Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.

Is tuberous sclerosis complex-associated autism a preventable and treatable disorder?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 and TSC2 genes, causing overactivation of the mechanistic (previously referred to as mammalian) target of rapamycin (mTOR) signaling pathway in fetal life. The mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy, intellectual disability, and autism spectrum disorder (ASD). Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic infants. DATA SOURCES: We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms "tuberous sclerosis", "autism", or "autism spectrum disorder"," animal models", "preclinical studies", "neurobiology", and "treatment". RESULTS: Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor, visual and social communication skills in the first year of life delays. Reliable genetic, cellular, electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and epilepsy. CONCLUSIONS: Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

Elaboração de uma cartilha informativa para familiares e cuidadores de crianças com autismo / Elaboración de un folleto informativo para familiares y cuidadores de niños con autismo / Development of an information booklet for family members and caregivers of children with autism

Objetivo: descrever a elaboração de uma cartilha informativa para familiares e cuidadores de crianças que vivem Transtorno do Espectro Autista. Método: pesquisa metodológica, realizada entre setembro de 2019 a julho de 2022 no sul do Brasil. Resultados: a elaboração envolveu a etapa teórica, validação de conteúdo e construção da cartilha denominada "Crianças autistas**: cartilha para familiares e cuidadores". Composta com seis capítulos: características do transtorno, comportamento da criança, direitos, futuro da criança com autismo e compartilhando experiências e visões. O conteúdo foi validado e para a construção da cartilha foram investigadas as preferências de dispositivos tecnológicos e layout de recursos informativos pelos familiares; após, o protótipo da cartilha passou por teste de usabilidade e navegação, hospedada no Articulate Storyline Software e está disponível para o público-alvo. Considerações finais: o processo de elaboração de recursos educativos para familiares pode auxiliar outros pesquisadores com interesse na área.

Objetivo: describir la elaboración de un folleto informativo para familiares y cuidadores de niños con Trastorno del Espectro Autista. Material y Método: investigación metodológica realizada entre septiembre de 2019 y julio de 2022 en el sur de Brasil. Resultados: la investigación incluyó una etapa teórica, la validación del contenido y la construcción de un folleto llamado "Niños autistas**: folleto para familiares y cuidadores". Consta de seis capítulos: características del trastorno, comportamiento del niño, derechos, futuro de los niños con autismo y compartir experiencias y visiones. Se validó el contenido y, para elaborar el folleto, se investigaron las preferencias de los familiares en cuanto a dispositivos tecnológicos y disposición de los recursos informativos; a continuación, el prototipo de folleto se sometió a pruebas de usabilidad y navegación, se alojó en Articulate Storyline Software y ya está a disposición del público destinatario. Consideraciones finales: el proceso de desarrollo de recursos educativos para familiares puede ayudar a otros investigadores interesados en el área.

Objective: to describe the development of an information booklet for family members and caregivers of children living with Autism Spectrum Disorder. Method: methodological research carried out between September 2019 and July 2022 in southern Brazil. Results: the study involved a theoretical stage, content validation and the construction of a booklet called Autistic children**: a booklet for family members and caregivers". It consists of six chapters: characteristics of the disorder, the child's behavior, rights, the future of children with autism and sharing experiences and visions. The content was validated and to build the booklet, family members' preferences for technological devices and the layout of information resources were investigated; afterwards, the prototype of the booklet underwent usability and navigation tests, was hosted on Articulate Storyline Software and is available to the target audience. Final considerations: the process of developing educational resources for family members can help other researchers with an interest in the area.

Portable HEPA filter air cleaner use during pregnancy and children's autistic behaviors at four years of age: The UGAAR randomized controlled trial.

BACKGROUND: Developmental exposure to airborne particulate matter (PM) may increase children's risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM2.5) concentrations during pregnancy and autistic traits. METHODS: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM2.5 concentrations and T-scores. RESULTS: We enrolled participants at a median of 11 weeks' gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: -2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m3) increase in indoor PM2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM2.5 concentrations by trimester were smaller and confidence intervals spanned no effect. CONCLUSION: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01741051.

LF-rTMS ameliorates social dysfunction of FMR1-/- mice via modulating Akt/GSK-3ß signaling.

Autism spectrum disorders (ASD) are a group of neurological disorders which affect approximately 1% of children around the world. Social dysfunction is one of the two core syndromes of ASD, and still lacks effective treatment. Transcranial magnetic stimulation (TMS) is a noninvasive and safe procedure that uses magnetic fields to modulate neural activity. Whether it were effective in modulating social function remains unclear. By using 3-chamber test, ultrasonic vocalization recording and Western-blotting, we demonstrated that FMR1 (fragile X mental retardation protein) mutant mice, a model of ASD, exhibited obvious defects in social preference and ultrasonic communication. In addition, we detected increase of p-Akt (S473) and p-GSK-3ß (S9), and decrease of p-PSD-95 (T19) in the anterior cingulate cortex (ACC) of FMR1-/- mice. Treating FMR1-/- mice with 1 Hz repetitive TMS (rTMS) exerted a long lasting effect in improving both the ultrasonic communication and social preference, as well as restoring the levels of Akt/GSK-3ß activity and spine density in the FMR1-/-ACC. Our data, for the first time, demonstrated a beneficial effect of low frequency rTMS (LF-rTMS) on the social function of FMR1-/- mice and an involvement of Akt/GSK-3ß signaling in this process, indicating LF-rTMS as a potential therapeutic strategy for ASD patients.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

Male preconception antioxidant supplementation may lower autism risk: a call for studies.

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs-specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow-or even cease-upon the initiation of public awareness campaigns.

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

OBJECTIVE: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). METHODS: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). RESULTS: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. INTERPRETATION: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

Beneficial effects of pioglitazone, a selective peroxisome proliferator-activated receptor-γ agonist in prenatal valproic acid-induced behavioral and biochemical autistic like features in Wistar rats.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in children. It is diagnosis by two main behavioral phenotypes i.e. social-communication impairments and repetitive behavior. ASD is complex disorder with unsolved etiology due to multiple genes involvement, epigenetic mechanism and environmental factors. Valproic acid (VPA), a teratogen is known to induce characteristic features related to ASD in rodents. Numerous studies suggest the potential therapeutic effects of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in different brain disorders. This research evaluates the utility of selective agonist of PPAR-γ, pioglitazone in prenatal VPA induced experimental ASD symptomatology in Wistar rats. The prenatal administration of VPA has induced social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity in rats. Also, prenatal VPA-treated rats have shown higher levels of oxidative stress (increased in thiobarbituric acid reactive species, and decreased in reduced glutathione level) and inflammation (increased in interleukin-6, tumor necrosis factor-alpha and decreased in interleukin-10) in the cerebellum, brainstem and prefrontal cortex. Treatment with pioglitazone significantly attenuated the prenatal VPA-induced social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, pioglitazone also reduced the prenatal VPA-induced oxidative stress and neuroinflammation in aforementioned brain regions. Hence, it may be concluded that pioglitazone may provide neurobehavioral and biochemical benefits in prenatal VPA-induced autistic phenotypes in rats.

Betaine ameliorates prenatal valproic-acid-induced autism-like behavioral abnormalities in mice by promoting homocysteine metabolism.

AIM: Abnormally high levels of homocysteine (Hcy) are associated with autism spectrum disorder. Betaine is a methyl group donor in Hcy metabolism, and is known to prevent noxious Hcy accumulation. This study explored whether betaine could influence Hcy metabolism in a mouse model of autism and ameliorate behavioral abnormalities. METHODS: Pregnant ICR mice were administered valproic acid (VPA) intraperitoneally on Embryonic Day 12.5. Serum Hcy concentrations in the offspring were measured by enzyme-linked immunosorbent assay. Expressions of Hcy-metabolism-related enzymes, betaine-Hcy methyltransferase, cystathionine ß-synthase, and methionine synthase, were measured by quantitative reverse transcription polymerase chain reaction and western blotting. Offspring were treated by either betaine or saline at the age of 8 weeks and serum Hcy concentrations were measured. Social behaviors were assessed by sniff-duration test and three-chamber test. Repetitive behavior was evaluated by marble-burying test. Tail-flick test was performed to measure nociceptive sensitivity. RESULTS: Prenatal VPA-exposed mice showed significantly elevated Hcy concentrations and decreased betaine-Hcy methyltransferase expression. Treatment with betaine could reduce Hcy level in VPA-exposed mice, attenuate social impairment and repetitive behavior, and normalize nociceptive sensitivity in this model. CONCLUSION: Betaine could ameliorate autism-like features and play a beneficial role in a mouse autism model induced by prenatal VPA exposure.

Prevention or Amelioration of Autism-Like Symptoms in Animal Models: Will it Bring Us Closer to Treating Human ASD?

Since the first animal model of valproic acid (VPA) induced autistic-like behavior, many genetic and non-genetic experimental animal models for Autism Spectrum Disorder (ASD) have been described. The more common non-genetic animal models induce ASD in rats and mice by infection/inflammation or the prenatal or early postnatal administration of VPA. Through the establishment of these models, attempts have been made to ameliorate or even prevent ASD-like symptoms. Some of the genetic models have been successfully treated by genetic manipulations or the manipulation of neurotransmission. Different antioxidants have been used (i.e., astaxanthin, green tea, piperine) to reduce brain oxidative stress in VPA-induced ASD models. Agents affecting brain neurotransmitters (donepezil, agmatine, agomelatine, memantine, oxytocin) also successfully reduced ASD-like symptoms. However, complete prevention of the development of symptoms was achieved only rarely. In our recent study, we treated mouse offspring exposed on postnatal day four to VPA with S-adenosine methionine (SAM) for three days, and prevented ASD-like behavior, brain oxidative stress, and the changes in gene expression induced by VPA. In this review, we describe, in addition to our data, the existing literature on the prevention/amelioration of ASD-like symptoms. We also discuss the possible mechanisms underlying some of these phenomena. Finally, we describe some of the clinical trials in children with ASD that were carried out as a result of data from animal studies, especially those with polyunsaturated fatty acids (PUFAs).

S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice.

INTRODUCTION: A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. METHODS: ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. RESULTS: Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. CONCLUSIONS: Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary.

Vitamin D and health in the Mediterranean countries.

Vitamin D, traditionally well known for its role in maintaining optimal health through its contribution to calcium metabolism and skeletal health, has received increased attention over the past two decades, with considerable focus being placed on its nonskeletal benefits. This paper is a narrative review of the nonskeletal health benefits of vitamin D, of particular interest to inhabitants of Mediterranean countries, namely, autism, cancer, cardiovascular disease, chronic obstructive pulmonary disease, dental caries, diabetes mellitus, erectile dysfunction, hypertension, metabolic syndrome, respiratory tract infections, all-cause mortality, and pregnancy and birth outcomes, because of the relatively high incidence and/or prevalence of these disorders in this region. Currently, the best evidence is coming out of observational studies related to serum 25-hydroxyvitamin D [25(OH)D] concentrations. Vitamin D clinical trials have generally been poorly designed and conducted, usually being based on vitamin D dose rather than 25(OH)D concentration. The optimal 25(OH)D concentration is above 75 nmol/l (30 ng/ml), with even better health outcomes in the range of 100-150 nmol/l. Achieving these concentrations with vitamin D3 supplements will require 1000-4000 IU/day of vitamin D3. Sensible sun exposure should also be encouraged. Countries should also consider fortifying grain and dairy products with vitamin D3.

Evidencia de la presencia e incremento de niños con diagnóstico de trastornos del espectro autista / Evidence of the presence and increase of children diagnosed with autism spectrum disorders

Introducción: Los Trastornos del Espectro Autista (TEA) son un grupo de complejos trastornos del desarrollo cerebral que se caracterizan por dificultades en la comunicación y la interacción social y por un repertorio de intereses y actividades restringido y repetitivo. Se está asistiendo a un incremento de los pacientes con este diagnóstico. Si bien las causas no están determinadas, se puede atribuir a una mayor concientización sobre el autismo y a la capacidad de detección de los profesionales. Material y Método: Estudio descriptivo. Investigación Cualitativa. Observación. Realizado entre enero y agosto de 2018. M-Chat: Lista de verificación para el autismo en niños pequeños. Criterios diagnósticos DSM V. Signos de alerta. Resultados: A través del trabajo interdisciplinario, de la oportuna observación y aplicación de la herramienta de pesquisa M-Chat destinada a la evaluación de factores de riesgo para autismo, se ha evidenciado la presencia de un número mayor de niños que presentaron signos acordes a un diagnostico dentro del espectro. Conclusión: La detección temprana es una variable determinante de un mejor pronóstico. Debido a la ausencia de marcadores biológicos, el principal medio de detección es la observación. Es por esto que el diagnóstico y la intervención temprana es la mejor respuesta, siendo importante la difusión sobre signos de alerta

Introduction: Autistic Spectrum Disorders (ASD) are a group of complex disorders of brain development characterized by difficulties in communication and social interaction and by a repertoire of interests and restricted and repetitive activities. We are seeing an increase in patients with this diagnosis. Although the causes are not determined, it can be attributed to a greater awareness of autism and the detection capacity of professionals. Material and Method: Descriptive study. Qualitative research. Observation. Made between January and August 2018. M-Chat: Checklist for autism in young children. Diagnostic criteria DSM V. Warning signs. Results: Through the interdisciplinary work, the timely observation and application of the M-Chat research tool aimed at the evaluation of risk factors for autism, the presence of a greater number of children who showed signs according to a diagnostic within the spectrum. Conclusion: Early detection is a determining variable of a better prognosis. Due to the absence of biological markers, the main means of detection is observation. This is why diagnosis and early intervention is the best response, being important the diffusion on warning signs.

Vitamin D and chronic diseases: the current state of the art.

The objective was to provide the current state of the art regarding the role of vitamin D in chronic diseases (osteoporosis, cancer, cardiovascular diseases, dementia, autism, type 1 and type 2 diabetes mellitus, male and female fertility). The document was drawn up by panelists that provided their contribution according to their own scientific expertise. Each scientific expert supplied a first draft manuscript on a specific aspect of the document's topic that was subjected to voting by all experts as "yes" (agreement with the content and/or wording) or "no" (disagreement). The adopted rule was that statements supported by ≥75 % of votes would be immediately accepted, while those with <25 % would be rejected outright. Others would be subjected to further discussion and subsequent voting, where ≥67 % support or, in an eventual third round, a majority of ≥50 % would be needed. This document finds that the current evidence support a role for vitamin D in bone health but not in other health conditions. However, subjects with vitamin D deficiency have been found to be at high risk of developing chronic diseases. Therefore, although at the present time there is not sufficient evidence to recommend vitamin D supplementation as treatment of chronic diseases, the treatment of vitamin D deficiency should be desiderable in order to reduce the risk of developing chronic diseases.