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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

Testicular cancer is a rare tumor with a worldwide incidence that has increased over the last few decades. The majority of these tumors are testicular non-germ (TNGCTs) and germ cell tumors (TGCTs); the latter divided into two broad classes - seminomatous (SGCTs) and non-seminomatous germ cell tumors (NSGCTs). Although ultrasonography (US) maintains a primary role in the diagnostic workup of scrotal pathology, magnetic resonance imaging (MRI) has emerged as the imaging modality recommended for challenging cases, providing additional information to clarify inconclusive/equivocal US. In this work we describe and publicly share a collection of 44 images of annotated T2-weighted MRI lesions from 42 patients. Given that testicular cancer is a rare tumor, we are confident that this collection can be used to validate statistical models and to further investigate TNGCT and TGCT peculiarities using medical imaging features., Measurement(s) sex cord-gonadal stromal tumor Technology Type(s) magnetic resonance imaging Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14511624

The consequences of pumping on food quality are poorly understood, and wine is a good example. Therefore, the present paper examines the use of four pumps and the application of inertization on wine quality. We develop a novel, physical qualitative index (PQI), which is the ratio between pumping specific energy and the net positive suction head, and examine the correlation with wine quality characteristics. Four pumps (a flexible impeller pump, a lobe pump, a peristaltic pump, and a rotary piston pump) that are widely-used in wine cellars were compared over a wide array of chemical-physical variables, during conventional racking, with and without inertization. The analysis found a correlation between the PQI and some quality variables, and this finding was confirmed by a conventional statistical analysis (ANOVA-GLM). Overall, the flexible impeller pump performed slightly differently compared to the other pumps with respect to some color-related parameters. All pumps behave differently as a function of inertization (or not). Inertization was effective in minimizing volatile losses.

Objective: To document antiretroviral use in Latin America during the last decade. Methods: We collected indicators from 79 HIV health care centres in 14 Latin American Spanish-speaking countries for 2013–2017. Indicators were analysed by age, sex and other characteristics and weighted by the estimated people under care (PUC) population in each country. Results: We gathered information on 116 299 PUC. One-third belonged to centres reporting a shortage of at least one antiretroviral therapy (ART) drug for >30 days during 2017. At end 2017, 95.1% of PUC were receiving ART. During 2013–2017, 45 329 people living with HIV were admitted to 39 centres. ART initiated during the first year after admission increased from 76.7% in 2013 to 83.8% in 2017. In 35 centres across the study period, 71.7% of PUC started ART with tenofovir disoproxil fumarate and lamivudine, and zidovudine use decreased. The third most common ART drug, EFV, reached 64.8%. Raltegravir and other alternatives increased annually to almost 10% of total use in 2017. Conclusions: Initial ART in Latin America is not based on the most recent scientific evidence and recommendations; use of drugs with higher efficacy and safety profiles and guarantee of ART availability continues to be a public health challenge.

How to differentiate with MRI-based techniques testicular germ (TGCTs) and testicular non-germ cell tumors (TNGCTs) is still under debate and Radiomics may be the turning key. Our purpose is to investigate the performance of MRI-based Radiomics signatures for the preoperative prediction of testicular neoplasm histology. The aim is twofold: (i), differentiating TGCTs and TNGCTs status and (ii) differentiating seminomas (SGCTs) from non-seminomatous (NSGCTs). Forty-two patients with pathology-proven testicular neoplasms and referred for pre-treatment MRI, were retrospectively enrolled. Thirty-two out of 44 lesions were TGCTs. Twelve out of 44 were TNGCTs or other histologies. Two radiologists segmented the volume of interest on T2-weighted images. Approximately 500 imaging features were extracted. Least Absolute Shrinkage and Selection Operator (LASSO) was applied as method for variable selection. A linear model and a linear support vector machine (SVM) were trained with selected features to assess discrimination scores for the two endpoints. LASSO identified 3 features that were employed to build fivefold validated linear discriminant and linear SVM classifiers for the TGCT-TNGCT endpoint giving an overall accuracy of 89%. Four features were employed to build another SVM for the SGCT-SNGCT endpoint with an overall accuracy of 86%. The data obtained proved that T2-weighted-based Radiomics is a promising tool in the diagnostic workup of testicular neoplasms by discriminating germ cell from non-gem cell tumors, and seminomas from non-seminomas.

STUDY OBJECTIVES: To investigate the prevalence of mildly collapsible upper airways (defined by therapeutic continuous positive airway pressure [CPAP] values ≤ 8 cm H(2)O) in moderate to severe obstructive sleep apnea patients treated with CPAP and to determine their clinical, functional, and nocturnal polysomnographic characteristics. METHODS: Eighty-seven patients with moderate to severe obstructive sleep apnea consecutively treated with CPAP were retrospectively investigated. Two nocturnal home sleep portable monitoring studies were performed at baseline and during treatment. Participants were categorized according to therapeutic CPAP values: ≤ 8 cm H(2)O (group 1), 8–12 cm H(2)O (group 2), ≥ 12 cm H(2)O (group 3). Anthropometric, awake respiratory function, symptoms, comorbidities, and nocturnal home sleep portable monitoring studies data were collected. RESULTS: Mild upper airway collapsibility (therapeutic CPAP values ≤ 8 cm H(2)O) was present in 25.3% of patients. They showed more favorable apnea-hypopnea index, oxygen desaturation index, mean nocturnal saturation, sleep time with oxygen saturation < 90%, desaturation nadir, and supine position. Oxygen desaturation index showed a weak association with anatomical collapsibility. Using the receiver operating characteristic curve, the area under the curve for the oxygen desaturation index vs CPAP pressure requirements ≤ 8 cm H(2)O was low and oxygen desaturation index ≤ 40.8/h showed a sensitivity of 63.3% and a specificity of 69.2% to detect patients with mild collapsibility. CONCLUSIONS: A quarter of moderate to severe patients under CPAP therapy had mild collapsibility and were likely to also be good candidates for alternative and better tolerated non-CPAP therapies. Baseline anthropometric, clinical, and respiratory function characteristics did not predict mild upper airway collapsibility determined by CPAP pressure requirements ≤ 8 cm H(2)O. CITATION: Bosi M, Incerti Parenti S, Fiordelli A, Poletti V, Alessandri-Bonetti A. Upper airway collapsibility in patients with OSA treated with continuous positive airway pressure: a retrospective preliminary study. 2020;16(11):1839–1846.

Dementia is a pathological condition characterized by a decline in memory, as well as in other cognitive and social functions. The cellular and molecular mechanisms of brain damage in dementia are not completely understood; however, neuroinflammation is involved. Evidence suggests that chronic inflammation may impair cognitive performance and that dietary protein source may differentially influence this process. Dietary protein source has previously been shown to modify systemic inflammation in mouse models. Thus, we aimed to investigate the effect of chronic dietary protein source substitution in an ageing and dementia male mouse model, the senescence-accelerated mouse-prone 8 (SAMP8) model. We observed that dietary protein source differentially modified memory as shown by inhibitory avoidance testing at 4 months of age. Also, dietary protein source differentially modified neuroinflammation and gliosis in male SAMP8 mice. Our results suggest that chronic dietary protein source substitution may influence brain ageing and memory-related mechanisms in male SAMP8 mice. Moreover, the choice of dietary protein source in mouse diets for experimental purposes may need to be carefully considered when interpreting results.

Mandibular advancement devices (MADs) are used to treat patients with obstructive sleep apnoea (OSA). To date, there are no data that identify the most effective MAD design for apnoea-hypopnea index (AHI) reduction. The purpose of this systematic review is to investigate the effectiveness of different MAD designs in AHI reduction and oxygen saturation improvement in OSA patients. An electronic search was performed in MEDLINE, Cochrane Database, Scopus, Web of Knowledge and LILACS. Randomised controlled trials (RCTs) investigating the reduction of AHI on adult patients wearing MAD for OSA were included. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and the risk of bias by the Cochrane Collaboration's tool for assessing risk of bias in randomised controlled trial. The success rate of each study was computed: [(mean baseline AHI−mean AHI after treatment)/mean baseline AHI]. Fifty RCTs were included. The risk of bias resulted with some concerns in most of the studies. The GRADE scores indicated that the quality of evidence was very low. The meta-analysis showed a success rate with mono-bloc and duo-bloc MADs respectively of 0.821 [0.722-0.887] and 0.547 [0.443-0.637]. The mono-bloc compared with duo-bloc better improved the minimum oxygen saturation (10.048 [7.733-12.363] and 3.357 [2.290-4.423], respectively). There is a very low quality body of evidence that mono-bloc MADs are more effective in reducing AHI and improving minimum oxygen saturation compared with duo-bloc MADs. The study protocol was registered on PROSPERO (n. CRD42019118084).

NO abstract available- Case report

A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSDs) has been proposed, but no consensus on management guidelines exists. The aim of this study was to describe current experiences with dietary lipid manipulations in hepatic GSD patients. An international study was set up to identify published and unpublished cases describing hepatic GSD patients with a dietary lipid manipulation. A literature search was performed according to the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share unpublished cases. Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine kinase concentrations (n = 19, P

Background Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glucose 6-phosphate (G6P) availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients. Methods Seventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed. Results Baseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients. Conclusions The present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11βHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.

Hematocolpos is a term given to a blood-filled dilated vagina due to menstrual blood. When there is concurrent uterine distention, the term hematometrocolpos is used. These conditions are mostly in the setting of an anatomical obstruction, usually an imperforate hymen. Usually, clinical presentation may be characterized by primary amenhorrea, recurrent abdominal or pelvic pain, urinary retention and dys-uria or constipation. Imaging techniques such as trans-abdominal ultrasound and nuclear magnetic res-onance are respectively the exam of choice and the “gold standard” exam for diagnosing hematocolpos. The paper reports the case of a 12-year-old girl with a sacral pain present for a month, not associated with other symptoms with a diagnosis of hematocolpos that became evident to the magnetic resonance.

The state of the art of stereotactic surgery is reported with particular attention to robot-based surgical systems in order to highlight what are the technical limits still present. From this basic knowledge, alternative operating methods based on thermoplastic masks, already in use in radiosurgery, are proposed, which can compensate for these technical limitations and improve the experience for both the patient and the surgeon. In particular, two different solutions using the mask are presented. Finally, a comparison between the two solutions is discussed and possible future developments are outlined.

This study investigates the effect of liquid-type organofluorine additives (OFAs) on the morphology, thermal conductivity and mechanical properties of rigid polyurethane (PU) and polyisocyanurate (PIR) foams. Foams were characterized in terms of their morphology (density, average cell size, anisotropy ratio, open cell content), thermal conductivity and compressive as well as flexural properties. Based on the results, we observed that OFAs efficiently reduced the average cell size of both PU and PIR foams, leading to improved thermal insulating and mechanical properties.

Objective Evaluate tolerability and effectiveness of golimumab-IV versus infliximab in patients with rheumatoid arthritis (RA) in a real-world setting. Methods AWARE, a prospective, real-world, pragmatic, observational, multicenter, phase 4 study, enrolled RA patients when initiating golimumab-IV or infliximab. Treatment decisions were made by the treating rheumatologist. The approved doses for RA are 2 mg/kg at weeks 0, 4, then Q8W for golimumab-IV and 3 mg/kg at weeks 0, 2, 6, then Q8W (dose escalation permitted) for infliximab. A prespecified formal interim analysis was conducted. The primary endpoint was the incidence of infusion reactions (any adverse event that occurred during or within 1 h of infusion) through week 52. Major secondary endpoints were mean change from baseline in CDAI at months 6 and 12 in biologic-naïve patients (non-inferiority margin in the CDAI = 6). Baseline characteristics were adjusted using propensity scores with inverse probability of treatment weights (IPTW). Results In the formal interim analysis (golimumab-IV, n = 479; infliximab, n = 354), the incidence of infusion reactions was significantly lower with golimumab-IV vs. infliximab (3.6 vs. 17.6%, p

Severe acute malnutrition (SAM), due to poor energy and/or protein intake, is associated with poor growth, depressed immune function, and long-term impacts on metabolic function. As the liver is a major metabolic organ and malnutrition poses metabolic stress, we hypothesize that SAM will be associated with alterations in the hepatic metabolome reflective of oxidative stress, gluconeogenesis, and ketogenesis. Thus, the purpose of this secondary analysis was to understand how SAM alters hepatic metabolism using a piglet model. Weanling piglets were feed either a reference (REF) or protein-energy deficient diet (MAL) for 5 weeks. After dietary treatment MAL piglets were severely underweight (weight-for-age Z-score of -3.29, Welch's t test, P = .0007), moderately wasted (weight-for-length Z-score of-2.49, Welch's t test, P = .003), and tended toward higher hepatic triglyceride content (Welch's t test, P = .07). Hematologic and blood biochemical measurements were assessed at baseline and after dietary treatment. The hepatic metabolome was investigated using 1H-NMR spectroscopy. Hepatic concentrations of betaine, cysteine, and glutathione tended to be lower in MAL (Welch's t test with FDR correction, P < .1), while inosine, lactate, and methionine sulfoxide concentrations were higher in MAL (inosine: P = .0448, lactate: P = .0258, methionine sulfoxide: P = .0337). These changes suggest that SAM is associated with elevated hepatic oxidative stress, increased gluconeogenesis, and alterations in 1-carbon metabolism.

Objective Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients. Design and methods In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed. Results 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death. Conclusions These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.

This paper presents the results of a dissertation that analyzes the presence of discussions regarding subjectivity in the theoretical production on Environmental Education (EA) and Training of Biology Teachers, published by Scientific Electronic Library Online (SciELO) between 2008 and 2018. We adopted three sets of search terms and twenty-seven (27) articles were identified. The analysis revealed the presence of discussions on subjectivity in the proposed association of nature to culture; the adoption of terms such as perception, conception, identity, meaning and significance in the elaboration of research problems; and the use of participatory and collaborative methodologies. The material analyzed allows the identification of the discussions about subjectivity regarding the adoption of certain theoretical categories and on the use of participatory methodologies in research with teachers.

Telomeres are structures located at the ends of chromosomes associated with a protein complex, known as the shelterin complex. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. In this context, bariatric surgery is one of the most effective treatment modalities in improving metabolic control. Therefore, the present study aimed to evaluate how a short postoperative period of gastric bypass affects TL and expression of POT1, TRF1 and TRF2 genes. Forty-eight women submitted to RYGB were evaluated before and after 6 months of the surgical procedure. Anthropometric measures of body weight and height (BMI), abdominal circumference (AC), body composition, food intake and blood collection for biochemical evaluation, TL analysis (DNA), and gene expression (RNA) were collected at each moment. There was a reduction of weight, BMI, AC, FM and FFM as well as of glycemia, total cholesterol, LDL-cholesterol, and triglycerides after gastric bypass. No difference in energy intake and macronutrients consumption was observed. There was no significant change in TL, but there was a significant increase of POT1 and TRF1 gene expression after surgery, while TRF2 expression did not change. Despite bariatric surgery is not capable of increasing telomere length in a short-term period, no reduction is observed; additionally, we found a correlation between serum triglycerides concentration and TL. The increase of POT1 and TRF1 gene expression may explain the maintenance of the TL after 6 months postoperative period.

Made available in DSpace on 2021-06-25T12:36:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01. Added 1 bitstream(s) on 2021-07-15T15:06:14Z : No. of bitstreams: 1 S0365-05962020000700001.pdf: 1881463 bytes, checksum: 96fc88ab45524d797f57de4680576471 (MD5) Background: Chronic leg ulcers affect a large portion of the adult population and cause a significant social and economic impact, related to outpatient and hospital care, absence from work, social security expenses, and reduced quality of life. The correct diagnosis and therapeutic approach are essential for a favorable evolution. Objective: To gather the experience of Brazilian dermatologists, reviewing the specialized literature to prepare recommendations for the diagnosis and treatment of the main types of chronic leg ulcers. Methods: Seven specialists from six university centers with experience in chronic leg ulcers were appointed by the Brazilian Society of Dermatology to reach a consensus on the diagnosis and therapeutic management of these ulcers. Based on the adapted DELPHI methodology, relevant elements were considered in the diagnosis and treatment of chronic leg ulcers of the most common causes; then, the recent literature was analyzed using the best scientific evidence. Results: The following themes were defined as relevant for this consensus - the most prevalent differential etiological diagnoses of chronic leg ulcers (venous, arterial, neuropathic, and hypertensive ulcers), as well as the management of each one. It also included the topic of general principles for local management, common to chronic ulcers, regardless of the etiology. Conclusion: This consensus addressed the main etiologies of chronic leg ulcers and their management based on scientific evidence to assist dermatologists and other health professionals and benefit the greatest number of patients with this condition. (C) 2020 Sociedade Brasileira de Dermatologia. Published by Elsevier Espana, S.L.U. Univ Estadual Paulista, Fac Med, Dept Infect Dis Dermatol Diagnost Imaging & Radio, Botucatu, SP, Brazil Univ Sao Paulo, Fac Med, Dept Internal Med, Dermatol Div, Ribeirao Preto, SP, Brazil Hosp Padre Bento de Guarulhos, Dermatol Serv, Guarulhos, SP, Brazil Univ Cidade Sao Paulo, Fac Med, Discipline Dermatol, Sao Paulo, SP, Brazil Fac Med, Discipline Dermatol, Jundiai, SP, Brazil Univ Fed Fluminense, Dept Clin Med, Discipline Dermatol, Niteroi, RJ, Brazil Univ Fed Minas Gerais, Hosp Clin, Dermatol Serv, Belo Horizonte, MG, Brazil Univ Sao Paulo, Hosp Clin, Fac Med, Dermatol Serv, Ribeirao Preto, SP, Brazil Univ Fed Sao Paulo, Dept Dermatol, Sao Paulo, SP, Brazil Univ Estadual Paulista, Fac Med, Dept Infect Dis Dermatol Diagnost Imaging & Radio, Botucatu, SP, Brazil

Background In preparation for the 2021 revision of the European Union Tobacco Products Directive, the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) has posted its Preliminary Opinion on Electronic Cigarettes. They concluded that e-cigarettes only achieve a sub-optimal level of protection of human health. In this paper, we provide evidence that the Opinion’s conclusions are not adequately backed up by scientific evidence and did not discuss the potential health benefits of using alternative combustion-free nicotine-containing products as substitute for tobacco cigarettes. Methods Searches for articles were conducted in PubMed and by citation chasing in Google Scholar. Articles were also retrieved with a review of references in major publications. Primary data from World Health Organization surveys, the conclusions of reviews, and peer-reviewed non-industry studies were cited to address errors and omissions identified in the Opinion. Results The Opinion omitted reporting on the individual and population health benefits of the substitution of e-cigarettes (ENDS) for cigarette smoking. Alternative hypotheses to the gateway theory were not evaluated. Its assessment of cardiovascular risk is contradicted by numerous reviews. It cites ever-use data that do not represent current patterns of use. It did not report non-nicotine use. It presented erroneous statements on trends in ENDS prevalence. It over-emphasized the role of flavours in youth ENDS initiation. It did not discuss cessation in sufficient length. Conclusions For the delivery of a robust and comprehensive final report, the members of the Working Group of the Scientific Committee on Health, Environmental and Emerging Risks will need to consider (1) the potential health benefits of ENDS substitution for cigarette smoking, (2) alternative hypotheses and contradictory studies on the gateway effect, (3) its assessment of cardiovascular risk, (4) the measurements of frequency of use, (5) non-nicotine use, (6) the role of flavours, and (7) a fulsome discussion of cessation.

Summary This systematic review and meta-analysis evaluated the diagnostic accuracy of screening questionnaires for pediatric obstructive sleep apnea (OSA). Studies comparing any questionnaire with polysomnography for OSA detection in subjects aged ≤18 y were considered eligible for qualitative analysis. The quality assessment of diagnostic accuracy studies (QUADAS-2) tool was used for bias assessment. Only questionnaires adopted by at least four studies using the currently accepted diagnostic threshold of apnea–hypopnea index (AHI) ≥1 were included for further selective quantitative analyses. A bivariate meta-analysis was performed to calculate sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio; summary receiver operator characteristic curves were constructed. 37 studies (20 questionnaires) were eligible for qualitative analysis; none were considered of low quality. Among these articles, 13 studies and two questionnaires (sleep-related breathing disorder scale of the pediatric sleep questionnaire (SRBD-PSQ) and OSA-18) satisfied the criteria for quantitative synthesis. SRBD-PSQ had higher sensitivity (0.76) than OSA-18 (0.56), while OSA-18 exhibited higher specificity (0.73) than SRBD-PSQ (0.43). SRBD-PSQ performed well and was the most sensitive screening questionnaire using the diagnostic threshold of AHI ≥1 for pediatric OSA. However, further well-designed studies are still required to assess the role of SRBD-PSQ in real-world clinical populations.

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.

Neuropathic pain is one of the most disabling forms of chronic pain and it is characterized by hyperalgesia and allodynia linked to an aberrant processing of pain transmission and to neuroinflammation. Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine, which protects against neuroinflammation. It has been demonstrated that TGF-β1 and opioid receptors signalling crosstalk results in an improvement of endogenous opioid analgesia, but it is not known whether mu opioid peptide receptor (MOPr) or delta opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway. In the present study, we examined the correlation between anti-allodynic effect of LP2, a dual-target MOPr/DOPr agonist, and TGF-β1 signalling in the chronic constriction injury (CCI) model. We detected a significant decrease of active TGF-β1 and of its type II receptor TGFβ-R2 levels in the spinal cord from CCI rats and a selective deficit of TGF-β1 in microglia cells both at days 11 and 21 post-ligature, as assessed by immunofluorescence analysis. LP2, when administered from the 11 days post-ligature to 21 days, was able to reduce CCI-induced mechanical allodynia by rescue of TGF-β1 and TGFβ-R2 levels. Our data suggest that the rescue of TGF-β1 signalling by dual-target MOPr/DOPr agonist LP2 could be mediated by DOPr activation in spinal microglia, thus the dual-target approach could represent a novel pharmacological approach to increase the analgesic efficacy of MOPr agonists.

This paper studies the deep and proximate determinants of the evolution of the cross-country distribution of GDP per worker in the period 1960–2008 by a novel method based on an information criterion. We find that countries of our sample follow three distinctive growth regimes identified by two deep determinants, namely life expectancy at birth in 1960 and the share of Catholics in 1965, and that each regime is characterized by non-linearities. Growth regimes appear to be the main cause of the increased inequality and polarization, while technological catch-up, proxied by the initial level of GDP per worker, acts in the opposite direction. Finally, human capital marginally reduces polarization, while investment rates and employment growth have no distributional effect.

Importance Obstructive sleep apnea (OSA) is a major public health issue that can have serious medical consequences. Although continuous positive airways pressure (CPAP) is currently the first-line treatment for OSA, there is increasing evidence on the effectiveness of oral appliances (OAs) which show higher treatment adherence compared with CPAP. This review focuses on indications, effectiveness and side effects of treatment with OAs in adult OSA patients. The role of dentists in the multidisciplinary diagnosis and management of OSA is also discussed and the most up-to-date scientific evidence for an evidence-based clinical decision-making process is summarized. Observations Qualified dentists in dental sleep medicine can screen patients for OSA using questionnaires and evaluating the presence of anatomic risk factors during routine examinations. Sleep physicians confirm the diagnosis of OSA, determine whether treatment is indicated and may recommend OAs. Qualified dentists evaluate patients for suitability of OAs and begin therapy with the proper device. A collaborative follow-up should be performed during treatment, with patients being periodically monitored by sleep physicians for objective sleep testing and, also, by qualified dentists for OA adjustment and management of any side effect. Conclusion and Relevance Custom-made and titratable OAs are indicated for adult OSA patients who do not tolerate or who are not good candidates for CPAP. A multidisciplinary approach allows to establish the least possible amount of mandibular advancement while achieving the highest reduction of OSA severity, thus optimizing the treatment effectiveness, reducing the occurrence of side effects and decreasing the risk of treatment discontinuation.

Objetivo.Mapear as características de implantação de novos cursos de Medicina nas universidades federais brasileiras, a partir de 2013.Métodos.Estudo exploratório com metodologia quantitativa e qualitativa. Foi realizado um levantamento das novas escolas de Medicina em universidades federais, com análise dos projetos pedagógicos dos cursos e entrevistas a estudantes, professores e profissionais de serviços de saúde vinculados às escolas de Medicina. Os dados coletados foram analisados quantitativa e qualitativamente.Resultados.Foram identificados 30 novos cursos de Medicina, dos quais 24 foram visitados. Todos os novos cursos se localizam fora dos grandes centros urbanos e capitais, nas cinco macrorregiões brasileiras; são organizados em arranjos formativos diversos, que buscam superar a fragmentação disciplinar com metodologias ativas e avaliação formativa. A rede de saúde é utilizada na formação para enfrentamento dos desafios da integração ensino-serviço-comunidade, com vistas a uma formação crítica e voltada à saúde pública. A criação dos cursos promoveu a interiorização de docentes, embora de forma limitada, e contribuiu para o ingresso de estudantes locais e a criação de residências médicas, expedientes potentes na fixação médica.Conclusões.Observou-se diversidade nas formas da materialidade e aderência ao disposto pelas Diretrizes Curriculares Nacionais de Medicina publicadas em 2014. A construção de modelos de formação médica condizentes com as particularidades locais e com as exigências do Sistema Único de Saúde (SUS) em seu papel de ordenador da formação dos profissionais da saúde pode contribuir para reduzir as desigualdades em saúde.

Assess if timing of removal of a percutaneous left ventricular assist device (pLVAD) after ventricular tachycardia (VT) ablation alters patient outcomes. Sixty-nine patients underwent pLVAD support. Patients were divided into early (

Clinical records of patients who underwent implant-supported rehabilitation according to the biologically oriented preparation technique (BOPT) principles were retrospectively analyzed. Records of 189 nonconsecutive patients who received 502 implants were reviewed. At the last follow-up visit (occurring on average 5.11 years after prosthesis delivery), 466 (92.8%) implants had a Gingival Index of 0, and 491 (97.8%) presented no bleeding on probing. Four hundred eighty-nine crowns on as many implants (97.4%) showed no sign of gingival recession. Technical complications occurred with 10 implants (2.0%) and 6 patients (3.2%). Biologic complications were detected with 14 implants (2.8%) and 6 patients (3.2%). When the BOPT approach is applied to rehabilitate patients using implant-supported prostheses, excellent medium-term results concerning soft tissue health may be achieved.

Background People living with HIV (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and prone to statin-related adverse events from drug-drug interactions with certain antiretroviral regimens. Objectives This study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV. Methods BEIJERINCK is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C Results A total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% CI: 61.6%, 52.3%) from baseline to week 24 versus placebo. An LDL-C level of Conclusions Evolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk.

Idiopathic pericarditis (IP) and pericardial mesothelioma (PM) are causes of pericardial effusion in dogs. Pericardiectomy can be a definitive treatment in the case of idiopathic pericardial effusion or a short-term intervention for mesothelioma. The aim of the present study was to investigate which histopathologic parameters are correlated with clinical outcomes in a cohort of dogs that underwent pericardiectomy. The histopathological findings of 22 IPs and 5 PMs were compared with clinical and survival data and the immunohistochemical characterization of immune cells (CD3, CD79α, Iba1). In IP, the mesothelium was lost in 20 cases, reactive in 9, atypical in 3, and mesothelial papillary hyperplasia (MPH) was observed in 4 cases. Numerous macrophages were found in both IPs and PMs especially at the superficial layer of the pericardium. T lymphocytes were observed in mild to moderate numbers and were more numerous than B lymphocytes in both IPs and PMs. MPH was correlated with the quantity of lymphoplasmacytic infiltrate in the superficial layer, inversely related to the thickness of the pericardium, and associated with a longer overall survival. Pericardial fibrosis was present in 19 out of 22 IPs and in all mesotheliomas and was correlated with increased time from initial presentation and pericardiectomy and lymphoplasmacytic infiltrate in the deep zone. Pericardial thickness was correlated with the amount of lymphoplasmacytic and macrophagic infiltrate in the deep zone. Mesothelioma was associated with an increased number of pericardiocentesis procedures before pericardiectomy and with the presence of macrophages in the superficial pericardial layer, edema, fibrin, and hemorrhage. Disease-free interval and overall survival were significantly shorter in patients with mesothelioma compared with IP.

Background Besides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin. Case presentation A 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient’s parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding. Conclusions This is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy.

Simple Summary Multidrug resistance of neoplastic cells to chemotherapeutic drugs is a phenomenon mediated by several molecular mechanisms. Among these, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) counteract the intracellular load of multiple drugs, preventing their efficacy. The basal (intrinsic) cellular expression can be further stimulated by drug exposure. P-gp and BCRP are a subject of intense investigation both in human and veterinary oncology since a better understanding of how their expression is distributed across different tumors allows planning alternative therapeutic strategies. In canine mammary carcinomas, a phenotypic classification similar to the one widely adopted for breast cancer is currently employed. For Basal- and Normal-like phenotypes, chemotherapy is still the main option. In this study, we observed that canine mammary carcinomas bear a high intrinsic expression of both P-gp and BCRP, regardless of their molecular phenotype, and their presence does not influence the outcome. Abstract P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are major actors in multidrug resistance (MDR) phenomenon in both human and canine mammary carcinomas (CMCs). The aim of this study was to investigate an association between the intrinsic expression of P-gp and BCRP compared to the immunophenotypes and outcome in CMCs. Fifty CMCs were evaluated at immunohistochemistry (IHC) for P-gp, BCRP, Estrogen receptor alpha (ER), Progesterone receptors (PR), Human Epidermal Growth Factor Receptor type 2 (HER2), basal cytokeratins 5/6 (CK5/6), Epidermal Growth Factor Receptor 1 (EGFR), and Ki67 proliferation index. P-gp and BCRP positive cases were, respectively, 52% and 74.5%, with a significantly higher expression of BCRP than P-gp. Five immunophenotypes were defined in 37 out of 50 CMCs: 9 (24.3%) Luminal A, 5 (13.5%) Luminal B, 9 (24.3%) HER2 overexpressing, 9 (24.3%) Triple-negative basal-like, and 5 (13.5%) Triple-negative non-basal-like. In all CMCs at least one marker was expressed. Follow-up data were available for 25 animals. The average cancer-specific survival was 739 ± 444 days. A number of CMCs bear a high expression of P-gp and BCRP but no significant association was found between their expression and the immunophenotypes, Ki67 index, the histological grade, and tumor-related death.

Pediatric small round blue cell tumors (SRBCTs) are a heterogeneous group of neoplasms with overlapping morphological appearance. Accordingly, their diagnosis is one of the most difficult in the field of surgical pathology. The most common tumors include rhabdomyosarcoma, Ewing’s sarcoma, neuroblastoma, lymphoblastic lymphoma and Wilms’ tumor (the blastemal component). Over time their diagnosis has become more difficult due to the increasing use of small biopsies. However, the advent of immunohistochemistry has improved the quality of diagnosis in most cases by the application of an adequate panel of immunomarkers. Recently, WT1 and Cyclin D1 have been shown to be useful in the differential diagnosis of SRBCTs on surgically-resected specimens, showing a diffuse cytoplasmic positivity of the former in all RMSs and a diffuse nuclear staining of the latter in both EWS and NB. The aim of the present study was to investigate the expression of WT1 and Cyclin D1 on small biopsies from a series of 105 pediatric SRBCTs to evaluate their diagnostic utility. Both immunomarkers were differentially expressed, with a diffuse and strong cytoplasmic staining for WT1 limited to all cases of RMS, and a diffuse nuclear staining for cyclin D1 restricted to all cases of EWS and NB. Notably, the expression of WT1 and cyclin D1 was also retained in those cases in which the conventional tumor markers (myogenin, desmin and MyoD1 for RMS; CD99 for EWS; NB84 for NB) were focally expressed or more rarely absent. The present study shows that WT1 and Cyclin D1 are helpful immunomarkers exploitable in the differential diagnosis of pediatric SRBCTs on small biopsies, suggesting their applicability in routine practice.

Background: Nowadays, there are many techniques to compensate bone atrophies of the posterior maxilla in order to obtain an implant-supported rehabilitation. Objective: This case series describes the Ebanist technique: a sinus lift procedure to be used in case of extremely resorbed bone crests (≤3 mm) allowing simultaneous implant placement. Methods: With a dedicated cylindrical trephine bur, it is possible to harvest a cylinder of bone from a fresh mineralized frozen homologous bone block graft and to simultaneously create a trapdoor on the recipient site. The trapdoor cortical bone is detached from the sinus membrane and removed. Dental implant is placed into the graft before the grafting procedure since the cylindrical block, once inserted in the recipient area, is not able to oppose sufficient resistance to the torque needed for implant placement. Results: Second-stage surgery and following prosthetic rehabilitation were performed after 5 months. In all cases, implant stability was manually checked and no pathological symptoms or signs were recovered at any follow-up visit. Conclusion: This technique can be considered a valid procedure for implant therapy on atrophic posterior upper maxillae, when the residual bone crest is extremely resorbed.

Nowadays, hybrid electric vehicles represent one of the main solutions for the reduction of greenhouse gases in the automotive sector. Alongside the reduction of CO2, hybrid electric vehicles serve as a strong alternative on drivability and performance to conventional internal combustion engine-based vehicles. Vehicles exist with various missions, super sport cars usually aim to reach peak performance and to guarantee a great driving experience to the driver, but great attention must also be paid to fuel consumption. According to the vehicle mission, hybrid electric vehicles can differ in the powertrain configuration and the choice of the energy storage system. Manufacturers have recently started to work on Lithium-Ion Capacitors (LiC) -based hybrid vehicles. This paper discusses the usage of a control-oriented vehicle and powertrain model to analyze the performance of a dual motor LiC-based hybrid V12 vehicle by Automobili Lamborghini. P3&ndash, P4 and P2&ndash, P4 parallel hybrid configurations have been selected and compared since they allow to fully exploit the potential of the LiC storage system characterized by high power. The validated model has been used to develop control strategies aimed at fuel economy and CO2 reduction, and in particular, both Rule Based Strategies (RBS) and Equivalent Consumption Minimization Strategies (ECMS) are presented in the paper. A critical comparison between the various powertrain configurations is carried out, keeping into account the peculiarities of the LiC technology and evaluating the performance of the different control approaches.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches., Graphical Abstract ga1

Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha‐glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients’ cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N‐acetylcysteine, idebenone, resveratrol, edaravone) improved alpha‐glucosidase activity in rhGAA‐treated cells, enhanced enzyme processing, and improved mannose‐6‐phosphate receptor localization. When co‐administered with rhGAA, antioxidants improved alpha‐glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder., Enzyme replacement therapy (ERT) with recombinant human alpha‐glucosidase (rhGAA) is currently the standard of care for the treatment of Pompe disease. However, this approach shows important limitations. We have tested whether modulation of oxidative stress may improve the efficacy of ERT.

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.

Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders. Despite hypoglycemia is one of the most common emergencies in neonatal age and childhood, no consensus on the definition and diagnostic work-up exists yet. Aims of this review are to present the current age-related definitions of hypoglycemia in neonatal-pediatric age, to offer a concise and practical overview of its main causes and management and to discuss the current diagnostic-therapeutic approaches. Since a systematic and prompt approach to diagnosis and therapy is essential to prevent hypoglycemic brain injury and long-term neurological complications in children, a comprehensive diagnostic flowchart is also proposed.

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.

International audience; We report the safety (primary endpoint) and efficacy (secondary endpoint) of a novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled, phase 1/2 clinical trial was performed in four patients aged 20, 26, 30, and 53 months. Treatment consisted of 16 intracerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human α-N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirty treatment-emergent adverse events were reported between 30 and 66 months after surgery, including three classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in the lumbar cerebrospinal fluid (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patients 2, 3, and 4 showed progressive brain atrophy and neurocognitive evolution that did not differ from untreated Sanfilippo A/B children. Patient 1, enrolled at 20 months of age, had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the three oldest patients. Milder disease in the youngest patient supports further investigations of adeno-associated vector-mediated intracerebral gene therapy in Sanfilippo B.

Introduction Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. Methods We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. Results Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value

All authors: Rouillard, A. P.; Pinto, R. F.; Vourlidas, A.; De Groof, A.; Thompson, W. T.; Bemporad, A.; Dolei, S.; Indurain, M.; Buchlin, E.; Sasso, C.; Spadaro, D.; Dalmasse, K.; Hirzberger, J.; Zouganelis, I.; Strugarek, A.; Brun, A. S.; Alexandre, M.; Berghmans, D.; Raouafi, N. E.; Wiegelmann, T.; Pagano, P.; Arge, C. N.; Nieves-Chinchilla, T.; Lavarra, M.; Poirier, N.; Amari, T.; Aran, A.; Andretta, V.; Antonucci, E.; Anastasiadis, A.; Auchère, F.; Bellot Rubio, L.; Nicula, B.; Bonnin, X.; Bouchemit, M.; Budnik, E.; Caminade, S.; Cecconi, B.; Carlyle, J.; Cernuda, I.; Davila, J. M.; Etesi, L.; Espinosa Lara, F.; Fedorov, A.; Fineschi, S.; Fludra, A.; Génot, V.; Georgoulis, M. K.; Gilbert, H. R.; Giunta, A.; Gomez-Herrero, R.; Guest, S.; Haberreiter, M.; Hassler, D.; Henney, C. J.; Howard, R. A.; Horbury, T. S.; Janvier, M.; Jones, S. I.; Kozarev, K.; Kraaikamp, E.; Kouloumvakos, A.; Krucker, S.; Lagg, A.; Linker, J.; Lavraud, B.; Louarn, P.; Maksimovic, M.; Maloney, S.; Mann, G.; Masson, A.; Müller, D.; Önel, H.; Osuna, P.; Orozco Suarez, D.; Owen, C. J.; Papaioannou, A.; Pérez-Suárez, D.; Rodriguez-Pacheco, J.; Parenti, S.; Pariat, E.; Peter, H.; Plunkett, S.; Pomoell, J.; Raines, J. M.; Riethmüller, T. L.; Rich, N.; Rodriguez, L.; Romoli, M.; Sanchez, L.; Solanki, S. K.; St Cyr, O. C.; Straus, T.; Susino, R.; Teriaca, L.; del Toro Iniesta, J. C.; Ventura, R.; Verbeeck, C.; Vilmer, N.; Warmuth, A.; Walsh, A. P.; Watson, C.; Williams, D.; Wu, Y.; Zhukov, A. N.-- Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. The Solar Orbiter spacecraft will be equipped with a wide range of remote-sensing (RS) and in situ (IS) instruments to record novel and unprecedented measurements of the solar atmosphere and the inner heliosphere. To take full advantage of these new datasets, tools and techniques must be developed to ease multi-instrument and multi-spacecraft studies. In particular the currently inaccessible low solar corona below two solar radii can only be observed remotely. Furthermore techniques must be used to retrieve coronal plasma properties in time and in three dimensional (3D) space. Solar Orbiter will run complex observation campaigns that provide interesting opportunities to maximise the likelihood of linking IS data to their source region near the Sun. Several RS instruments can be directed to specific targets situated on the solar disk just days before data acquisition. To compare IS and RS, data we must improve our understanding of how heliospheric probes magnetically connect to the solar disk. Aims. The aim of the present paper is to briefly review how the current modelling of the Sun and its atmosphere can support Solar Orbiter science. We describe the results of a community-led effort by European Space Agency's Modelling and Data Analysis Working Group (MADAWG) to develop different models, tools, and techniques deemed necessary to test different theories for the physical processes that may occur in the solar plasma. The focus here is on the large scales and little is described with regards to kinetic processes. To exploit future IS and RS data fully, many techniques have been adapted to model the evolving 3D solar magneto-plasma from the solar interior to the solar wind. A particular focus in the paper is placed on techniques that can estimate how Solar Orbiter will connect magnetically through the complex coronal magnetic fields to various photospheric and coronal features in support of spacecraft operations and future scientific studies. Methods. Recent missions such as STEREO, provided great opportunities for RS, IS, and multi-spacecraft studies. We summarise the achievements and highlight the challenges faced during these investigations, many of which motivated the Solar Orbiter mission. We present the new tools and techniques developed by the MADAWG to support the science operations and the analysis of the data from the many instruments on Solar Orbiter. Results. This article reviews current modelling and tool developments that ease the comparison of model results with RS and IS data made available by current and upcoming missions. It also describes the modelling strategy to support the science operations and subsequent exploitation of Solar Orbiter data in order to maximise the scientific output of the mission. Conclusions. The on-going community effort presented in this paper has provided new models and tools necessary to support mission operations as well as the science exploitation of the Solar Orbiter data. The tools and techniques will no doubt evolve significantly as we refine our procedure and methodology during the first year of operations of this highly promising mission. © 2020 A. P. Rouillard et al., Solar Orbiter is a joint ESA and NASA mission. A. Vourlidas' Solar Orbiter effort is supported by NRL grant N00173-16-1-G029. P. Pagano would like to thank D. H. Mackay and S. L. Yardley for their valuable contributions, the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program (grant agreement No. 647214), and the DiRAC Data Centric system at Durham University, operated by the Institute for Computational Cosmology on behalf of the STFC DiRAC HPC Facility (http://www.dirac.ac.uk).This equipment was funded by a BIS National E-infrastructure capital grant ST/K00042X/1, STFC capital grant ST/K00087X/1, DiRAC Operations grant ST/K003267/1 and Durham University. DiRAC is part of the National E-Infrastructure. A. Rouillard, V. Genot, M. Janvier, Elie Soubrier, F. Auchere, E. Buchlin and E. Pariat acknowledge support from the French space agency (Centre National d'Etudes Spatiales; CNES; https://cnes.fr/fr) that funds activity in plasma physics data center (Centre de Donnees de la Physique des Plasmas; CDPP; http://cdpp.eu/) and the Multi Experiment Data and Operation Center (MEDOC; https://idoc.ias.u-psud.fr/MEDOC), and the space weather team in Toulouse (Solar-Terrestrial Observations and Modelling Service; STORMS; http://storms-service.irap.omp.eu/).This includes funding for Gaia-DEM, the data mining tools AMDA (http://amda.cdpp.eu/), CLWEB (clweb.cesr. fr/) and the propagation tool (http://propagationtool.cdpp.eu).R.Pinto, M. Lavarra, Y. Wu and A. Kouloumvakos acknowledge financial support from the ANR project SLOW_ SOURCE No. ANR-17-CE31-0006-01, ANR project COROSHOCK No. ANR-18-ERC1-0006-01 and FP7 HELCATS project https://www.helcats-fp7.eu/under the FP7 EU contract number 606692. A. Warmuth acknowledges the support by DLR under grant No. 50 QL 0001. The STEREO SECCHI data are produced by a consortium of RAL (UK), NRL (USA), LMSAL (USA), GSFC (USA), MPS (Germany), CSL (Belgium), IOTA (France) and IAS (France). The ACE data were obtained from the ACE science center. The WIND data were obtained from the Space Physics Data Facility. Javier Rodriguez-Pacheco acknowledges Spanish Project: FEDER/MCIU-AEI/Project ESP2017-88436-R.

Background The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. Methods Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48–53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D1 receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. Results FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D1 receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. Limitations This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue. Conclusions The results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment.

In the absence of target treatments or vaccination, the SARS-CoV-2 pandemic can be impeded by effectively implementing containment measures and behaviors. This relies on individuals’ adoption of protective behaviors, their perceived risk, and the use and trust of information sources. During a health emergency, receiving timely and accurate information enables individuals to take appropriate actions to protect themselves, shaping their risk perception. Italy was the first western country plagued by COVID-19 and one of the most affected in the early phase. During this period, we surveyed 2,223 Italians before the national lockdown. A quarter of the sample perceived COVID-19 less threatening than flu and would not vaccinate, if a vaccine was available. Besides, most people perceived containment measures, based on social distancing or wearing masks, not useful. This perceived utility was related to COVID-19 threat perception and efficacy beliefs. All these measures were associated with the use of media and their truthfulness: participants declared to mainly use the Internet, while health organizations’ websites were the most trusted. Although social networks were frequently used, they were rated lower for trustfulness. Our data differ from those obtained in other community samples, suggesting the relevance to explore changes across different countries and during the different phases of the pandemic. Understanding these phenomena, and how people access the media, may contribute to improve the efficacy of containment measures, tailoring specific policies and health communications.

PURPOSE: We studied microRNAs as potential biomarkers for Pompe disease. METHODS: We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. RESULTS: In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. CONCLUSION: Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy.