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Christopher L Robinson,1,* Alexandra CG Fonseca,2,* Efemena M Diejomaoh,3,* Ryan S D’Souza,4 Michael E Schatman,5,6,* Vwaire Orhurhu,7,8,* Trent Emerick9,* 1Beth Israel Deaconess Medical Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Harvard Medical School, Boston, MA, USA; 2Department of Anesthesiology, Perioperative & Pain Medicine, Harvard Medical School, Brigham & Women’s Hospital, Boston, MA, USA; 3Department of Psychiatry & Behavioral Science, Meharry Medical College, Nashville, TN, USA; 4Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Rochester, Rochester, MN, USA; 5Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 6Department of Population Health-Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 7University of Pittsburgh Medical Center, Susquehanna, Williamsport, PA, USA; 8MVM Health, East Stroudsburg, PA, USA; 9University of Pittsburgh Medical Center, Department of Anesthesiology and Perioperative Medicine, Chronic Pain Division, Pittsburgh, PA, USA*These authors contributed equally to this workCorrespondence: Vwaire Orhurhu, University of Pittsburgh Medical Center, Susquehanna, Williamsport, PA, USA, Email vwo569@mail.harvard.eduIntroduction: Amid a lack of effective chronic pain treatments, psychedelics have gained attention as a potential solution, although their Schedule 1 classification poses challenges. Psychedelics, such as lysergic acid diethylamide (LSD) and psilocybin, have gained popularity as alternatives and adjuncts for chronic pain treatment. Studies suggest that they may modulate pain processing through agonism primarily at the serotonin receptor, 5-HT2A. One of the first of its nature, we present an artificial intelligence (AI)-powered scoping review primarily focusing on evaluating psychedelics for chronic pain conditions such as cluster headache, phantom limb pain, and fibromyalgia.Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we used an AI-powered comprehensive search strategy utilizing the ChatGPT4.0 Bing chat to search Medline, Embase, Cochrane, and Google Scholar for articles addressing chronic pain. The query was performed on June 1, 2023, focusing on psychedelics for chronic, non-cancer pain including headache disorders. Inclusion criteria were English-only, peer-reviewed articles involving human participants > 18 years, focusing on chronic pain conditions (eg, phantom limb pain and cluster headache), using LSD, 2.5-dimethoxy-4-bromophenethylamine (2C-B), N, N-dimethyltryptamine (DMT), psilocybin, or mescaline. Exclusion criteria were reviews, editorials, and opinion articles and studies focusing on tetrahydrocannabinol/cannabis and/or ketamine.Results: A total of 186 unique database entries were retrieved, of which nine studies were included in the scoping review. These included four case reports/series, an open-label study, a cohort study, two online surveys, and a randomized, double-blind, placebo-controlled trial. They comprised three studies addressing phantom limb pain, four addressing cluster headaches, and two addressing fibromyalgia, spinal cord injury, complex regional pain syndrome, and lumbar radiculopathy.Conclusion: Psychedelics may have potential in alleviating pain symptoms secondary to a multitude of chronic pain conditions. However, further randomized, double-blind, placebo-controlled trials are needed to further explore and evaluate the role of psychedelics in chronic, non-cancer pain.Keywords: psilocybin, mescaline, lysergic acid diethylamide, headache, phantom limb pain, scoping review

Ana Carolina Proença da Fonseca,1 Gabriella de Medeiros Abreu,1 Verônica Marques Zembrzuski,1 Mario Campos Junior,1 João Regis Ivar Carneiro,2 Fernanda Cristina C Mattos Magno,3 Eliane Lopes Rosado,3 José Firmino Nogueira Neto,4 Giselda Maria Kalil de Cabello,1 Pedro Hernán Cabello1,5 1Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil; 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Institute of Nutrition Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 4Department of Pathology and Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil; 5Human Genetics Laboratory, Grande Rio University, Rio de Janeiro, Brazil Background: Melanocortin 4 receptor gene (MC4R) is an important regulator of food intake, body weight, and blood pressure. Mutations in MC4R are associated with the most common form of nonsyndromic monogenic obesity. MC4R variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding MC4R variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the MC4R gene in a Brazilian cohort of severely obese adults and to investigate the phenotype–genotype correlation within MC4R variant carriers. Methods: This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0–11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12–21 years). The entire coding region of MC4R gene was screened by Sanger sequencing. Results: As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of MC4R. It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with MC4R missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying MC4R variants had higher median of waist–hip ratio when compared to noncarriers (P=0.048). These missense variants were also associated with hypertension (P=0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers (P=0.020 and P=0.065, respectively). Val103Ile was also associated with hypertension (P=0.003). Conclusion: This study showed the prevalence of MC4R variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of MC4R on body fat distribution and blood pressure. Keywords: MC4R, severe obesity, mutation, start lost, blood pressure

Fernanda Cristina Carvalho Mattos Magno,1 Helena Chrispim Guaraná,1 Ana Carolina Proença Fonseca,2 Giselda Maria Kalil Cabello,2 João Régis Ivar Carneiro,3 Aline Pereira Pedrosa,1 Ana Carolina Ximenes,1 Eliane Lopes Rosado1 1Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 2Oswaldo Cruz Foundation (FIOCRUZ), Oswaldo Cruz Institute (IOC), Human Genetics Laboratory, Rio de Janeiro, RJ, Brazil; 3Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Service of Nutrology, Rio de Janeiro, RJ, Brazil Background: The fat mass and obesity-related (FTO) gene has a strong relationship with obesity, extreme obesity and inflammatory state, and may also be associated with food intake regulation.Objective: The aim of the present study was to evaluate the influence of the rs9939609 single-nucleotide polymorphism of the FTO gene on appetite, ghrelin, leptin, interleukin 6 (IL6), tumor necrosis factor α (TNFα) levels and food intake of morbidly obese women.Materials and methods: The study comprised 70 women, aged between 20 and 48 years, from Rio de Janeiro, Brazil. The participants were selected according to the body mass index between 40 and 60 kg/m2. Anthropometric and biochemical data were measured during fasting. Hormones and inflammatory data were measured before and after the participants ate an isocaloric meal. Dietary records were calculated and analyzed using a nutritional assessment program. Visual analog scales were used for behaviors of the sensations of appetite and food preferences. The FTO rs9939609 variant was genotyped using real-time polymerase chain reaction.Results: Participants with the AA genotype had lower values of ghrelin and IL6 and higher values of leptin than those with TT and TA in the postprandial period. Comparing the plasma concentrations of ghrelin, insulin, IL6 and TNFα intragenotypes, it was observed that those with TT had decreased leptin and increased IL6 at the postprandial period. Subjects with TA showed increased postprandial IL6, and those with AA had decreased postprandial ghrelin. There was no difference in TNFα intra- and intergenotypes. The postprandial sensations of hunger were lower in AA than those with TT. There were differences between genotypes regarding ingested grams of protein by weight, cholesterol, B3, B5, B6 and B12 vitamins, and selenium potassium and sodium minerals.Conclusion: These findings suggest that genetics may exert an influence on physiologic factors and might alter eating behavior. Keywords: obesity, rs9939609, hormones, inflammatory cytokines, food intake, binge eating

Background: Spinal cord stimulation (SCS) is often an option of last resort for patients with post-laminectomy syndrome or an alternative option for patients with complex regional pain syndrome, chronic nonsurgical low back pain, or painful diabetic peripheral neuropathy when conservative management has failed. Although SCS is a helpful option, it is not without complications that can frequently lead to explantation of the SCS device and dissatisfaction with the treatment. Furthermore, as with any technology, SCS has potential issues that may lead to patient frustration and ultimately result in patient noncompliance and lack of follow-up visits., Objectives: The goals of this study are to explore the magnitude of and reasons for patient loss to follow-up after SCS device implantation., Study Design: A cross-sectional phone survey., Setting: A tertiary-care academic hospital., Methods: A cross-sectional phone survey was performed on 49 patients who were deemed lost to follow-up when they did not return to the clinic one month after being implanted with permanent SCS devices at Beth Israel Deaconess Medical Center. Patients were administered an institutional review board-approved questionnaire exploring their reasons for not returning to the clinic., Results: Over a 5-year period, 257 patients underwent full implantation of an SCS device. Of the 49 patients lost to follow-up, 24 were able to be contacted, and they completed the questionnaire. Twenty of the patients continued to use the SCS device but were lost to follow-up for the following reasons: 58% (14/24) due to improvement of pain, 13% (3/24) due to minimal improvement in pain control, 4% (1/24) due to other urgent health conditions, and 8% (2/24) due to patient noncompliance and missing follow-up appointments (4/24). Four patients discontinued using the SCS device after an average of 1.5 years +/- one year, 12% (3/24) due to inadequate pain control and 4% (1/24) due to inability to recharge the device (1/24). Of these patients, 2 of the 4 contacted their SCS representatives for help with troubleshooting prior to discontinuation. None of the patients was explanted., Limitations: The main limitation of this study was the incompletion rate, which was 51.0% (25 out of 49 patients)., Conclusions: This paper, the first cross-sectional study of loss to follow-up among patients who are implanted with SCS devices, identifies that up to 19% of patients are quickly lost to follow-up after implantation. Only half of the patients in this study could be reached, with most successfully using their device for meaningful pain control, but a substantial number of patients likely required additional device optimization for pain relief.

Although the ankle is often involved in low energy trauma, high-energy trauma may occur, being this considered more serious and more common of affecting young and active men. The purpose of the present study was to evaluate and compare the functionality, pain and quality of life of active and inactive adult individuals whose ankle fracture was surgically treated. Seventy-six patients split into two groups (active, n = 58 X inactive, n = 18), of the men (active, n = 38; inactive, n = 9) and women (active, n = 20; inactive, n = 9) gender participated in this prospective study. The IPAQ, MMSE, SF-36, VAS, sociodemographic and clinical questionnaires were applied in person right after surgery. The SF-36 and VAS questionnaires were reapplied 3 months in average after the surgery. Active and inactive patients of both genders show significant differences (p ≤ 0.05) in the functional capacity and physical aspect domains; and the bodily pain domain revealed significant difference in active and inactive men (p ≤ 0.05) between the periods post-surgical and 3 months after surgery (on average). Moderate and significant correlations were found (p ≤ 0.05) between functional capacity, physical aspect and bodily pain domains of the SF-36 and the VAS pain scores for active and inactive patients of both genders in the final follow-up period. Other significant correlations (p < 0.05) for inactive men (physical aspect and bodily pain) and inactive women (functional capacity and bodily pain) are observed (after 3 months of surgery). Three months after surgery (on average), active and inactive men had functional limitations and pain symptoms. These factors seem to have negatively influenced the patient's social involvement, worsening their quality of life. Most active and inactive patients had a positive self-perception of their general health status, emotional aspects and mental health domains. Regarding active women, we observed lower energy and vitality after the same postoperative period., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate collagen fibers during the bone repair process in critical defects created in the tibias of rats, treated with zoledronic acid (AZ) associated with low-level laser therapy (LLLT)., Methods: Ten rats were distributed according to treatment: group 1) saline solution; group 2) LLLT; group 3) AZ; group 4) AZ and LLLT. AZ was administered at the dose of 0.035 mg/kg at fortnightly intervals over eight weeks. Next, 2-mm bone defects were created in the tibias of all animals. The bone defects in groups 2 and 4 were irradiated LLLT in the immediate postoperative period. After periods 14 and 28 of application, the animals were euthanized, and birefringence analysis was performed., Results: Approximately 90% of the total area was occupied by collagen fibers within the red color spectrum, this area being statistically larger in relation to the area occupied by collagen fibers within the green and yellow spectrum, in the four groups. Over the 14-day period, there was no statistically significant difference between the groups. In the 28-day period, group 2 (14.02 ± 15.9%) was superior in quantifying green birefringent fibers compared to group 1 (3.06 ± 3.24%), with p = 0.009., Conclusions: LLLT associated with ZA is effective in stimulating the neoformation of collagen fibers. The LLLT group without the association with ZA showed a greater amount of immature and less organized matrix over a period of 28 days.

Background: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age., Methods: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS., Results: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women., Conclusions: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS., Competing Interests: Competing interests: JP: shareholder of Olvi Oyj. TT: has served/serves on scientific advisory boards for Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva and Portola Pharm., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV., Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed., Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00-4.06): 102 (2.13% 95% CI 1.73-2.56) with stroke and 81 (1.68% 95% CI 1.33-2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet's disease (9.5%, 95% CI 5.79-14.37), polyarteritis nodosa (6.2%, 95% CI 3.25-10.61), and Takayasu's arteritis (6.0%, 95% CI 4.30-8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09-3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20-3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05-9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01-2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period., Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet's. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence., (© 2024. The Author(s).)

IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals and that single-nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production in innate lymphoid cells (ILCs) but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33's influence on IL-22-dependent antibacterial defense was dependent on housing conditions of the mice and mediated by IL-33's modulatory effect on the gut microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We conclude that both genetic and environmental factors influence the gut microbiota, thereby impacting the efficacy of antibacterial immune defense and susceptibility to pneumonia., Competing Interests: Competing interests statement:The authors declare no competing interest.

Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1 + /CD44 + /BMI-1 - tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1 high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSC high E-cadherin low (ALDH1 high p75NTR high E-cadherin low ) and CSC intermediate E-cadherin low (ALDH1 or p75NTR high E-cadherin low ) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSC high E-cadherin low at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC., (© 2024. The Author(s).)

The transition from fossil fuels is in part limited by our inability to store energy at different scales. Batteries are therefore in high demand, and we need them to store more energy, be more reliable, durable and have less social and environmental impact. Silica-poly(vinyl alcohol) (PVA) composite aerogels doped with sodium perchlorate were synthesized as novel electrolytes for potential application in solid-state sodium batteries. The aerogels, synthesized by one-pot synthesis, are light (up to 214 kg m -3 ), porous (~85%), exhibit reduced shrinkage on drying (up to 12%) and a typical silica aerogel microstructure. The formation of a silica network and the presence of PVA and sodium perchlorate in the composite were confirmed by FTIR and TGA. The XRD analysis also shows that a predominantly amorphous structure is obtained, as crystalline phases of polymer and salt are present in a very reduced amount. The effects of increasing polymer and sodium salt concentrations on the ionic conductivity, assessed via electrochemical impedance spectroscopy, were studied. At a PVA concentration of 15% ( w / w silica precursors), the sodium conduction improved significantly up to (1.1 ± 0.3) × 10 -5 S cm -1 . Thus, this novel material has promising properties for the envisaged application.

Background: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation., Methods: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments., Results: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45-1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28-2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35-5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53-20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18-0.88]; P interaction =0.009)., Conclusions: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings., Competing Interests: Disclosures Disclosures provided by Dr Nguyen in compliance with American Heart Association annual Journal Editor Disclosure Questionnaire are available at https://www.ahajournals.org/editor-coi-disclosures. Dr Arnold reports compensation from Boehringer Ingelheim, AstraZeneca, Bayer, Bristol-Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Sanofi, Pfizer, Medtronic, Novo Nordisk, and Amgen for consultant services. Dr Lester reports a provisional patent for Methods and compositions for disrupting tau aggregates. Dr Touze reports compensation from Elsevier for other services and employment by Caen. J.E. Kaufman reports grants from Goldschmidt Jacobson-Stiftung. Dr Traenka reports travel support from Bayer Healthcare. Dr Aguiar de Sousa reports compensation from Daiichi Sankyo, Bayer, AstraZeneca, Johnson & Johnson, and Fundação Bial for other services; compensation from the University of British Columbia for data and safety monitoring services; compensation from Organon & Co for consultant services. Dr Rosa reports grants from Merck Sharp & Dohme Corporation. Dr Field reports compensation from HLS Therapeutics, AstraZeneca Canada, and Roche for consultant services; service as a board member for Destine Health; and compensation from the Canadian Medical Protective Association for expert witness services; and grants from Bayer. Dr Leker reports compensation from Medtronic, Ischemaview, Bayer, Abbott Diabetes Care, Biogen, Janssen Biotech, and Boehringer Ingelheim for other services. Dr Nolte reports compensation from Daiichi Sankyo Europe GmbH, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Alexion Pharmaceuticals for consultant services; and compensation from AstraZeneca, Abbott Canada, Deutsches Zentrum für Neurodegenerative Erkrankungen, Novartis, Portola Pharmaceuticals, Deutsches Zentrum für Herz-Kreislaufforschung, and Novartis for other services. Dr Poppe reports grants from Foundation Brain Canada, Heart and Stroke Foundation of Canada, and Stryker; and compensation from Roche for other services. Dr Liebeskind reports compensation from Medtronic, Genentech, Cerenovus, Stryker, and Rapid Medical Ltd, for consultant services. B. Mac Grory reports grants from the National Institutes of Health; employment by Duke University Medical Center; compensation from Bayer for other services; grants from the American Heart Association, Duke Bass Connections, and the Duke Office of Physician Scientist Development. Dr Al Kasab reports compensation from Stryker for other services and employment by Medical University of South Carolina. Dr Kicielinski reports compensation from Stryker, Penumbra Inc, Medtronic, and MicroVention Inc, for other services; travel support from MicroVention Inc; and employment by Medical University of South Carolina and Elsevier. Dr de Havenon reports stock options in TitinKM and Certus; grants from the National Institutes of Health; and compensation from Novo Nordisk for consultant services. Dr Siegler reports grants from Philips and employment by the University of Chicago. Dr Willey reports compensation from Edwards Lifesciences Corporation and Abbott Fund for end point review committee services; compensation from Uptodate for other services; and compensation from the Abbott Laboratories for consultant services. Dr Sharma reports a provisional patent for a stroke etiology classifier algorithm and grants from the National Institutes of Health Clinical Center. Dr Martins reports compensation from Pfizer, Medtronic, Servier Affaires Medicales, Daiichi Sankyo, Bayer, Novo Nordisk, Novartis, Penumbra Inc, and Boehringer Ingelheim for other services. Dr Simpkins reports grants from the National Institutes of Health. Dr Stretz reports grants from Massachusetts General Hospital. Dr Furie reports compensation from Janssen Biotech for consultant services. The other authors report no conflicts

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored., Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults., Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness., Results: Increased LA stiffness was found in 36% of patients and in 18% of controls ( P  < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders ( P  = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P  < 0.05)., Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725)., Competing Interests: The SECRETO study has been funded by the 10.13039/501100002341Academy of Finland under grant numbers 318075 and 322656, Helsinki and Uusimaa Hospital District (TYH2018318), and 10.13039/501100006306Sigrid Juselius Foundation. Dr Cramariuc has received clinical researcher funds and open project support from the Regional Health Authorities in Western Norway (project numbers F-12557 and F-12615). Dr Sarkanen has received grant number 322663 from the Academy of Finland. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: Young adults with increased LA stiffness have significantly higher risk of CIS independent of LA size and in the absence of atrial fibrillation. TRANSLATIONAL OUTLOOK: Patients with premature LA disease may benefit from early intervention, like antithrombotic therapy. This should be further investigated in clinical studies addressing preventive and therapeutic interventions in young patients at high risk of ischemic stroke., (© 2024 The Authors.)

This study aimed to (1) evaluate how population levels of anxiety and depression grow and correlate from middle childhood through early adulthood, and (2) determine whether sex, family socioeconomic status, parental education, academic achievement, learning disabilities, or externalizing symptoms predict anxiety and/or depression levels and growth trajectory. We used two longitudinal samples (N = 445, 448) of Portuguese children. Mean depression levels increased from mid-childhood through adolescence before stabilizing in early adulthood and were most strongly predicted by academic achievement and learning disabilities. Mean anxiety levels increased until adolescence before decreasing across early adulthood and were most strongly predicted by academic achievement, learning disabilities, and externalizing symptoms. Quadratic models of growth fit best for both depression and anxiety, and depression and anxiety growth trajectories were strongly correlated. Though anxiety and depression trajectories differ in pattern and predictors, the two are highly interrelated and pathways to comorbid anxiety and depression should be characterized., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The treatment of burn wounds remains a clinical challenge due to the need for repeated dressings changes. Therefore, the development of a dressing system that can be atraumatically removed from the wound bed can be considered a breakthrough and improve treatment times. In this work, the development of an injectable, fast-gelling hydrogel is proposed that can change its mechanical properties when exposed to visible light. The hydrogels are prepared by a "click" amino-yne reaction between poly(ethylene glycol) (PEG) functionalized with propiolic acid and the amino groups of poly(ethyleneimine) (PEI). The hydrogels exhibit a fast gelation time, which can be adjusted by changing the weight percentage and molecular weight of the precursors. They also exhibit good swelling ability and adhesion to living tissues. More importantly, their mechanical properties changed upon irradiation with green light. This loss of properties is achieved by a 1 O 2 -mediated mechanism, as confirmed by the degradation of the β-aminoacrylate linker. Moreover, the in vitro cell compatibility results of the hydrogels and their degradation products show good cytocompatibility. Therefore, it is believed that these hydrogels can be considered as materials with great potential for an innovative strategy for the treatment of burn wounds., (© 2023 Wiley-VCH GmbH.)

Background: The National Institutes of Health Stroke Scale (NIHSS) does not equitably assess stroke severity in the two cerebral hemispheres. By attributing a maximum of two points for neglect and seven for language, it undervalues right hemisphere deficits. We aimed to investigate if NIHSS equally predicts right hemisphere lesion volumes in patients with and without neglect, and if a modification of the neglect scoring rules could increase its predictive capacity., Methods: We analyzed a prospective cohort of acute right middle cerebral artery ischemic stroke patients. First, we calculated the correlation between NIHSS scores and lesion volume and analyzed the partial correlation of neglect. Then, we applied different modifications in the neglect scoring rules and investigated how they interfered with lesion volume predictive capacity., Results: A total of 162 ischemic stroke patients were included, 108 with neglect and 54 without. The correlation between lesion volume and NIHSS was lower in patients with neglect (r = 0.540 vs. r = 0.219, p = 0.004) and neglect was a statistically significant covariate in the partial correlation analysis between NIHSS and lesion volume (p = 0.017). With the neglect score tripled and with the duplication or triplication of all neglect modalities, the correlation was significantly higher than with the standard NIHSS (p = 0.043, p = 0.005, p = 0.001, respectively). With these modifications, neglect was no longer a significant covariable in the partial correlation between lesion volume and NIHSS., Conclusion: A modification of NIHSS neglect scoring might improve the scale's capacity to predict lesion volume., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Liquid biopsy is a non-invasive method used to detect cancer and monitor treatment responses by analyzing blood or other bodily fluids for cancer biomarkers. Meningiomas are the most common primary central nervous system tumors, and biomarkers play a crucial role in their diagnosis, prognosis, and treatment monitoring. The World Health Organization (WHO) classifies meningiomas based on tumor grades and molecular alterations in genes such as in NF2, AKT1, TRAF7, SMO, PIK3CA, KLF4, SMARCE1, BAP1, H3K27me3, TERT promoter, and CDKN2A/B. Liquid biopsy, specifically cell-free DNA (cfDNA) analysis, has shown potential for monitoring meningiomas as it can detect ctDNA release in the blood, unaffected by the blood-brain barrier. MicroRNAs (miRNAs) have also been found to be deregulated in various cancers, including meningiomas, presenting potential as diagnostic biomarkers. Additionally, studying cytokines in the tumor microenvironment may aid in establishing prognostic or diagnostic panels for meningiomas., Methods: In the present study we analyzed the DNA coming from both the plasma and tumor samples, in addition to analyze miRNA-21 and cytokines in the plasma of 28 meningioma patients., Discussion and Conclusion: Our findings indicate that the detection of ctDNA in the plasma of meningioma patients is feasible. However, it's important to note that certain challenges persist when comparing plasma DNA analysis to that of tumor tissues. In our study, we observed a paired identification of mutations in only one patient, highlighting the complexities involved. Furthermore, we successfully identified miR-21 and cytokines in the plasma samples. Notably, our analysis of Interleukin 6 (IL-6) unveiled higher expression in the clear cell subtype compared to the other types. Despite the ongoing research, the clinical implementation of liquid biopsy in meningiomas remains somewhat limited. Nevertheless, our promising results underscore the need for further investigation., Competing Interests: FA was employed by Rede D'Or. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor PG declared a past collaboration with the author VM-N., (Copyright © 2024 Aran, Lyra Miranda, Heringer, Carvalho da Fonseca, Andreiuolo, Chimelli, Devalle, Niemeyer Filho and Moura-Neto.)

Introduction: Carotid webs (CaWs) are increasingly recognized as a cause of cryptogenic acute ischemic stroke (AIS). Due to the risk of recurrent ischemic stroke associated with CaW, it is important to identify them. Although several studies report digital subtraction angiography and computerized tomography angiography (CTA) to be better at diagnosing CaW than Doppler ultrasound (DUS), it remains to be defined which is the best radiological method to diagnose CaW. Our aim was to evaluate sensitivity and accuracy of DUS compared to CTA for CaW diagnosis., Methods: We searched PUBMED and EMBASE databases from inception through August 2022. We included studies with patients with CaW diagnosed by DUS and/or CTA, in which both methods were used in each patient. Demographic characteristics, diagnostic reports of each method, and histology reports were collected. Descriptive analysis and sensitivity and accuracy estimates were made to evaluate DUS compared to CTA., Results: We included 27 articles in the systematic review (121 patients with CaW). DUS identified 94 patients with CaW and CTA 116 patients. DUS missed diagnosis in 22.3% (27 patients) and CTA did not identify CaW detected by DUS in 4.13% (5 patients). Accuracy rate between DUS and CTA was 73.6% (95% CI: 64.8-81.2%). Sensitivity of DUS to diagnose CaW compared to CTA was 76.7% (95% CI: 68.0-84.1%). Most common misdiagnosis with DUS was normal exam (44.4%), atherosclerosis (22.2%), and dissection (22.2%)., Conclusion: The sensitivity and accuracy of DUS to diagnosis of CaW were moderate. It might detect CaW in some cases in which it was not identified by CTA. Increased recognition of CaW and specific ultrasound protocols may enhance diagnosis of CaW by DUS., (© 2023 S. Karger AG, Basel.)

The study examined the relationship between mistrust and aggression from childhood to adulthood. The participants resided in Portugal and were tested during middle childhood (Mage = 7.5, SD = 0.81 years, n = 445, 240 male), preadolescence (Mage = 11.92, SD = 0.96 years, n = 431, 200 male), mid-adolescence (Mage = 14.70, SD = 0.91 years, n = 326, 201 male), late adolescence (Mage = 18.14, SD = 1.19 years, n = 410, 216 male), and adulthood (Mage = 26.56, SD = 1.13, years, n = 417, 197 male). Mothers reported the participants' mistrust during childhood and preadolescence on items from the Child Behavior Checklist. Aggression was assessed by standardized self-report measures at each age period. It was found that mistrust was associated with aggression during preadolescence and predicted changes in aggression to mid-adolescence and adulthood. The findings supported the conclusion that mistrust during preadolescence predisposes individuals to show aggression later in the life course., (© 2023 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

Accurately predicting functional outcomes in stroke patients remains challenging yet clinically relevant. While brain CTs provide prognostic information, their practical value for outcome prediction is unclear. We analyzed a multi-center cohort of 743 ischemic stroke patients (<72 h onset), including their admission brain NCCT and CTA scans as well as their clinical data. Our goal was to predict the patients' future functional outcome, measured by the 3-month post-stroke modified Rankin Scale (mRS), dichotomized into good (mRS ≤ 2) and poor (mRS > 2). To this end, we developed deep learning models to predict the outcome from CT data only, and models that incorporate other patient variables. Three deep learning architectures were tested in the image-only prediction, achieving 0.779 ± 0.005 AUC. In addition, we created a model fusing imaging and tabular data by feeding the output of a deep learning model trained to detect occlusions on CT angiograms into our prediction framework, which achieved an AUC of 0.806 ± 0.082. These findings highlight how further refinement of prognostic models incorporating both image biomarkers and clinical data could enable more accurate outcome prediction for ischemic stroke patients.

Purpose of Review: To review the evidence regarding stroke and recent myocardial infarction (MI), reduced left ventricular ejection fraction, left ventricular thrombus (LVT), and wall motion abnormalities (WMA)., Recent Findings: The risk of ischemic stroke associated with acute MI has been greatly reduced with reperfusion treatments that improved myocardium salvage. Acute ischemic stroke is an uncommon complication of diagnostic coronary angiography and percutaneous coronary intervention. For established LVT, anticoagulation is superior to antiplatelet medications to reduce the risk of ischemic stroke. The duration of anticoagulation should be at least 3 to 6 months. Direct oral anticoagulants have been used off-label in this context. In patients with low ejection fraction or WMA, there is no evidence that anticoagulation is superior to antiplatelet treatment in preventing ischemic stroke. In patients with ischemic stroke and recent MI (< 3 months), type of MI (STEMI or NSTEMI), timing, and location should be considered when deciding whether intravenous thrombolysis should be used for stroke treatment. Mechanical thrombectomy should be considered as a therapeutic alternative to intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion and recent MI. Most guidelines regarding prevention of ischemic stroke in patients with these cardiac causes of stroke are derived from expert opinion. There is a need for high quality evidence to support stroke prevention treatments in these patients., (© 2023. The Author(s).)

The hair follicle (HF) is a multicellular complex structure of the skin that contains a reservoir of multipotent stem cells. Traditional hair repair methods such as drug therapies, hair transplantation, and stem cell therapy have limitations. Advances in nanotechnology offer new approaches for HF regeneration, including controlled drug release and HF-specific targeting. Until recently, embryogenesis was thought to be the only mechanism for forming hair follicles. However, in recent years, the phenomenon of wound-induced hair neogenesis (WIHN) or de novo HF regeneration has gained attention as it can occur under certain conditions in wound beds. This review covers HF-specific targeting strategies, with particular emphasis on currently used nanotechnology-based strategies for both hair loss-related diseases and HF regeneration. HF regeneration is discussed in several modalities: modulation of the hair cycle, stimulation of progenitor cells and signaling pathways, tissue engineering, WIHN, and gene therapy. The HF has been identified as an ideal target for nanotechnology-based strategies for hair regeneration. However, some regulatory challenges may delay the development of HF regeneration nanotechnology based-strategies, which will be lastly discussed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paiva-Santos, A.C. reports financial support was provided by Foundation for Science and Technology., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The recommended cardiac rhythm evaluation to determine the etiology of ischemic stroke (IS) is similar in all patients regardless of their age and includes an electrocardiogram and at least a 24-hour heart rhythm monitoring. However, it is known that the main causes of IS vary according to patients' age. There is a higher preponderance of arterial dissections and patent foramen ovale in younger patients, while atrial fibrillation (AF) is more common in older patients., Aims: To determine the proportion of AF in young IS reported in the literature and determine if young IS patients found to have AF had known structural cardiac pathology., Methods: Systematic review of the literature searching PubMed and Embase for articles published since their inception to August 2020. Inclusion criteria were studies including at least 10 patients, aged 14-50 years-old, clinical or radiological diagnosis of IS and quantification of patients found to have AF. We conducted a meta-analysis using a random-effects model and calculated pooled proportions with 95% confidence intervals., Results: 8331 articles were screened, 154 were selected for full-text review. 43 studies were included in our final analysis (902800 patients). The proportion of AF in young IS overall was 3.1% [95%CI 2.4-3.7], I 2 93.88%. Sub-analysis revealed a proportion of AF of 3.8% [95% CI 0.3-7.3] in lower-middle-income economies, versus 5.4% [95% CI 3-7.9] in upper-middle-income economies, and 2.2% [95% CI 1.6-2.8] in high-income economies. Only 3 studies mentioned the proportion of patients with AF that had structural cardiac pathology., Conclusion: The proportion of AF in young IS was low. More studies are needed to better understand if young IS patients diagnosed with AF had a priori known structural cardiac pathology that could increase the probability of finding AF. This could lead to a reevaluation of the need for 24 hours cardiac rhythm evaluation in young patients without cardiac pathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are often complicated by vasospasm and ischemia. Monitoring with transcranial color-coded Doppler (TCCD) could be useful, but its role is not established. We studied the incidence of ultrasonographic vasospasm (uVSP) in PRES/RCVS and its relationship with ischemic lesions and clinical outcome., Materials and Methods: We conducted a multicenter retrospective study of all patients with PRES/RCVS from 2008 to 2020 who underwent TCCD and magnetic resonance imaging (MRI). TCCD exams were analyzed for uVSP. Diffusion-weighted MRI was analyzed for positive lesions (DWI-positive). Functional outcome was assessed by modified Rankin scale (mRS) at 90 days. The associations with outcomes were determined by logistic regression., Results: We included 80 patients (mean age of 46 (standard deviation, 17) years; 66% females; 41 with PRES, 28 with RCVS and 11 with overlap phenotype). uVSP was detected in 25 (31%) patients. DWI-positive lesions were more often detected in uVSP-positive than uVSP-negative patients (36% vs. 15%; adjusted odds ratio [aOR] 4.05 [95% CI 1.06 - 15.5], P=0.04). DWI-positive lesions were independently associated with worse functional prognosis (mRS 2-6, 43% vs. 10%; aOR, 10 [95% CI 2.6 - 43], P<0.01). Having additional uVSP further increased the odds of a worse outcome (P interaction=0.03)., Conclusion: Ultrasonographic vasospasm was detected in a third of patients with PRES/RCVS and was associated with brain ischemic lesions. TCCD bedside monitoring can help to stratify patients at risk for cerebral ischemia, a strong predictor of functional outcome., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: The COVID-19 pandemic produced alarming rates of disease and mortality globally, yet few nations were as severely impacted as Brazil. The pandemic also exposed and exacerbated persistent forms of structural violence across Brazil, which complicated gender-based violence (GBV) prevention and response efforts. While structural violence is not new, the systemic pressure and uncertainty introduced by COVID-19 intensified the detrimental impact of structural violence on the lives of Brazilians impacted by GBV. This work qualitatively investigated how the COVID-19 pandemic amplified structural violence and GBV in Brazil., Methods: We analyzed key informant interviews (KII) conducted with 12 service providers working in sectors related GBV prevention and response in Roraima, Boa Vista, and Rio de Janeiro. Interviews were audio-recorded, transcribed, and translated from Portuguese or Spanish into English, before applying deductive and inductive coding approaches through a collaborative data reduction process. The theoretical lens of structural violence outlined by Farmer and Rylko-Bauer guided the thematic development., Results: Analyses identified three themes. First, structural violence manifests as policies of inaction and erasure, which reduce the opportunity for upward social mobility among GBV survivors including Black women, trans persons, and people who live in the favelas. Policies of inaction and erasure fail to acknowledge/adequately respond to the significant health and safety needs of these communities. Second, structural violence is a fundamental cause of violence against women and children. Finally, service providers described community driven responses that address the dire survival needs (i.e., food insecurity) imposed by COVID-19, within a context of structural violence. These community driven responses were innovative, agile, and based on dire needs expressed to, and observed by, the service providers interviewed., Conclusion: This analysis highlights how the COVID-19 pandemic exacerbated existing forms of structural violence prevalent throughout Brazil. Findings stress the urgency with which the Brazilian government and international organization must act to support community driven programs that strive to address the most basic human needs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Recently, highly stretchable and tough hydrogels that are photodegradable on-demand have been reported. Unfortunately, the preparation procedure is complex due to the hydrophobic nature of the photocrosslinkers. Herein, a simple method is reported to prepare photodegradable double-network (DN) hydrogels that exhibit high stretchability, toughness, and biocompatibility. Hydrophilic ortho-nitrobenzyl (ONB) crosslinkers incorporating different poly(ethylene glycol) (PEG) backbones (600, 1000, and 2000 g mol -1 ) are synthesized. These photodegradable DN hydrogels are prepared by the irreversible crosslinking of chains by using such ONB crosslinkers, and the reversible ionic crosslinking between sodium alginate and divalent cations (Ca 2+ ). Remarkable mechanical properties are obtained by combining ionic and covalent crosslinking and their synergistic effect, and by reducing the length of the PEG backbone. The rapid on-demand degradation of these hydrogels is also demonstrated by using cytocompatible light wavelength (λ = 365 nm) that degrades the photosensitive ONB units. The authors have successfully used these hydrogels as skin-worn sensors for monitoring human respiration and physical activities. A combination of excellent mechanical properties, facile fabrication, and on-demand degradation holds promise for their application as the next generation of substrates or active sensors eco-friendly for bioelectronics, biosensors, wearable computing, and stretchable electronics., (© 2023 Wiley-VCH GmbH.)

The need to belong with peers is an essential component of development, and when individuals face peer rejection they often experience a host of negative outcomes, including internalizing and externalizing problems. There exists conflicting evidence whether peer rejection precedes, succeeds, or reciprocally influences psychopathology. This study used two longitudinal community samples recruited from Portuguese schools with data from middle childhood through early adulthood. The obtained data measured mean levels and assessed stability of peer rejection, and peer rejection's association with demographic and psychopathology variables concurrently across development. Analyses fit developmental cascade models of peer rejection, depression, anxiety, and externalizing problems. Mean peer rejection levels remained relatively stable over time, and peer rejection scores were mildly to moderately correlated at measurement points closer together but attenuated at timepoints that were further apart in time. At some timepoints, age, and parental SES and education were associated with peer rejection. Peer rejection was associated with depression, anxiety, and externalizing problems concurrently at each time point (r = ~0.3-0.5). Developmental cascade models supported depression and anxiety temporally preceding peer rejection and some reciprocal relationships between depression and peer rejection. Anxiety was a robust temporal precedent of psychopathology and peer rejection., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intracranial and extracranial large-artery atherosclerosis (LAA) are a main cause of ischemic stroke. Biomarkers may aid in the diagnosis of LAA and help to stratify patients' risk of stroke. We performed a narrative review of the literature, mainly published in the last five years, with the aim of identifying biomarkers associated either with intracranial or extracranial LAA in humans. Several potential biomarkers of LAA, mainly related to lipidic pathways and inflammation, have been studied. Diagnostic biomarkers of LAA were evaluated by measuring biomarkers levels in patients with LAA stroke and other stroke etiologies. Some biomarkers were associated with the functional prognosis of LAA stroke patients. Increased levels of IL-6 and sLOX-1 were associated with a risk of progression of carotid atherosclerotic disease. Findings support the notion that the immune system plays a central role in the pathogenesis of LAA. Overall, in most studies, results were not externally validated. In the future, biomarkers could be useful for the selection of patients for clinical trials. To adopt these biomarkers in clinical practice, we will need robust multicentric studies proving their reproducibility and a clear practical applicability for their use.

This study investigates the osteogenic differentiation of umbilical-cord-derived human mesenchymal stromal cells (hUC-MSCs) on biphasic calcium phosphate (BCP) scaffolds derived from cuttlefish bone doped with metal ions and coated with polymers. First, the in vitro cytocompatibility of the undoped and ion-doped (Sr 2+ , Mg 2+ and/or Zn 2+ ) BCP scaffolds was evaluated for 72 h using Live/Dead staining and viability assays. From these tests, the most promising composition was found to be the BCP scaffold doped with strontium (Sr 2+ ), magnesium (Mg 2+ ) and zinc (Zn 2+ ) (BCP-6Sr2Mg2Zn). Then, samples from the BCP-6Sr2Mg2Zn were coated with poly(ԑ-caprolactone) (PCL) or poly(ester urea) (PEU). The results showed that hUC-MSCs can differentiate into osteoblasts, and hUC-MSCs seeded on the PEU-coated scaffolds proliferated well, adhered to the scaffold surfaces, and enhanced their differentiation capabilities without negative effects on cell proliferation under in vitro conditions. Overall, these results suggest that PEU-coated scaffolds are an alternative to PCL for use in bone regeneration, providing a suitable environment to maximally induce osteogenesis.

Methodology: Inducible nitric oxide synthase (iNOS) is one of the enzymes responsible for the synthesis of nitric oxide (NO), which is an important signaling molecule with effects on blood vessels, leukocytes, and bone cells. However, the role of iNOS in alveolar bone healing remains unclear. This study investigated the role of iNOS in alveolar bone healing after tooth extraction in mice. C57Bl/6 wild type (WT) and iNOS genetically deficient (iNOS-KO) mice were subjected to upper incision tooth extraction, and alveolar bone healing was evaluated by micro-computed tomography (μCT) and histological/histomorphometric, birefringence, and molecular methods., Results: The expression of iNOS had very low control conditions, whereas a significant increase is observed in healing sites of WT mice, where iNOS mRNA levels peak at 7d time point, followed by a relative decrease at 14d and 21d. Regarding bone healing, both WT and iNOS-KO groups showed the usual phases characterized by the presence of clots, granulation tissue development along the inflammatory cell infiltration, angiogenesis, proliferation of fibroblasts and extracellular matrix synthesis, bone neoformation, and remodeling. The overall micro-computed tomography and histomorphometric and birefringence analyses showed similar bone healing readouts when WT and iNOS-KO strains are compared. Likewise, Real-Time PCR array analysis shows an overall similar gene expression pattern (including bone formation, bone resorption, and inflammatory and immunological markers) in healing sites of WT and iNOS-KO mice. Moreover, molecular analysis shows that nNOS and eNOS were significantly upregulated in the iNOS-KO group, suggesting that other NOS isoforms could compensate the absence of iNOS., Conclusion: The absence of iNOS does not result in a significant modulation of bone healing readouts in iNOS-KO mice. The upregulation of nNOS and eNOS may compensate iNOS absence, explaining the similar bone healing outcome in WT and iNOS-KO strains.

Background and Purpose: Incongruent beliefs about self-localization in space markedly disturb patients' behavior. Spatial delusions, or reduplicative paramnesias, are characterized by a firm conviction of place reduplication, transformation, or mislocation. Evidence suggests they are frequent after right hemisphere lesions, but comprehensive information about their clinical features is lacking., Methods: We prospectively screened 504 acute right-hemisphere stroke patients for the presence of spatial delusions. Their behavioral and clinical features were systematically assessed. Then, we analyzed the correlation of their duration with the magnitude of structural disruption of belief-associated functional networks. Finally, we described the syndrome subtypes and evaluated whether the clinical categorization would be predicted by the structural disruption of familiarity-associated functional networks using an unsupervised k-means clustering algorithm., Results: Sixty patients with spatial delusions were identified and fully characterized. Most (93%) localized the misidentified places closer to home than the hospital. The median time duration was 3 days (interquartile range = 1-7 days), and it was moderately correlated with the magnitude of structural-functional decoupling of belief-associated functional networks (r = 0.39, p = 0.02; beta coefficient regressing for lesion volume = 3.18, p = 0.04). Each clinical subtype had characteristic response patterns, which were reported, and representative examples were provided. Clustering based on structural disruption of familiarity- and unfamiliarity-associated functional networks poorly matched the clinical categorization (lesion: Rand index = 0.47; structural disconnection: Rand index = 0.51)., Conclusions: The systematic characterization of the peculiar clinical features of stroke-associated spatial delusions may improve the syndrome diagnosis and clinical approaches. The novel evidence about their neural correlates fosters the clarification of the pathophysiology of delusional misidentifications., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Preventing, detecting, and monitoring invasive marine species is a big challenge as it is not possible to visualize all invasion extensions. Their early detection may be the best chance to achieve eradication. The Indo-pacific scleractinian coral Tubastraea coccinea invasion in the Atlantic dates from the late 1930s. Since then, disruptive populations were found along ~8.000 km of west Atlantic, and in the Canarian Islands of Spain (east Atlantic), related to vessel fouling in the oil and gas industry. Their impacts have been noticed from endemic species to ecosystems. In Brazil, initiatives to control Tubastraea spp. have been done mostly by local environmental managers and researchers, but recently a National Plan for Prevention, Control and Monitoring (NPPCM) for Tubastraea spp. was approved. We applied an Individual-based Model within the invasion history of Tubastraea coccinea in its southern distribution limit in the Atlantic, on the rocky shore of the Arvoredo Biological Marine Reserve. We indicated hotspots for the occurrence of possible emerging invasion sites in the region and expect to support ongoing monitoring programs in defining priority areas for their early detection. The model is easily replicated and might be a valuable tool for decision makers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The alveolar bone repair process may be influenced by multiple local and systemic factors, which include immune system cells and mediators. Macrophages allegedly play important roles in the repair process, and the transition of an initial inflammatory M1 profile into a pro-reparative M2 profile theoretically contributes to a favorable repair outcome. In this context, considering immunoregulatory molecules as potential targets for improving bone repair, this study evaluated the role of the immunoregulatory molecule FTY720, previously described to favor the development of the M2 phenotype, in the process of alveolar bone healing in C57Bl/6 (WT) mice. Experimental groups submitted to tooth extraction and maintained under control conditions or treated with FTY720 were evaluated by microtomographic (μCT), histomorphometric, immunohistochemical and molecular analysis to characterize healing and host response features at 0, 1, 3, 7 and 14 days. Our results demonstrated that the FTY720 group presented higher bone tissue density, higher bone tissue volume, greater tissue volume fraction, greater number and thickness of trabeculae and a higher number of osteoblasts and osteoclasts than the control group. Accordingly, the bone markers BMP2, BMP7, ALPL, SOST and RANK mRNA expressions increased in the FTY720 treated group. Furthermore, the levels of FIZZ, ARG2 and IL-10 mRNA increased in the FTY720 group together with the presence of CD206 + cells, suggesting that the boost of bone formation mediated by FTY720 involves an increased polarization and activity of M2 macrophages in healing sites. Thus, our results demonstrate that FTY720 favored the process of alveolar bone repair, probably trough a strengthened M2 response, associated with an increased expression of markers osteogenic differentiation and activity markers. Immunoregulatory strategies based in the modulation of macrophage polarization profile can comprise effective tools to improve the bone repair process., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Poly(2,5-furandicarboxylate)s incorporating aliphatic moieties represent a promising family of polyesters, typically entirely based on renewable resources and with tailored properties, notably degradability. This study aims to go beyond by developing poly(isosorbide 2,5-furandicarboxylate- co -dodecanedioate) copolyesters derived from isosorbide (Is), 2,5-furandicarboxylic acid (FDCA), and 1,12-dodecanedioic acid (DDA), and studying their degradation under environmental conditions, often overlooked, namely seawater conditions. These novel polyesters have been characterized in-depth using ATR-FTIR, 1 H, and 13 C NMR and XRD spectroscopies and thermal analysis (TGA and DSC). They showed enhanced thermal stability (up to 330 °C), and the glass transition temperature increased with the content of FDCA from ca. 9 to 60 °C. Regarding their (bio)degradation, the enzymatic conditions lead to the highest weight loss compared to simulated seawater conditions, with values matching 27% vs. 3% weight loss after 63 days of incubation, respectively. Copolymerization of biobased FDCA, Is, and DDA represents an optimal approach for shaping the thermal/(bio)degradation behaviors of these novel polyesters.

Introduction: Cognitive impairment and retinal atrophy have been proposed as two potential markers of neurodegeneration in multiple sclerosis (MS). We aimed at assessing the relation between peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) atrophy and cognitive performance in early MS., Methods: This is a multicenter cross-sectional study on patients with early MS (clinically isolated syndrome and relapsing-remitting MS), with an EDSS score ≤ 3.0. Patients with previous optic neuritis, other ocular diseases, psychiatric illness, or recent relapse were excluded. All patients underwent standardized optical coherence tomography (OCT) and neuropsychological evaluation with validated tests for MS patients. Cognitive impairment was defined as having two cognitive tasks below age- and education-adjusted norms., Results: We recruited 52 patients with early MS, with an average age of 37 years (SD = 10.5), an average disease duration of 3.69 years (SD = 2.3), and a median EDSS of 1.0 (IQR = 0.5). In this sample, 15/52 patients presented cognitive impairment. Regarding OCT measurements, 7/52 patients had an average pRNFL below the 5th percentile and 2/52 had an average mGCL below the 5th percentile. The average pRNFL thickness was comparable in cognitively impaired and cognitively preserved patients (100.3 μm vs 103.1 μm, p = 0.52); the average mGCL thickness had also similar values between groups (50.5 μm vs 53 μm, p = 0.38)., Conclusions: Cognitive impairment was frequent in our sample of early MS. However, no association with reduced pRNFL or mGCL thickness was found. When compared to OCT, cognitive assessment could provide an earlier marker of neurodegeneration in MS., (© 2022. Fondazione Società Italiana di Neurologia.)