Search

Background: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. Objective: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post‐partum outcomes. Methods: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18–49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. Results: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3–118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2–24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug‐associated risk for adverse pregnancy, congenital, neonatal or post‐partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. Conclusions: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research. [ABSTRACT FROM AUTHOR]

This paper reports hybrid gels combining a low‐molecular‐weight gelator (LMWG) and a photoinitiated crosslinked polymer gel (PG). The presence of the PG enhanced the stiffness and strength of the gel. The gels were loaded with heparin, and in the hybrid gel, the interpenetrated LMWG and PG networks somewhat restricted its release. In terms of stem cell growth, the hybrid gel significantly improved the performance of the PG because of the presence of the LMWG, which is an excellent substrate for stem cells in its own right. Furthermore, the presence of heparin in the hybrid gels also enhanced stem cell proliferation over longer timescales. Finally, these gels were photopatterned within the well‐plates used for tissue culture, with patterning helping control stem cell proliferation. In summary, these hybrid gels combine the advantageous features of both LMWG and PG: rheological performance is endowed by the PG with stem cell compatibility provided by the LMWG. The hybrid gels also control the release of the bioactive agent heparin and have capacity to be shaped and patterned. Patterned gels such as these, capable of directing stem cell growth, have potential in regenerative medicine. [ABSTRACT FROM AUTHOR]

Background: Eyelid dermatitis is a frequent reason of dermatological consultation. Its aetiology is not univocal, being contact dermatitis, both allergic and irritant, the most frequent. The primary sources of allergen exposure include cosmetics, metals, and topical medications, from direct, indirect, or airborne contact. Objectives: To define the frequency of positive patch test reactions to SIDAPA baseline series allergens, to document positive allergens, and to precise the final diagnosis in patients with eyelid involvement. Methods: A total of 8557 consecutive patients from 12 Italian Dermatology Clinics underwent patch testing with SIDAPA baseline series in 2018 and 2019. Patients were divided into two groups: (i) with eyelid involvement with or without other involved sites (E‐Group) and (ii) without eyelid involvement (NE‐Group). The final diagnosis and the frequency of positive relevant patch test reactions were evaluated. Results: E‐Group consisted of 688 patients (females 78.6%, mean age 45.3 years), 8.0% of 8557 consecutively patch‐tested patients. The final diagnosis in E‐Group was ADC in 42.4%, ICD in 34.2%, and AD in 30.5%. The highest reaction rates were elicited by nickel sulphate and methylchloroisothiazolinone/methylisothiazolinone in both E‐Group and NE‐Group, even if these allergens were significantly more frequently positive in NE‐Group patients than in E‐Group ones. Positive patch test reactions to fragrance Mix II, dimethylaminopropylamine, and sorbitan sesquiolate were significantly more frequent in E‐Group patients than in NE‐Group ones. Conclusions: Eyelid dermatitis is a frequent dermatological complaint. Allergic contact dermatitis is the most frequent diagnosis commonly caused by nickel sulphate, isothiazolinones, and fragrances. The surfactants dimethylaminopropylamine and sorbitan sesquioleate are emerging causes of eyelid allergic contact dermatitis. [ABSTRACT FROM AUTHOR]

Skin oxidative stress results in structural damage, leading to premature senescence, and pathological conditions such as inflammation and cancer. The plant‐derived prenylated pyrone–phloroglucinol heterodimer arzanol, isolated from Helichrysum italicum ssp. microphyllum (Willd.) Nyman aerial parts, exhibits anti‐inflammatory, anticancer, antimicrobial, and antioxidant activities. This study explored the arzanol protection against hydrogen peroxide (H2O2) induced oxidative damage in HaCaT human keratinocytes in terms of its ability to counteract cytotoxicity, reactive oxygen species (ROS) generation, apoptosis, and mitochondrial membrane depolarization. Arzanol safety on HaCaT cells was preliminarily examined by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and microscopic observation. The arzanol pre‐incubation (5–100 μM, for 24 h) did not induce cytotoxicity and morphological alterations. The phloroglucinol, at 50 μM, significantly protected keratinocytes against cytotoxicity induced by 2 h‐incubation with 2.5 and 5 mM H2O2, decreased cell ROS production induced by 1 h‐exposure to all tested H2O2 concentrations (0.5–5 mM), as determined by the 2′,7′‐dichlorodihydrofluorescein diacetate (H2DCFDA) assay, and lipid peroxidation (thiobarbituric acid reactive substances [TBARS] method). The 2‐h incubation of keratinocytes with H2O2 determined a significant increase of apoptotic cells versus control cells, evaluated by NucView® 488 assay, from the dose of 2.5 mM. Moreover, an evident mitochondrial membrane potential depolarization, monitored by fluorescent mitochondrial dye MitoView™ 633, was assessed at 5 mM H2O2. Arzanol pre‐treatment (50 μM) exerted a strong significant protective effect against apoptosis, preserving the mitochondrial membrane potential of HaCaT cells at the highest H2O2 concentrations. Our results validate arzanol as an antioxidant agent for the prevention/treatment of skin oxidative‐related disorders, qualifying its potential use for cosmeceutical and pharmaceutical applications. The 2 h‐exposure of human HaCaT keratinocytes to H2O2 induced cytotoxicity, morphological alterations, ROS production, apoptosis, and mitochondrial depolarization. Pre‐treatment (24 h) of keratinocytes with the phloroglucinol arzanol (50 μM), obtained from Helichrysum italicum ssp. microphyllum (Willd.) Nyman, preserved against H2O2‐induced oxidative damage. The phloroglucinol significantly protected keratinocytes against cytotoxicity induced by 2‐h incubation with 2.5 and 5 mM H2O2, decreased cell ROS production induced by 0.5–5 mM H2O2, and significantly reduced apoptotic cell number and mitochondrial membrane depolarization. [ABSTRACT FROM AUTHOR]

Luspatercept is a recently approved drug for treating anemia in individuals with transfusion-dependent beta-thalassemia. However, it is contraindicated for pregnant and lactating women due to observed teratogenic effects in animal studies. Two cases are presented in the article where women became pregnant while undergoing luspatercept therapy. In both cases, the pregnancies resulted in healthy newborns, but the article emphasizes the importance of effective contraception during treatment and the need for factual information and counseling in the event of pregnancy. The article also mentions the potential risks associated with luspatercept and the consideration of termination if concerns about teratogenic effects arise. [Extracted from the article]

Aims: Antisocial personality disorder (ASPD) and conduct disorder (CD) are characterized by a persistent pattern of violations of societal norms and others' rights. Ample evidence shows that the pathophysiology of these disorders is contributed by orbitofrontal cortex (OFC) alterations, yet the underlying molecular mechanisms remain elusive. To address this knowledge gap, we performed the first‐ever RNA sequencing study of postmortem OFC samples from subjects with a lifetime diagnosis of ASPD and/or CD. Methods: The transcriptomic profiles of OFC samples from subjects with ASPD and/or CD were compared to those of unaffected age‐matched controls (n = 9/group). Results: The OFC of ASPD/CD‐affected subjects displayed significant differences in the expression of 328 genes. Further gene‐ontology analyses revealed an extensive downregulation of excitatory neuron transcripts and upregulation of astrocyte transcripts. These alterations were paralleled by significant modifications in synaptic regulation and glutamatergic neurotransmission pathways. Conclusion: These preliminary findings suggest that ASPD and CD feature a complex array of functional deficits in the pyramidal neurons and astrocytes of the OFC. In turn, these aberrances may contribute to the reduced OFC connectivity observed in antisocial subjects. Future analyses on larger cohorts are needed to validate these results. [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin‐converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. Methods: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two‐sample Mendelian randomization (MR) approach. Results: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04–1.10], P = 5 × 10−07) and frontotemporal dementia (1.16 [1.04–1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. Discussion: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin‐converting enzyme (ACE) inhibition association with dementias.The results suggest an association between ACE inhibition and Alzheimer's disease.The results suggest an association between ACE inhibition and frontotemporal dementia.Those associations can be interpreted as potentially causal. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is characterized by high heritability estimates and recurrence rates; its genetic underpinnings are very heterogeneous and include variable combinations of common and rare variants. Array‐comparative genomic hybridization (aCGH) offers significant sensitivity for the identification of copy number variants (CNVs), which can act as susceptibility or causal factors for ASD. Methods: The aim of this study was to evaluate both diagnostic yield and clinical impact of aCGH in 329 ASD patients of Italian descent. Results: Pathogenic/likely pathogenic CNVs were identified in 50/329 (15.2%) patients, whereas 89/329 (27.1%) carry variants of uncertain significance. The 10 most enriched gene sets identified by Gene Ontology Enrichment Analysis are primarily involved in neuronal function and synaptic connectivity. In 13/50 (26.0%) patients with pathogenic/likely pathogenic CNVs, the outcome of array‐CGH led to the request of 25 additional medical exams which would not have otherwise been prescribed, mainly including brain MRI, EEG, EKG, and/or cardiac ultrasound. A positive outcome was obtained in 12/25 (48.0%) of these additional tests. Conclusions: This study confirms the satisfactory diagnostic yield of aCGH, underscoring its potential for better, more in‐depth care of children with autism when genetic results are analyzed also with a focus on patient management. [ABSTRACT FROM AUTHOR]

This study was designated to investigate the chemical composition, the antifungal activity and antibiofilm properties of Glycyrrhiza foetida (Desf.) growing in Tunisia and recognized for its pharmacological and therapeutic effects. The chemical analysis of essential oil samples prepared via hydrodistillation of the aerial parts was performed by gas chromatography–mass spectrometry (GC–MS). Moreover, the antifungal activity of G. foetida essential oil was developed against three dermatophyte strains, two molds and Candida spp. yeasts using the broth microdilution assay. According to the percentages, the main constituents are δ‐cadinene (13.9%), (E)‐caryophyllene (13.2%) and γ‐cadinene (8.3%). The efficiency of the essential oil in inhibiting Candida albicans biofilms formation was also evaluated in terms of inhibitory percentages. The results showed that C. albicans and Microsporum canis were the most sensitive to G. foetida essential oil with a complete inhibition at 0.4 and 0.2 mg ml−1, respectively. Candida albicans biofilm development was reduced by 80% by the volatile oil at a concentration of 0.8 mg ml−1. The essential oil of G. foetida has a promising role in the control of fungal agents with medical interest and in inhibition of Candida biofilm development. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 2 (HSV‐2) is the most common cause of genital disease worldwide. The development of an effective HSV‐2 vaccine would significantly impact global health based on the psychological distress caused by genital herpes for some individuals, the risk transmitting the infection from mother to infant, and the elevated risk of acquiring HIV‐1. Five nonclinical safety studies were conducted with the replication defective HSV529 vaccine, alone or adjuvanted with GLA‐SE, and the G103 subunit vaccine containing GLA‐SE. A biodistribution study was conducted in guinea pigs to evaluate distribution, persistence, and shedding of HSV529. A preliminary immunogenicity study was conducted in rabbits to demonstrate HSV529‐specific humoral response and its enhancement by GLA‐SE. Three repeated‐dose toxicity studies, one in guinea pigs and two in rabbits, were conducted to assess systemic toxicity and local tolerance of HSV529, alone or adjuvanted with GLA‐SE, or G103 containing GLA‐SE. Data from these studies show that both vaccines are safe and well tolerated and support the ongoing HSV‐2 clinical trial in which the two vaccine candidates will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects. Herpes simplex virus type 2 (HSV‐2) is the most common cause of genital disease worldwide, with no preventive or curative vaccine available. Five nonclinical safety studies were conducted with the replication defective HSV529 vaccine, alone or adjuvanted with GLA‐SE, and the G103 subunit vaccine containing GLA‐SE. The two vaccine candidates were found safe and well tolerated supporting the ongoing HSV‐2 clinical trial in which they will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects. [ABSTRACT FROM AUTHOR]

While synthesis‐properties‐performance correlations are being studied for organophosphonic acid grafted TiO2, their stability and the impact of the exposure conditions on possible changes in the interfacial surface chemistry remain unexplored. Here, the impact of different ageing conditions on the evolution of the surface properties of propyl‐ and 3‐aminopropylphosphonic acid grafted mesoporous TiO2 over a period of 2 years is reported, using solid‐state 31P and 13C NMR, ToF‐SIMS and EPR as main techniques. In humid conditions under ambient light exposure, PA grafted TiO2 surfaces initiate and facilitate photo‐induced oxidative reactions, resulting in the formation of phosphate species and degradation of the grafted organic group with a loss of carbon content ranging from 40 to 60 wt %. By revealing its mechanism, solutions were provided to prevent degradation. This work provides valuable insights for the broad community in choosing optimal exposure/storage conditions that extend the lifetime and improve the materials′ performance, positively impacting sustainability. [ABSTRACT FROM AUTHOR]

The fatty acid (FA) composition of cell membranes represents a metabolic biomarker. However, the FA profile reproducibility in cell cultures remains a significant challenge. In this study, cell FA ratios are validated as metabolic markers alternative to cell FA. To this goal, cell samples belonging to cancer HeLa cells and normal 3T3 fibroblasts, from various experimental sets, are analyzed by a high‐performance liquid chromatography system coupled with a photodiode array detector and evaporative light scattering detector (HPLC‐DAD/ELSD), and the ratios among the main FA are calculated. Principal component analysis (PCA) separately performed on FA and FA ratio data indicates similar clustering of cell samples concerning the cell type. Moreover, similar scores values t[1] and t[2] and graphical distances are calculated in the PCA plots separately performed on FA and FA ratios measured in cancer HeLa cells subjected to various antitumoral compounds. Last, PCA applied to selected FA ratios measured in various cell lines, obtained in similar experimental conditions, allows to discriminate between normal and tumoral cells. The results substantiate FA ratios as a cell‐specific fingerprint, characterized by reproducibility across intra‐laboratory conditions, useful for cell characterization, discrimination between normal and tumoral cells, and the comparison of different drug treatments. Practical Applications: The reproducibility of the fatty acid (FA) profile in cell cultures remains a significant challenge. Results obtained from this study improve knowledge about the role of the FA ratio profile as a cell‐specific fingerprint characterized by reproducibility across intra‐laboratory conditions. The characterization of the specific FA ratio profile of a cell culture, under standardized experimental conditions, can facilitate the comparative evaluation of cell data sets for nutritional, metabolic, and pharmacological studies, overcoming differences in cell culture conditions and FA extraction/analytical procedures. [ABSTRACT FROM AUTHOR]

In this paper, we propose a recursive approach to estimate the spatial error model. We compare the suggested methodology with standard estimation procedures and we report a set of Monte Carlo experiments which show that the recursive approach substantially reduces the computational effort affecting the precision of the estimators within reasonable limits. The proposed technique can prove helpful when applied to real‐time streams of geographical data that are becoming increasingly available in the big data era. Finally, we illustrate this methodology using a set of earthquake data. [ABSTRACT FROM AUTHOR]

Summary: We compared by a chemometric approach the composition of essential (EO) and fixed (FO) oils previously obtained from several vegetable matrices by supercritical CO2 extraction (CO2‐SFE) and conventional techniques (n‐hexane in a Soxhlet apparatus and hydrodistillation). A multivariate approach, by determining the principal components analysis (PCA) applied to data of FO fatty acids and EO volatile compounds, generally indicated that the vegetable oils extracted with CO2‐SFE tightly clustered with those obtained by conventional methods. The graphical distances calculated in the PCA plots between the score of each SFE oil and the corresponding conventional oil revealed that the CO2‐SFE FO and EO profiles were quite similar to conventional oils, with the additional benefit of not having unwanted traces of solvent. SFE FO were more similar to conventional oils than SFE EO (mean values of calculated graphical distances were 0.83 and 1.46 for FO and EO, respectively). Our results strongly corroborate the role of CO2‐SFE as a suitable, environmentally safe and efficient method alternative to the traditional ones for the extraction of natural vegetable oils for food and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Salt (sodium chloride) is an essential component of daily food, crucial for many physiological processes. Due to health risks related to salt over consumption, considerable interest is devoted to strategies to reduce dietary salt intake. In this work we evaluated the sensory dimensions of sea salts flavored with Mediterranean aromatic plants with the aim to confirm the role of herbs/spices in the enhancement of salty perception and to validate the use of flavored salts as a strategy to reduce salt intake. To this goal we compared taste dimensions (pleasantness, intensity, and familiarity) of solutions obtained with salt and sea salts flavored with Mediterranean herbs, spices, and fruits. Sensorial differences were analyzed using a seven‐point hedonic Likert‐type scale on 58 non‐trained judges. RESULTS: Main flavor compounds, identified by gas chromatography‐flame ionization detection‐mass spectrometry (GC‐FID‐MS) analysis, were α‐pinene and 1,8‐cineole in myrtle salt (FS 1), verbenone, α‐pinene, 1,8‐cineole, and rosifoliol in herbs/plants salt (FS 2), and limonene in orange fruits/saffron salt (FS 3). At the dose of 0.04 g mL−1, saline solutions obtained with flavored salt (containing approximately 6–30% less sodium chloride) were perceived as more intense, less familiar, but equally pleasant than pure salt solution. In particular, sea salt flavored with orange fruits/saffron emerged as the most interesting in potentiating saltiness perception. CONCLUSION: Our study confirmed the important role of Mediterranean aromatic plants in the enhancement of saltiness perception and qualified the use of flavored sea salt during food preparation/cooking instead of normal salt as a potential strategy to reduce the daily salt intake. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'‐O‐ribose cap needed for viral immune escape. We find that the host cap 2'‐O‐ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS‐CoV‐2 replication. Using in silico target‐based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti‐SARS‐CoV‐2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co‐substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID‐19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection‐induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID‐19. Synopsis: A target‐based drug repurposing approach to inhibit SAM‐dependent methyltransferases (Mtases) shows that the host MTase MTr1 can compensate for loss of the viral encoded NSP16 MTase. Targeting both MTr1 and NSP16 is needed to suppress SARS‐CoV‐2 replication. Host 2'‐O‐ribose methyltransferase MTr1 is a novel host factor of SARS‐CoV‐2 and compensates for the loss of NSP16.Concomitant inhibition of MTr1 and NSP16 is required to efficiently suppress SARS‐CoV‐2 replication.Target‐based drug repurposing identified a bispecific MTr1/NSP16 inhibitor tubercidin, which is highly antiviral against SARS‐CoV‐2.Host‐directed SAM‐cycle inhibitors, exerting indirect broad spectrum methyltransferase inhibition, are potent antivirals against SARS‐CoV‐2 with additional immunomodulatory and fibrosis‐curbing functions. [ABSTRACT FROM AUTHOR]

This article describes a case study of a 42-year-old woman who presented with heavy vaginal bleeding. A transvaginal ultrasound scan revealed a normal uterus with an intrauterine system (IUS) in place, but also detected an ectopic pregnancy in the left adnexa. Three-dimensional (3D) ultrasound was then used to confirm the presence of both the IUS and the ectopic pregnancy. The patient underwent emergency surgery to remove the ectopic pregnancy. The article suggests that 3D ultrasound can be a valuable tool in diagnosing complicated cases of ectopic pregnancy and recommends its use in early pregnancy scans. [Extracted from the article]

This article focuses on the estimation of the spatial Durbin model and associated relative impacts implemented in the R library sphet. Specifically, the current version of the library offers two ways of performing inference: one based on drawing samples from a multivariate normal distribution, and the other based on an analytical formula. The performance of these two methods is compared using an extensive Monte Carlo experiment. As an illustration of the kind of analysis that can be performed with sphet, the article also presents an empirical application looking at economic growth of Italian provinces. [ABSTRACT FROM AUTHOR]

Background: Necrotizing meningoencephalitis (NME) in the pug dogs is a fatal neuroinflammatory disease associated with rapid progression and poor response to conventional immunosuppressive therapy. Diagnosis is typically made after severe neurological abnormalities have manifested. Hypothesis/Objective: Pug dogs at genetic risk for NME might manifest neurological abnormalities before developing pathognomonic clinical signs of NME. Animals: Thirty‐six pug dogs less than 4 years of age asymptomatic for NME. Methods: Prospective observational cohort study with germline genome‐wide genotyping. Neurological examinations were performed 4 weeks apart to document reproducible findings of central nervous system disease. Magnetic resonance imaging, cerebrospinal fluid analysis, and testing for infectious diseases were performed in all pugs with reproducible abnormalities detected on neurological examination. Results: The overall risk allele frequency in this cohort was 40%; 5 (14%) dogs were high risk, 19 (53%) dogs were medium risk, and 12 (33%) dogs were low genetic risk for NME. Reproducible abnormalities detected on neurological examination were identified in 8/24 (33%) genetically at‐risk dogs and 0/12 (0%) low risk dogs. Clinical abnormalities included multifocal spinal pain in 8/8, reduced menace response in 5/8, and lateralizing postural reaction deficits in 5/8 pugs. There was a strong association between genotype risk and the presence of this clinical phenotype (P =.03). Conclusions and Clinical Importance: Our findings suggest the presence of a novel early clinical phenotype of NME in apparently asymptomatic genetically at‐risk pugs which might be used to plan early diagnostic and therapeutic clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Adjuvant radiation therapy (RT) following primary surgery in women affected by early breast cancer (EBC) plays a central role in reducing local recurrences and overall mortality. The FAST‐FORWARD trial recently demonstrated that 1‐week hypofractionated adjuvant RT is not inferior to the standard schedule in terms of local relapse, cosmetic outcomes and toxicity. The aim of this in silico study was to evaluate the dosimetric aspects of a 1‐week RT course, administered through volumetric modulated arc therapy (VMAT), compared with traditional three‐dimensional conformal radiation therapy (3D‐CRT) with tangential fields. Methods: Patients affected by left‐side EBC undergoing adjuvant RT were selected. ESTRO guidelines for the clinical target volume (CTV) delineation and FAST‐FORWARD protocol for CTV to planning target volume (PTV) margin definition were followed. Total prescribed dose was 26 Gy in five fractions. The homogeneity index (HI) and the global conformity index (GCI) were taken into account for planning and dose distribution optimisation purposes. Both 3D‐CRT tangential fields and VMAT plans were generated for each patient. Results: The analysis included 21 patients. PTV coverage comparison between 3D‐CRT and VMAT plans showed significant increases for GCI (P < 0.05) in VMAT technique; no statistically significant differences were observed regarding HI. For organs at risks (OAR), statistically significant increases were observed in terms of skin V103% (P < 0.002) and ipsilateral lung V30% (P < 0.05) with 3D‐CRT and of heart V5% (P < 0.05) with VMAT technique. Conclusions: This in silico study showed that both 3D‐CRT and VMAT are dosimetrically feasible techniques in the framework of 1‐week hypofractionated treatments for left EBC. [ABSTRACT FROM AUTHOR]

Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose‐dependent effects on metabolic parameters with changes for weight, blood pressure, lipid and glucose profiles being modelled using linear mixed‐effects models. The risk of metabolic abnormalities including early weight gain (EWG) (≥5% during first month) was assessed using mixed‐effects logistic regression models. In 392 olanzapine‐treated patients (median age 38.0 years, interquartile range [IQR] = 26.0–53.3, median dose 10.0 mg/day, IQR = 5.0–10.0 for a median follow‐up duration of 40.0 days, IQR = 20.7–112.2), weight gain was not associated with olanzapine dose (p = 0.61) although it was larger for doses versus ≤10 mg/day (2.54 ± 5.55 vs. 1.61 ± 4.51% respectively, p = 0.01). Treatment duration and co‐prescription of >2 antipsychotics, antidepressants, benzodiazepines and/or antihypertensive agents were associated with larger weight gain (p < 0.05). Lower doses were associated with increase in total and HDL cholesterol and systolic and diastolic blood pressure (p < 0.05), whereas higher doses were associated with glucose increases (p = 0.01). Patients receiving >10 mg/day were at higher EWG risk (odds risk: 2.15, 1.57–2.97). EWG might be prominent in high‐dose olanzapine‐treated patients with treatment duration and co‐prescription of other medications being weight gain moderators. The lack of major dose‐dependent patterns for weight gain emphasizes that olanzapine‐treated patients are at weight gain risk regardless of the dose. [ABSTRACT FROM AUTHOR]

Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age‐related changes in mitochondrial metabolism. We have found that aging in MSCs is associated with a decrease in mitochondrial membrane potential and lower NADH levels in mitochondria. Mitochondrial DNA content is higher in aged MSCs, but the overall mitochondrial mass is decreased due to increased rates of mitophagy. Despite the higher level of ATP in aged cells, a higher rate of ATP consumption renders them more vulnerable to energy deprivation compared to younger cells. Changes in mitochondrial metabolism in aged MSCs activate the overproduction of reactive oxygen species in mitochondria which is compensated by a higher level of the endogenous antioxidant glutathione. Thus, energy metabolism and redox state are the drivers for the aging of MSCs/mesenchymal stromal cells. [ABSTRACT FROM AUTHOR]

Background: An aneurysmal bone cyst (ABC) is a rare benign lytic lesion affecting the medullary canal of long bones. It has been widely reported in human medicine, but rarely described in domestic animals. Objective: To report the surgical treatment and long term follow‐up of a dog affected by ABC. Methods: An 8‐month‐old, intact female Weimaraner was presented with lameness affecting the left front limb and progressive swelling of the mid‐distal radius. Survey radiographs revealed a mid‐distal diaphyseal radial lesion. Fine needle aspirates, biopsy, CT scan and histopathology results supported the diagnosis of ABC. Treatment consisted of partial corticotomy of the affected radius, filling of the cystic cavity with demineralised bone matrix and autologous bone graft and stabilisation using lag screws and a neutralisation plate. Results: The long‐term follow‐up, at 36 post‐operative months, showed no recurrence of the cyst and bone modelling. Comparing preoperative radiographs with those at 36 months, bone modelling reduced the radial area by 23.3% in the craniocaudal radiographic view and 30% in the mediolateral projection. Conclusions: This treatment was sucessful in the case here described, with a 3 years follow‐up. [ABSTRACT FROM AUTHOR]

"Sense of agency" (SoA), the feeling of control for events caused by one's own actions, is deceived by visuomotor incongruence. Sensorimotor networks are implicated in SoA, however little evidence exists on brain functionality during agency processing. Concurrently, it has been suggested that the brain's intrinsic resting‐state (rs) activity has a preliminary influence on processing of agency cues. Here, we investigated the relation between performance in an agency attribution task and functional interactions among brain regions as derived by network analysis of rs functional magnetic resonance imaging. The action‐effect delay was adaptively increased (range 90–1,620 ms) and behavioral measures correlated to indices of cognitive processes and appraised self‐concepts. They were then regressed on local metrics of rs brain functional connectivity as to isolate the core areas enabling self‐agency. Across subjects, the time window for self‐agency was 90–625 ms, while the action‐effect integration was impacted by self‐evaluated personality traits. Neurally, the brain intrinsic organization sustaining consistency in self‐agency attribution was characterized by high connectiveness in the secondary visual cortex, and regional segregation in the primary somatosensory area. Decreased connectiveness in the secondary visual area, regional segregation in the superior parietal lobule, and information control within a primary visual cortex‐frontal eye fields network sustained self‐agency over long‐delayed effects. We thus demonstrate that self‐agency is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. Our observation is relevant for current models of psychopathology in clinical conditions in which both rs activity and sense of agency are altered. [ABSTRACT FROM AUTHOR]

The ENIGMA‐DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder‐oriented working groups used the ENIGMA‐DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA‐defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross‐diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large‐scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross‐diagnosis features. [ABSTRACT FROM AUTHOR]

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive–compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi‐site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA‐OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA. [ABSTRACT FROM AUTHOR]

Modern phylogenetic comparative methods allow us to estimate evolutionary rates of phenotypic change, how these rates differ across clades, and to assess whether the rates remained constant over time. Unfortunately, currently available phylogenetic comparative tools express the rate in terms of a scalar dimension, and do not allow us to determine rate variations among different parts of a single, complex phenotype, or chart realized rate variation directly onto the phenotype. We present a new method which allows the mapping of evolutionary rate variation directly onto three‐dimensional phenotypes, informing on the direction and magnitude of trait change automatically. Implemented using the function rate.map embedded in the R package RRphylo, this method is based on phylogenetic ridge regression rate estimates. Since the latter represent ridge regression slopes, they possess sign and magnitude. In RRphylo, different rates are calculated for different districts of the phenotype, which can then be visualized directly onto the phenotype itself. We present the application of rate.map to the evolution of facial skeleton in Hominoidea, the primate clade inclusive of Homo and the greater apes (including living and fossil taxa). We found that the highly derived, unique shape of the face in modern humans evolved through rapid phenotypic changes affecting the nasal bones, the brow ridge and the maxillary region. The canine fossa, a facial feature unique to Homo sapiens, did not belong to a region of rapid phenotypic change, and could be seen as the by‐product of midface evolution as suggested by previous studies. [ABSTRACT FROM AUTHOR]

Background: SuperAgers are individuals aged 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The causal factors for SuperAging are not known. Observational studies have linked psychiatric disorders with the risk for late life cognitive decline. It is not known if psychiatric disorders or their genetic liability have a causal effect on SuperAging. We sought to assess the causal relationship between genetically proxied psychiatric disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and SuperAging using a 2‐sample Mendelian randomization (MR). For comparison, we performed secondary analyses for the association of the same exposures with Alzheimer's dementia (AD), Lewy Body dementia (LBD), and Frontotemporal dementia (FTD). Method: Genome‐wide significant single nucleotide polymorphisms (SNPs) associated with MD (102 SNPs, 246,363 cases, 561,190 controls), BD (64 SNPs, 41,917 cases, 371,549 controls) and SCZ (287 SNPs, 76,755 cases, 243,649 control), were used as genetic proxies for the exposures. Summary statistics of the genome wide association study (GWAS) for SuperAging was included as the primary outcome (69 SuperAgers, 3,479 controls). Summary statistics were obtained for the largest GWAS studies of neurodegenerative disorders: AD (111,326 cases, 677,663 controls), LBD (2,591 cases, 4,027 controls) and FTD (2,154 cases, 4,308 controls). Inverse variance weighted MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Result: MR analyses showed a significant association between higher genetic liability to SCZ and lower likelihood of SuperAging (OR = 0.98, P = 0.02), but no significant association between MD or BD with SuperAging (P>0.05). Secondary analyses showed that genetic liability to BD was associated with an increased risk for AD (OR = 1.1, P = 0.003), while genetic liability to SCZ was associated with an increased risk for FTD (OR = 1.16, P = 0.04). Conclusion: This is the first study to investigate the potentially causal factors for SuperAging. We found that genetic liability to SCZ is causally associated with lower likelihood of SuperAging. We also found that the genetic liability to BP and SCZ are associated with an increased risk for AD and FTD, respectively. Further exploration of causal factors to SuperAging is warranted. [ABSTRACT FROM AUTHOR]

Background: Necrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy. Hypothesis/Objectives: That genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs. Animals Forty Pug dogs asymptomatic for NME from a hospital sample. Methods: Prospective observational cohort study, including germline genome‐wide genotyping, plasma cytokine determination by multiplexed profiling, and leukocyte subset characterization by flow cytometric analysis. Results: Seven (18%) dogs were high risk, 10 (25%) medium risk, and 23 (58%) low risk for NME, giving a risk haplotype frequency of 30%. High and medium risk Pugs had significantly lower proportion of CD4+ T cells (median 22% [range, 7.3%‐38%] vs 29% [range, 16%‐41%], P =.03) and higher plasma IL‐10 concentrations than low‐risk Pugs (median 14.11 pg/mL [range, 9.66‐344.19 pg/mL] vs 12.21 pg/mL [range, 2.59‐18.53 pg/mL], P =.001). No other variables were significantly associated with the NME haplotype‐based risk. Conclusions and Clinical Importance: These data suggest an immunological underpinning to NME and a biologic rationale for future clinical trials that investigate novel diagnostic, preventative, and therapeutic strategies for this disease. [ABSTRACT FROM AUTHOR]

Background: Growing up on traditional, single‐family farms is associated with protection against asthma in school age, but the mechanisms against early manifestations of atopic disease are largely unknown. We sought determine the gut microbiome and metabolome composition in rural Old Order Mennonite (OOM) infants at low risk and Rochester, NY urban/suburban infants at high risk for atopic diseases. Methods: In a cohort of 65 OOM and 39 Rochester mother‐infant pairs, 101 infant stool and 61 human milk samples were assessed by 16S rRNA gene sequencing for microbiome composition and qPCR to quantify Bifidobacterium spp. and B. longum ssp. infantis (B. infantis), a consumer of human milk oligosaccharides (HMOs). Fatty acids (FAs) were analyzed in 34 stool and human 24 milk samples. Diagnoses and symptoms of atopic diseases by 3 years of age were assessed by telephone. Results: At a median age of 2 months, stool was enriched with Bifidobacteriaceae, Clostridiaceae, and Aerococcaceae in the OOM compared with Rochester infants. B. infantis was more abundant (p <.001) and prevalent, detected in 70% of OOM compared with 21% of Rochester infants (p <.001). Stool colonized with B. infantis had higher levels of lactate and several medium‐ to long/odd‐chain FAs. In contrast, paired human milk was enriched with a distinct set of FAs including butyrate. Atopic diseases were reported in 6.5% of OOM and 35% of Rochester children (p <.001). Conclusion: A high rate of B. infantis colonization, similar to that seen in developing countries, is found in the OOM at low risk for atopic diseases. [ABSTRACT FROM AUTHOR]

Hybrid gel beads based on combining a low‐molecular‐weight gelator (LMWG) with a polymer gelator (PG) demonstrate an enhanced ability to self‐propel in water, with the LMWG playing an active role. Hybrid gel beads were loaded with ethanol and shown to move in water owing to the Marangoni effect changes in surface tension caused by the expulsion of ethanol – smaller beads move farther and faster than larger beads. Flat shapes of the hybrid gel were cut using a "stamp" – circles moved the furthest, whereas stars showed more rotation on their own axes. Comparing hybrid LMWG/PG gel beads with PG‐only beads demonstrated that the LMWG speeds up the beads, enhancing the rate of self‐propulsion. Self‐assembly of the LMWG into a "solid‐like" network prevents its leaching from the gel. The LMWG also retains its own unique function – specifically, remediating methylene blue pollutant dye from basic water as a result of noncovalent interactions. The mobile hybrid beads accumulate this dye more effectively than PG‐only beads. Self‐propelling gel beads have potential applications in removal/delivery of active agents in environmental or biological settings. The ability of self‐assembling LMWGs to enhance mobility and control removal/delivery suggests that adding them to self‐propelling systems can add significant value. [ABSTRACT FROM AUTHOR]

This article describes the fabrication of new pH‐responsive hybrid gel beads combining the polymer gelator calcium alginate with two different low‐molecular‐weight gelators (LMWGs) based on 1,3 : 2,4‐dibenzylidene‐d‐sorbitol: pH‐responsive DBS‐COOH and thermally responsive DBS‐CONHNH2, thus clearly demonstrating that different classes of LMWG can be fabricated into gel beads by using this approach. We also demonstrate that self‐assembled multicomponent gel beads can be formed by using different combinations of these gelators. The different gel bead formulations exhibit different responsiveness – the DBS‐COOH network can disassemble within those beads in which it is present upon raising the pH. To exemplify preliminary data for a potential application for these hybrid gel beads, we explored aspects of the delivery of the lipid‐lowering active pharmaceutical ingredient (API) rosuvastatin. The release profile of this statin from the hybrid gel beads is pH‐dependent, with greater release at pH 7.4 than at pH 4.0 – primary control of this process results from the pKa of the API. The extent of pH‐mediated API release is also significantly further modified according to gel bead composition. The DBS‐COOH/alginate beads show rapid, highly effective drug release at pH 7.4, whereas the three‐component DBS‐COOH/DBS‐CONHNH2/alginate system shows controlled slow release of the API under the same conditions. These initial results indicate that such gel beads constitute a promising, versatile and easily tuned platform suitable for further development for controlled drug‐delivery applications. [ABSTRACT FROM AUTHOR]

Background: Budesonide was included in the European Baseline Series in 2000 as the most suitable marker forcorticosteroid hypersensitivity. In the last two decades, a decreasing trend of budesonide allergy has been observed. Objectives: To estimate the prevalence of positive patch test reactions to budesonide in a large, Italian patch test population, characterizing patients according to MOAHLFA index and evaluating the benefit with extended readings of budesonide patch test. Methods: Retrospective analysis of patient demographics and patch test results over a 2‐year period (2018–2019) was performed at 14 patch test clinics in Italy. Results: Ninety out of 14 544 (0.6%) patients reacted to budesonide 0.01% pet.. Positive reactions were mild in 54.4% and late readings at day 7 showed new positive reactions in 37.8% of patients. The MOAHLFA index showed a significant positive association with male gender, atopic dermatitis, and age >40 years and a significant negative association with hand and face dermatitis. Conclusions: We documented a low prevalence of budesonide allergy in Italy, confirming its decreasing trend recently reported in the literature. Nevertheless, budesonide needs to be maintained in the baseline series for its good ability to detect corticosteroid sensitization. [ABSTRACT FROM AUTHOR]

Highly efficient, tunable, biocompatible, and environmentally friendly electrochemical sensors featuring graphene‐based materials pose a formidable challenge for computational chemistry. In silico rationalization, optimization and, ultimately, prediction of their performance requires exploring a vast structural space of potential surface‐analyte complexes, further complicated by the presence of various defects and functionalities within the infinite graphene lattice. This immense number of systems and their periodic nature greatly limit the choice of computational tools applicable at a reasonable cost. An alternative approach using finite nanoflake models opens the doors to many more advanced and accurate electronic structure methods, while sacrificing the realism of representation. Locating the surface‐analyte complex is followed by an in‐depth in silico analysis of its energetic and electronic properties using, for example, energy decomposition schemes, as well as simulation of the signal, for example, a zero‐bias transmission spectra or a current–voltage curve, by means of the nonequilibrium Green's function method. These and other properties are examined in the context of a sensor's selectivity, sensitivity, and limit of detection with an aim to establish design principles for future devices. Herein, we analyze the advantages and limitations of diverse computational chemistry methods used at each of these steps in simulating graphene‐based electrochemical sensors. We present outstanding challenges toward predictive models and sketch possible solutions involving such contemporary techniques as multiscale simulations and high‐throughput screening. This article is categorized under:Structure and Mechanism > Computational Materials ScienceElectronic Structure Theory > Density Functional TheoryElectronic Structure Theory > Ab Initio Electronic Structure Methods [ABSTRACT FROM AUTHOR]

Objectives: The statistical analysis of fossil remains is essential to understand the evolution of the genus Homo. Unfortunately, the human fossil record is straight away scarce and plagued with severe loss of information caused by taphonomic processes. The recently developed field of Virtual Anthropology helps to ameliorate this situation by using digital techniques to restore damaged and incomplete fossils. Materials and methods: We present the package Arothron, an R software suite meant to process and analyze digital models of skeletal elements. Arothron includes tools to digitally extract virtual cavities such as cranial endocasts, to statistically align disarticulated or broken bony elements, and to visualize local variations between surface meshes and landmark configurations. Results: We describe the main functionalities of Arothron and illustrate their usage through reproducible case studies. We describe a tool for segmentation of skeletal cavities by showing its application on a malleus bone, a Neanderthal tooth, and a modern human cranium, reproducing their shape and calculating their volume. We illustrate how to digitally align a disarticulated model of a modern human cranium, and how to combine piecemeal shape information on individual specimens into one. In addition, we present useful visualization tools by comparing the morphological differences between the right hemisphere of the Neanderthal and the modern human brain. Conclusions: The Arothron R package is designed to study digital models of fossil specimens. By using Arothron, scientists can handle digital models with ease, investigate the inner morphology of 3D skeletal models, gain a full representation of the original shapes of damaged specimens, and compare shapes across specimens. [ABSTRACT FROM AUTHOR]

Aims: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α‐synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α‐synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin‐associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. Methods: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. Results: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA. Conclusions: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA. [ABSTRACT FROM AUTHOR]

In the Video S1, a modified technique for submandibular gland resection in benign disease is shown. The main plane of dissection is below the fascia and immediately superficial to the fibrous capsule of the gland. The video shows the surgical steps and the structures that become evident along the procedure and illustrates some tips and tricks. Facial vessels are dissected, easily spared, and not ligated as it occurs in the classical technique. This technical variant is minimally invasive, respectful of anatomy, and through preservation of the fascial layer investing the gland aims at reducing the risk of injury to the marginalis mandibulae branch of the facial nerve, which lies within the fascia itself. [ABSTRACT FROM AUTHOR]

Aims: To investigate the interrelations between glycaemic metrics of fasting plasma glucose (FPG), postprandial glucose (PPG), glycated haemoglobin (HbA1c), and percentage of time in target range 3.9 to 10.0 mmol/L (%TIR) in patients on insulin therapy. Materials and methods: A pooled analysis was conducted using datasets extracted from an integrated database of insulin lispro clinical trials (Eli Lilly and Company). Studies in patients with type 2 diabetes on basal‐bolus or basal‐plus insulin therapy, and with ≥7‐point self‐monitored blood glucose profiles were included in the analysis. A multivariate regression model was used to quantify the contribution of FPG and PPG change to the change in HbA1c and %TIR. In addition, a linear regression model was used to describe the relationship between %TIR and HbA1c. Results: Five studies encompassing 1572 patients met the criteria for inclusion. On average, a 1‐mmol/L change in FPG was associated with 2.7 mmol/mol (0.25%) change in HbA1c (range 2.0 to 2.8 mmol/mol [0.18%–0.26%]; all P <0.0001), and a 1‐mmol/L change in PPG with 1.8 mmol/mol (0.16%) change in HbA1c (range 1.2 to 2.1 mmol/mol [0.11%–0.19%]; all P <0.01). Furthermore, a 1‐mmol/L reduction in FPG and PPG was associated with an increase in TIR of 6.5% (range 5.8%–9.2%) and 5.3% (range 4.1%–8.7%), respectively, all P <0.0001. A decrease in HbA1c of 10.9 mmol/mol (1%) corresponded with an increase in TIR of 8.3%, on average. Conclusions: In patients with type 2 diabetes on basal‐bolus or basal‐plus insulin therapy, management of both FPG and PPG is important for achievement of HbA1c and TIR goals. [ABSTRACT FROM AUTHOR]

Objective: Fine needle aspiration cytology (FNAC) is a well‐established diagnostic procedure for head and neck masses not clearly originating from mucosal or cutaneous surfaces. We analysed head and neck masses evaluated over a 2‐year period, to assess the reliability of FNAC for the evaluation of malignancy. Methods: We enrolled all patients undergoing FNAC, from April 2013 to July 2015, in a single service of a large Italian university hospital. Relevant clinical data and ultrasonographic parameters of the lesions were recorded. We performed both conventional and thin‐prep smears. Clinical presentation, ultrasonographic features and final cytology diagnoses were analysed and correlated with histology. Results: The series included 301 lesions in 285 patients, with a single (94.4%) or two (5.6%) lesions. Only eight samples were considered non‐diagnostic/inadequate (2.6%). Among the cases, 139 FNAC (46.1%) underwent surgery. Cytological‐histological correspondence was found in 89% of the cases. Concerning malignancy, we documented less than 4% false positives and less than 2.5% false negatives, with 92.7% sensitivity and 94.6% specificity. Conclusion: FNAC diagnosis can be highly specific. Most importantly, it is highly reliable in assessing malignancy, thus defining the priority and guiding the management procedures. Fine needle aspiration cytology for non‐thyroid head and neck masses, when performed with ultrasound guidance and rapid on‐site evaluation, offers a high reliability in preliminarily assessing malignancy. Ultrasound‐guided fine needle aspiration cytology is a powerful tool in the hands of clinicians to determine the priority and guide further diagnostic work‐up. [ABSTRACT FROM AUTHOR]

This paper analyzes the determining factors of South to Center‐North migration flows in Italy for five different educational groups. We find strong support for the paramount role of total and education‐specific migration networks. Furthermore, we unveil an inverse relationship between the magnitude of the response of migration flows by educational level and the regional endowment of human capital. More generally, it emerges that once migrants educational attainment is explicitly considered, the reaction of migration flows is highly heterogeneous with respect to the push and pull factors that usually determine them. In the economics of migration literature, these results have not yet been documented. [ABSTRACT FROM AUTHOR]

Studies regarding the neoplastic infiltration of the skin overlying canine subcutaneous soft tissue sarcoma (sSTS) are lacking. In case of the absence of tumor infiltration, there would be the possibility of leaving this unaffected skin in place, thus simplifying surgery. The aim of the study was to investigate whether the skin overlying sSTSs is infiltrated by neoplastic cells. Dogs with sSTSs treated surgically were prospectively enrolled. After excision, the skin was dissected from the tumor along the natural surgical plane of cleavage and histologically evaluated. Twenty‐nine dogs with an sSTS were included (22 grade I, 6 grade II, and 1 grade III). The sSTS‐overlying skin was not tumor‐infiltrated in 14/29 cases (48.3%). A higher frequency of infiltration was observed in higher grade sSTSs (grades II and III, 100%; P =.006); nevertheless, 8/22 grade I sSTSs (36%) also showed cutaneous infiltration. This infiltration involved the dermis of the skin directly in contact with the tumor (multifocal in 11 and diffuse in four cases). Although the cutaneous tumor infiltration is less frequent in grade I sSTSs and a wide excision may still be the safest treatment for any sSTS for a greater possibility of local control, this study opens the possibility to a less aggressive cutaneous excision, but still with a local curative intent, as only the skin directly in contact with the sSTS has been proven to be tumor‐infiltrated. Additional studies are warranted to confirm that excision of only this skin may guarantee a complete local control, especially in lower‐grade sSTSs. [ABSTRACT FROM AUTHOR]

Experts keep a steady final fixation at a specific location just before final movement initiation, the so-called "quiet eye" (QE). However, the eyes are rarely "quiet", and small eye movements occur during visual fixation. The current research investigated the subtle eye movements and underlying mechanisms immediately prior to and during QE. The gaze behaviour of 8 intermediate-level goalkeepers was recorded as they moved (either left or right) in an attempt to predict the future direction of the ball during a soccer penalty kick. Goalkeepers were more likely to predict the direction of the penalty, which was coupled with delaying movement initiation. The temporal sequence of microsaccade rates dropped ∼1000 ms before goalkeepers' final movement initiation. Saccade rates increased, reaching a peak ∼500 ms before final movement initiation, concomitant with microsaccades reduction. Microsaccades predicted the goalkeepers' direction, oriented to the right when goalkeepers moved to the right, and conversely to the left when they moved to the left. Microsaccades may be modulated by attention and appear functionally related to saccadic intrusions. Pupil-size increased proportionally with the lead up to the instance of the penalty being kicked, reaching a plateau at final movement initiation. In conclusion, microsaccades and small saccades could improve the perception of the soccer penalty kick, helping athletes during the period that precedes the critical movement initiation, shifting from covert to overt attention for identifying the useful cues necessary to guide the action. [ABSTRACT FROM AUTHOR]