Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT.

ABSTRACT: For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates.

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas.

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.

Music therapy intervention in community-dwelling older adults with mild cognitive impairment: A pilot study.

The purpose of the pilot study was twofold, seeking to investigate both the feasibility and preliminary effects of a music therapy intervention on the global cognitive state (attention, immediate and delayed memory, and executive function) and gait parameters (gait velocity, cadence, and right and left stride length) in older adults with mild cognitive impairment (MCI). Sixteen participants attended the one-hour music therapy sessions three times a week for 12 weeks. The intervention was feasible, achieving a retention rate of 84%. Significant effects were found in global cognitive state (p = .001), attention (p = .007), immediate memory (p < .001), delayed memory (p = .001), executive function (p = .002), gait velocity (p = .021), right stride length (p = .007), and left stride length (p = .014). These results suggest that music therapy intervention is a potentially innovative strategy for improving cognition and gait parameters in older adults with MCI.

[Effect of traffic-light labeling on nutritional content and on consumption of carbonated beverages in EcuadorEfeito da rotulagem nutricional com modelo de semáforo no consumo de refrigerantes no Equador]. / Efecto del etiquetado de semáforo en el contenido nutricional y el consumo de bebidas gaseosas en Ecuador.

OBJECTIVE: To evaluate the effect of "traffic-light" nutritional labeling on the purchase of soft drinks and on their nutritional content in Ecuador. METHODS: Two databases were used: the first was provided by Ecuador's National Agency for Health Regulation, Control, and Surveillance; the second was obtained from the international market research company Kantar World Panel. A before/after study was conducted of introducing traffic-light labeling, using Student's t-tests to evaluate changes in average nutritional content and the purchase of soft drinks. Multiple linear regression methods were used to evaluate changes in purchases resulting from the introduction of traffic-light labeling. RESULTS: After labeling, average per capita consumption of soft drinks declined by 0.003 L/month--a small change with respect to average per capita consumption of 1.678 L/month. The results of the Student's t-tests indicated that this difference was not statistically significant. Furthermore, the regression analyses found no empirical evidence that traffic-light labeling affected soft drink consumption. With regard to sugar content, an average reduction of 0.93 gm/100 ml of beverage was observed. CONCLUSIONS: No empirical evidence was found that implementation of traffic-light labeling changed soft-drink purchase habits in Ecuador, but there is evidence that it reduced sugar content in carbonated beverages in the country.

OBJETIVO: Avaliar o efeito da rotulagem nutricional com modelo de semáforo na compra e no teor nutricional dos refrigerantes no Equador. MÉTODOS: As informações foram obtidas do banco de dados da Agência Nacional de Regulamentação, Controle e Vigilância Sanitária do Equador e do banco de dados da Kantar World Panel, empresa internacional de pesquisa de mercado. Foi feita uma análise do tipo antes-depois da introdução da rotulagem com modelo de semáforo. Foram usados testes t de Student para avaliar a variação nas médias do teor nutricional e na compra de refrigerantes e métodos de regressão linear multivariada para avaliar a variação na compra com a introdução da rotulagem com modelo de semáforo. RESULTADOS: Foi observada uma redução de 0,003 litro/mês no consumo médio per capita de refrigerantes com a introdução da rotulagem, que representa um valor pequeno em relação ao consumo médio per capita (1,678 litro/mês). Os resultados dos testes t de Student indicaram que esta diferença não foi estatisticamente diferente de zero. As análises de regressão também não forneceram evidências empíricas de que a rotulagem com modelo de semáforo tenha influído no consumo de refrigerantes. Com relação ao teor de açúcar, foi verificada uma redução média de 0,93 g por 100 ml de bebida. CONCLUSÕES: Não foram observadas evidências empíricas de que a implantação da rotulagem nutricional com modelo de semáforo alterou os hábitos de compra de refrigerantes, porém houve uma diminuição no teor de açúcar destas bebidas no Equador.

R-wave sensing in an implantable cardiac monitor without ECG-based preimplant mapping: results from a multicenter clinical trial.

INTRODUCTION: Reducing the form factor of an implantable cardiac monitor (ICM) may simplify device implant. This study evaluated R-wave sensing at a range of electrode distances and a preferred device implant location without mapping. METHODS: Patients scheduled for a Medtronic Reveal® ICM implant (Medtronic Inc., Minneapolis, MN, USA) underwent a preimplant pocket recording using a diagnostic recording catheter. The ICM implant location was left to the discretion of the implanting physician, but a "recommended" position spanned the V2 -V3 electrocardiogram electrode location in an oblique 45° angle. R-wave amplitudes were analyzed from ICM follow-up. RESULTS: Seventeen of 41 subjects (15 male, age 57 ± 16 years) had the maximum surface-filtered R-wave at the recommended location. Fourteen patients underwent diagnostic recording across the range of electrode spacing. There was a strong correlation between the R-wave amplitude and electrode distance (r(2) = 0.97, P < 0.001) with an increase of 29 µV per 2.5 mm. Comparing normalized R-wave distributions between the recommended ICM implant group (Group 1, n = 19) and the remaining patients (Group 2, n = 7), the proportion of ICM R-wave counts of amplitude 0.25-1.2 mV was higher (79% vs 46%, P < 0.05). Of 17 patients in Group 1 who had ≥ 1-month ICM follow-up (79 ± 45 days), no sensing-related false arrhythmia detection was found in 16 (93%) patients. CONCLUSIONS: The subcutaneous R-wave amplitude correlates with electrode spacing in the implant zone of ICM patients. Implant locations at the V2 -V3 position at a 45° angle offer an adequate R wave for sensing. Preimplant mapping to achieve acceptable R-wave amplitude may not be necessary.

Fractional order memcapacitive neuromorphic elements reproduce and predict neuronal function.

There is an increasing need to implement neuromorphic systems that are both energetically and computationally efficient. There is also great interest in using electric elements with memory, memelements, that can implement complex neuronal functions intrinsically. A feature not widely incorporated in neuromorphic systems is history-dependent action potential time adaptation which is widely seen in real cells. Previous theoretical work shows that power-law history dependent spike time adaptation, seen in several brain areas and species, can be modeled with fractional order differential equations. Here, we show that fractional order spiking neurons can be implemented using super-capacitors. The super-capacitors have fractional order derivative and memcapacitive properties. We implemented two circuits, a leaky integrate and fire and a Hodgkin-Huxley. Both circuits show power-law spiking time adaptation and optimal coding properties. The spiking dynamics reproduced previously published computer simulations. However, the fractional order Hodgkin-Huxley circuit showed novel dynamics consistent with criticality. We compared the responses of this circuit to recordings from neurons in the weakly-electric fish that have previously been shown to perform fractional order differentiation of their sensory input. The criticality seen in the circuit was confirmed in spontaneous recordings in the live fish. Furthermore, the circuit also predicted long-lasting stimulation that was also corroborated experimentally. Our work shows that fractional order memcapacitors provide intrinsic memory dependence that could allow implementation of computationally efficient neuromorphic devices. Memcapacitors are static elements that consume less energy than the most widely studied memristors, thus allowing the realization of energetically efficient neuromorphic devices.

Adoptive T cell therapy for solid tumors: current landscape and future challenges.

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.

Masticatory Myofascial Pain Disorders.

Masticatory myofascial pain disorders (MMPD) are a common group of orofacial pain conditions affecting the muscles of mastication, with headache and cervical disorders as well as chronic widespread pain and psychosocial disorders being common comorbid conditions. As their pathophysiology is multifactorial in nature, a multimodal and interdisciplinary approach should be considered. Overall treatment goals include decreasing pain and disability, increasing mandibular range of motion, and improving quality of life. This article describes a complex case exhibiting common characteristics of MMPD while additionally reviewing the literature on classification, pathophysiology, and evidence-based treatment planning.

Current Landscape of Immunotherapy for Advanced Sarcoma.

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine-kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature.

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

Global Cardio Oncology Registry (G-COR): Registry Design, Primary Objectives, and Future Perspectives of a Multicenter Global Initiative.

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Effect of Altitude on Respiratory Functional Status in COVID-19 Survivors: Results from a Latin American Cohort-FIRCOV.

Laura Gochicoa-Rangel, Santiago C. Arce, Carlos Aguirre-Franco, Wilmer Madrid-Mejía, Mónica Gutiérrez-Clavería, Lorena Noriega-Aguirre, Patricia Schonffeldt-Guerrero, Agustín Acuña-Izcaray, Arturo Cortés-Telles, Luisa Martínez-Valdeavellano, Federico Isaac Hernández-Rocha, Omar Ceballos-Zúñiga, Rodrigo Del Rio Hidalgo, Sonia Sánchez, Erika Meneses-Tamayo, and Iván Chérrez-Ojeda; and on Behalf of the Respiratory Physiology Project in COVID-19 (FIRCOV). Effect of altitude on respiratory functional status in COVID-19 survivors: results from a Latin American Cohort-FIRCOV. High Alt Med Biol 24:37-48, 2023. Persistent symptoms and lung function abnormalities are common in COVID-19 survivors. Objectives: To determine the effect of altitude and other independent variables on respiratory function in COVID-19 survivors. Methods: Analytical, observational, cross-sectional cohort study done at 13 medical centers in Latin America located at different altitudes above sea level. COVID-19 survivors were invited to perform pulmonary function tests at least 3 weeks after diagnosis. Results: 1,368 participants (59% male) had mild (20%), moderate (59%), and severe (21%) disease. Restriction by spirometry was noted in 32%; diffusing capacity of the lung for carbon monoxide (DLCO) was low in 43.7%; and 22.2% walked less meters during the 6-minute walk test (6-MWT). In multiple linear regression models, higher altitude was associated with better spirometry, DLCO and 6-MWT, but lower oxygen saturation at rest and during exercise. Men were 3 times more likely to have restriction and 5.7 times more likely to have a low DLCO. Those who had required mechanical ventilation had lower DLCO and walked less during the 6-MWT. Conclusions: Men were more likely to have lower lung function than women, even after correcting for disease severity and other factors. Patients living at a higher altitude were more likely to have better spirometric patterns and walked farther but had lower DLCO and oxygen saturation.

Limitations of occasional reinforced extinction to alleviate spontaneous recovery and reinstatement effects: Evidence for a trial-signalling mechanism.

Fear extinction is not permanent but is instead more vulnerable than the original fear memory, as traditionally shown by the return of fear phenomena. Because of this, techniques to mitigate the return of fear are needed in the clinical treatment of related psychological conditions. One promising strategy is the occasional reinforced extinction treatment, introducing a gradual and sparse number of conditioned stimulus-unconditioned stimulus (CS-US) pairings within the extinction treatment. We present the results of three experiments in which we used a threat conditioning procedure in humans. Our main aim was to evaluate whether occasional reinforced extinction could reduce two different forms of relapse: spontaneous recovery (Experiments 1 and 2) and reinstatement (Experiment 3). Contrary to our predictions and previous literature, the results indicate that an occasional reinforcement treatment did not mitigate relapse compared with standard extinction. From a theoretical standpoint, these results are more consistent with the idea that extinction entails the acquisition of new knowledge than with the idea that there are conditions in which extinction leads to a weakening of the original fear memory. These findings also question the generality of the potential benefits of using occasional reinforced extinction in clinical settings.

Implication of Neutrophils Extracellular Traps in the Pathogenesis of SARS-CoV-2 pneumonia.

Peripheral blood polymorphonuclear neutrophils (PMNs) forming extracellular traps (NETs), as well as endothelial- and platelet-derived parameters, have been analyzed in patients with SARS-CoV-2 pneumonia, and their prognostic role has been evaluated. Eighty-seven consecutive patients hospitalized with SARS-CoV-2 pneumonia were prospectively selected. A sample of 30 healthy individuals served as the control group. Clinical and oxygenation (oxygen saturation to fraction of inspired oxygen ratio-SpO2/FiO2) characteristics and PMNs forming NETs, serum levels of myeloperoxidase, E-selectin, vascular cell adhesion molecule 1-VCAM1-vascular endothelial growth factor, P-selectin, platelet factor 4 and plasma concentrations of D-dimer were evaluated at hospital admission, at discharge and 14 days after discharge. Intensive care unit admission or death was the primary composite endpoint. Patients showed a higher number of PMNs forming NETs than healthy controls. The absolute number of PMNs forming NETs was inversely correlated with oxygen status (SpO2/FiO2) and positively with inflammatory (C-reactive protein, ferritin) markers and VCAM1. A decrease in, but not a normalization of NETs and endothelial-derived parameters was observed in patients who survived. In conclusion, the formation of NETs runs parallel to that of other inflammatory and endothelial activation markers, and is inverse to the oxygenation parameters, supporting a pathogenic role for PMNs in this entity.

Perceived Risks of Infection, Hospitalization, and Death From COVID-19 at the Equator: Ecuador and Kenya.

OBJECTIVES: This study's goal was to determine the perceived risks of infection as well as the perceived risks of hospitalization and death from COVID-19 in Ecuador and Kenya. It also assessed the factors associated with the risk-related perceptions. METHODS: Cross-sectional studies with samples from the adult populations in both countries were conducted to assess the perceived risks of contracting COVID-19. Data were collected online using the Qualtrics platform (Qualtrics, Provo, Utah, United States) from samples of 1050 heads of households, aged 18 years or older, in each country. A total of 3 statistical analyses were conducted: summary statistics, correlation, and linear regression. RESULTS: The average perceived risks of COVID-19 infection, hospitalization, and death in the Kenyan sample were 27.1%, 43.2%, and 17.2%, respectively, and the values for the Ecuadorian sample were 34%, 32.8%, and 23.3%, respectively. The Pearson's correlation coefficients between the risk measures in each country were less than 0.38. Risk measures were associated with several sociodemographic variables (e.g., income, gender, location), but not with age. CONCLUSIONS: The perceived risks of COVID-19 infection, hospitalization, and death in Kenya and Ecuador were significantly higher relative to the statistics reported; however, no strong association existed between perceived risk and age, which is a key factor in adverse health outcomes, including death, among COVID-19 infected individuals.

High prevalence of obstructive sleep apnea syndrome in Spain's Stroke Belt.

OBJECTIVE: Spain's so-called Stroke Belt is an area with high prevalence of vascular disease. We aimed to determine the prevalence of undetected obstructive sleep apnea-hypopnea syndrome (OSAHS) among patients with acute ischemic stroke (AIS) in southern Spain. METHODS: We conducted a cross-sectional study at the Virgen Macarena University Hospital Stroke Unit during 2018 to 2019. We included patients <72 hours after AIS with a neuroimaging lesion and performed sleep tests. RESULTS: Seventy-two patients were included. The median participant age was 72 years. Mean body mass index was 27.07 kg/m2, and 40.28% were daily alcohol drinkers. Hypertension, atrial fibrillation, ischemic cardiomyopathy, and previous stroke were detected in 63.9%, 11.1%, 15.3%, and 17.6% of patients, respectively. Polygraphy was feasible in 91.38% of patients. The prevalence of OSAHS was 84.72% (apnea-hypopnea index ≥5). Patients with moderate and severe OSAHS were more likely to be obese and to have a larger neck circumference and facial palsy. The diagnostic criteria of central sleep apnea syndrome were met in only 1.38% of patients. CONCLUSIONS: The high prevalence of OSAHS found in the Spanish Stroke Belt justifies further investigation and development of a screening program as a strategy to identify patients with undetected OSAHS.

Cardiovascular Manifestations From Therapeutic Radiation: A Multidisciplinary Expert Consensus Statement From the International Cardio-Oncology Society.

Radiation therapy is a cornerstone of cancer therapy, with >50% of patients undergoing therapeutic radiation. As a result of widespread use and improved survival, there is increasing focus on the potential long-term effects of ionizing radiation, especially cardiovascular toxicity. Radiation therapy can lead to atherosclerosis of the vasculature as well as valvular, myocardial, and pericardial dysfunction. We present a consensus statement from the International Cardio-Oncology Society based on general principles of radiotherapy delivery and cardiovascular risk assessment and risk mitigation in this population. Anatomical-based recommendations for cardiovascular management and follow-up are provided, and a priority is given to the early detection of atherosclerotic vascular disease on imaging to help guide preventive therapy. Unique management considerations in radiation-induced cardiovascular disease are also discussed. Recommendations are based on the most current literature and represent a unanimous consensus by the multidisciplinary expert panel.

Clinical characterization and outcomes of 85 patients with neurosarcoidosis.

To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis.