal-restricted derangement of mitochondrial homeostasis already occurs during the asymptomatic state exclusively in a mouse model of PMS. Data further our understanding of mechanisms related to EAE progression, and point to very early axonal mitochondrial dysfunction as central to the neuropathogenesis of MS evolution.

IntroductionBoth osteoporosis and periodontitis are pathologies characterized by an imbalance in the bone tissue. Vitamin C is an important factor involved in maintaining the health of the periodontium; its deficiency causes characteristic lesions to periodontal tissues such as bleeding and redness of the gums. Among the essential minerals for the health of the periodontium we find instead calcium.Objectives of the studyThe objectives of the proposed study are to study the association between the presence of osteoporosis and periodontal disease. We tried to identify the possible connections between particular dietary patterns and therefore the etiopathogenesis of periodontal disease and secondarily of osteoporosis.Materials and methods110 subjects were recruited in a single-center observational cross-sectional study carried through the collaboration between the University of Florence and the private institute of dentistry Excellence Dental Network based in Florence, suffering of periodontitis, 71 osteoporotic/osteopenic and 39 non-osteoporotic/osteopenic. Anamnestic data and information on eating habits were collected.ResultsThe population showed eating habits that do not meet the intake levels recommended by the L.A.R.N. Regarding the relationship between nutrient intake and plaque index, it appears that in the population, the higher the intake of vitamin C through food, the lower the plaque index value is. This result could reinforce the scientific evidence that there is a protective factor in the onset of periodontal disease by the consumption of vitamin C which to date is still the subject of investigation. In addition, the same type of trend would also have been observed for calcium intake, but a larger sample size would be required to make this effect significant.ConclusionsThe relationship between osteoporosis and periodontitis and the role of nutrition in influencing the evolution of these pathologies still seems to be deeply explored. However, the results obtained seem to consolidate the idea that there is a relationship between these two diseases and that eating habits play an important role in their prevention.

Abstract Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

Abstract Cardiovascular (CV) engagement in coronavirus disease 2019 (COVID‐19) is a huge determinant of prognosis during the acute phase of the disease. However, little is known about the potential chronic implications of the late phase of COVID‐19 and about the appropriate approach to these patients. Heart failure, type 1 and type 2 myocardial infarction, arrhythmias, myocarditis, pulmonary fibrosis, and thrombosis have been shown to be related to severe acute respiratory syndrome coronavirus 2 infection, and a ‘long COVID‐19’ illness has been recognized with fatigue, chest pain, and dyspnoea among the most frequent symptoms reported after discharge from hospital. This paper focuses on some open questions that cardiologists are going to face during the next months in a general cardiology outpatient clinic, in particular how to evaluate a ‘post‐COVID’ patient during follow‐up of CV complications of the acute phase and how to manage new CV symptoms that could be the consequence, at least in part, of heart/vessels and/or lung involvement of the previous virus infection. Present symptoms and signs, history of previous CV disease (both preceding COVID‐19 and occurring during viral infection), and specific laboratory and imaging measurements during the acute phase may be of interest in focusing on how to approach the clinical evaluation of a post‐COVID patient and how to integrate in our standard of care the new information on COVID‐19, possibly in a multidisciplinary view. Dealing with the increased COVID‐associated CV risk burden and becoming acquainted with potential new e‐cardiology approaches aimed at integrating the cardiology practice are relevant new challenges brought by severe acute respiratory syndrome coronavirus 2 infection and its sequelae.

L’articolo tratta i temi legati allo sviluppo di un makerspace scolastico all’interno di una scuola primaria e secondaria di primo grado. Indire nel 2018 ha condotto una prima indagine, alla quale è seguito un follow-up per comprendere le dinamiche che si instaurano intorno al makerspace e che coinvolgono dirigente, insegnanti e terze parti (makers, associazioni, genitori). L’articolo si basa su interviste semi-strutturate a tutti gli attori coinvolti e ha lo scopo di verificare la sostenibilità di tale azione sotto tutti i punti di vista: didattico, economico, logistico. I risultati che si rilevano sono incoraggianti, ma mettono in evidenza numerosi problemi correlati alle dinamiche di comunità tra le figure professionali coinvolte. L’articolo mette in evidenza la necessità di una visione di lungo corso con obiettivi condivisi e programmi ben definiti, sostenuti, possibilmente, da una stabilità in termini di personale.

This study investigates the linguistic processing and non-linguistic cognitive abilities of monolingual and bilingual children with and without reading difficulties and examines the relationship between these skills and reading. There were 72 Italian-speaking children: 18 monolingual good readers (MONO-GR, Mage = 10;4), 19 monolingual poor readers (MONO-PR, Mage = 10;3), 21 bilingual good readers (BI-GR, Mage = 10;6), and 16 bilingual poor readers (BI-PR, Mage = 10;6). All bilingual children spoke Italian as their L2. Children completed a battery of standardized Italian reading tests, language-dependent tasks: nonword repetition (NWR), sentence repetition (SR), and phonological awareness (PA), and language-independent tasks: timing anticipation, beat synchronization, inhibition control, auditory reaction time, and rapid automatized naming (RAN). Poor readers scored below good readers on the language-dependent tasks, including NWR, PA, and SR. Beat synchronization was the only language-independent task sensitive to reading ability, with poor readers showing greater variability than good readers in tapping to fast rhythms. SR was the only task influenced by language experience as bilinguals underperformed monolinguals on the task. Moreover, there were weak to moderate correlations between performance on some language-dependent tasks (NWR, PA), language-independent tasks (inhibition control, RAN), and reading measures. Performance on the experimental tasks (except for RAN) was not associated with the length of exposure to Italian. The results highlight the potential of NWR, PA, SR, and beat synchronization tasks in identifying the risk of dyslexia in bilingual populations. Future research is needed to validate these findings and to establish the tasks’ diagnostic accuracy.

Adipokines are peptide hormones produced by the adipose tissue involved in several biological functions. Among adipokines, adiponectin (ADPN) has antidiabetic and anti-inflammatory properties. It can also modulate food intake at central and peripheral levels, acting on hypothalamus and facilitating gastric relaxation. ADPN exerts its action interacting with two distinct membrane receptors and triggering some well-defined signaling cascades. The ceramidase activity of ADPN receptor has been reported in many tissues: it converts ceramide into sphingosine. In turn, sphingosine kinase (SK) phosphorylates it into sphingosine-1 phosphate (S1P), a crucial mediator of many cellular processes including contractility. Using a multidisciplinary approach that combined biochemical, electrophysiological and morphological investigations, we explored for the first time the possible role of S1P metabolism in mediating ADPN effects on the murine gastric fundus muscle layer. By using a specific pharmacological inhibitor of SK2, we showed that ADPN affects smooth muscle cell membrane properties and contractile machinery via SK2 activation in gastric fundus, adding a piece of knowledge to the action mechanisms of this hormone. These findings help to identify ADPN and its receptors as new therapeutic targets or as possible prognostic markers for diseases with altered energy balance and for pathologies with fat mass content alterations.

Antibiotics are one of the greatest scientific achievements of modern medicine, but excessive use is creating challenges for the future of medicine. Antibiotic resistance (AR) is thought to cause changes in bowel habits and an increased risk of gastroenteritis, but it may also increase the risk of overweight, obesity, autoimmune and atopic diseases, and a low response to vaccines and cancer, likely mediated by antibiotic-induced gut dysbiosis. Probiotic add-on therapy could partially prevent antibiotic-induced gut dysbiosis, but their antibiotic sensitivity features likely limits this potential. The EFSA (European Food Safety Authority) guidelines consider the use of probiotics whose antibiotic-resistant profile could be transferable an important hazard. Recently, a strain of B. breve (PRL2020) has shown to be resistant to amoxicillin and amoxicillin-clavulanate (AC) by applying the microdilution protocol according EFSA guidelines. After verifying that horizontal gene transfer is unlikely to take place, this feature suggests its concomitant use with these specific antibiotics. The results of our tests demonstrated that the strain PRL2020 is indeed endowed with amoxicillin- and AC-resistant properties and that it is also insensitive to ampicillin. In-depth analysis of the annotated genome sequence of B. breve PRL2020 was employed to query the Comprehensive Antibiotic Resistance Database (CARD) using Resistance Gene Identifier (RGI) software (version 5.2.1). The similarity among the AR determinants found was studied through nucleotide sequence alignment, and it was possible to verify not only the absence of genes explaining these features in the flanking regions but also the presence of genetic sequences (rpoB and erm(X)) putatively responsible for rifampicin and erythromycin resistance. Both features are not phenotypically expressed, and for these antibiotics, the strain is within the EFSA limits. Analysis of the flanking regions of these genes revealed possible mobile elements upstream and downstream only in the case of the erm(X) gene, but the features of the Insertion Sequences (IS) are described as not to cause horizontal transfer. Our findings on strain PRL2020 demonstrate that its AR profile is compatible with antibiotics when taken with the aim of reducing the risk of dysbiosis.