Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Bayesian reaction optimization as a tool for chemical synthesis.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimization outperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

Evaluation and application of American College of Radiology Thyroid Imaging Reporting and Data System for improved malignancy detection in paediatric thyroid nodules.

OBJECTIVE: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. METHODS: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. RESULTS: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. CONCLUSIONS: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children.

Looking Outside the Square: The Growth, Structure, and Resilient Two-Dimensional Surface Electron Gas of Square SnO2 Nanotubes.

Nanotechnology has delivered an amazing range of new materials such as nanowires, tubes, ribbons, belts, cages, flowers, and sheets. However, these are usually circular, cylindrical, or hexagonal in nature, while nanostructures with square geometries are comparatively rare. Here, a highly scalable method is reported for producing vertically aligned Sb-doped SnO2 nanotubes with perfectly-square geometries on Au nanoparticle covered m-plane sapphire using mist chemical vapor deposition. Their inclination can be varied using r- and a-plane sapphire, while unaligned square nanotubes of the same high structural quality can be grown on silicon and quartz. X-ray diffraction measurements and transmission electron microscopy show that they adopt the rutile structure growing in the [001] direction with (110) sidewalls, while synchrotron X-ray photoelectron spectroscopy reveals the presence of an unusually strong and thermally resilient 2D surface electron gas. This is created by donor-like states produced by the hydroxylation of the surface and is sustained at temperatures above 400 °C by the formation of in-plane oxygen vacancies. This persistent high surface electron density is expected to prove useful in gas sensing and catalytic applications of these remarkable structures. To illustrate their device potential, square SnO2 nanotube Schottky diodes and field effect transistors with excellent performance characteristics are fabricated.

Projection of extreme heat- and cold-related mortality in Sweden based on the spatial synoptic classification.

BACKGROUND: Climate change is projected to result in increased heat events and decreased cold events. This will substantially impact human health, particularly when compounded with demographic change. This study employed the Spatial Synoptic Classification (SSC) to categorize daily weather into one of seven types. Here we estimated future mortality due to extremely hot and cold weather types under different climate change scenarios for one southern (Stockholm) and one northern (Jämtland) Swedish region. METHODS: Time-series Poisson regression with distributed lags was used to assess the relationship between extremely hot and cold weather events and daily deaths in the population above 65 years, with cumulative effects (6 days in summer, 28 days in winter), 1991 to 2014. A global climate model (MPI-M-MPI-ESM-LR) and two climate change scenarios (RCP 4.5 and 8.5) were used to project the occurrence of hot and cold days from 2031 to 2070. Place-specific projected mortality was calculated to derive attributable numbers and attributable fractions (AF) of heat- and cold-related deaths. RESULTS: In Stockholm, for the RCP 4.5 scenario, the mean number of annual deaths attributed to heat increased from 48.7 (CI 32.2-64.2; AF = 0.68%) in 2031-2040 to 90.2 (56.7-120.5; AF = 0.97%) in 2061-2070, respectively. For RCP 8.5, heat-related deaths increased more drastically from 52.1 (33.6-69.7; AF = 0.72%) to 126.4 (68.7-175.8; AF = 1.36%) between the first and the last decade. Cold-related deaths slightly increased over the projected period in both scenarios. In Jämtland, projections showed a small decrease in cold-related deaths but no change in heat-related mortality. CONCLUSIONS: In rural northern region of Sweden, a decrease of cold-related deaths represents the dominant trend. In urban southern locations, on the other hand, an increase of heat-related mortality is to be expected. With an increasing elderly population, heat-related mortality will outweigh cold-related mortality at least under the RCP 8.5 scenario, requiring societal adaptation measures.

A Multi-Objective Active Learning Platform and Web App for Reaction Optimization.

We report the development of an open-source experimental design via Bayesian optimization platform for multi-objective reaction optimization. Using high-throughput experimentation (HTE) and virtual screening data sets containing high-dimensional continuous and discrete variables, we optimized the performance of the platform by fine-tuning the algorithm components such as reaction encodings, surrogate model parameters, and initialization techniques. Having established the framework, we applied the optimizer to real-world test scenarios for the simultaneous optimization of the reaction yield and enantioselectivity in a Ni/photoredox-catalyzed enantioselective cross-electrophile coupling of styrene oxide with two different aryl iodide substrates. Starting with no previous experimental data, the Bayesian optimizer identified reaction conditions that surpassed the previously human-driven optimization campaigns within 15 and 24 experiments, for each substrate, among 1728 possible configurations available in each optimization. To make the platform more accessible to nonexperts, we developed a graphical user interface (GUI) that can be accessed online through a web-based application and incorporated features such as condition modification on the fly and data visualization. This web application does not require software installation, removing any programming barrier to use the platform, which enables chemists to integrate Bayesian optimization routines into their everyday laboratory practices.

A data-driven computational scheme for the nonlinear mechanical properties of cellular mechanical metamaterials under large deformation.

Cellular mechanical metamaterials are a special class of materials whose mechanical properties are primarily determined by their geometry. However, capturing the nonlinear mechanical behavior of these materials, especially those with complex geometries and under large deformation, can be challenging due to inherent computational complexity. In this work, we propose a data-driven multiscale computational scheme as a possible route to resolve this challenge. We use a neural network to approximate the effective strain energy density as a function of cellular geometry and overall deformation. The network is constructed by "learning" from the data generated by finite element calculation of a set of representative volume elements at cellular scales. This effective strain energy density is then used to predict the mechanical responses of cellular materials at larger scales. Compared with direct finite element simulation, the proposed scheme can reduce the computational time up to two orders of magnitude. Potentially, this scheme can facilitate new optimization algorithms for designing cellular materials of highly specific mechanical properties.

Investigation of unknown impurities of paromomycin in a 15% topical cream by liquid chromatography combined with mass spectrometry.

RATIONALE: Characterization of unknown impurities in degraded paromomycin 15% topical cream samples by ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) gas-phase fragmentation is described. METHODS: A volatile reversed-phase high-performance liquid chromatography/charged aerosol detection (RP-HPLC/CAD) method was developed and validated for fast and consistent analysis of the paromomycin potency and impurity values in drug substance and drug product samples. A Veo charged aerosol detector was chosen for routine analysis. The method shows separation of two paromomycin isomers as well as twelve unknown impurity peaks. The identity of the unknown impurities was investigated by LC/MS/MS using a quadrupole time-of-flight (QTOF) mass spectrometer. RESULTS: Six of the HPLC/CAD impurity peaks met the ICH Q3B(R2) threshold for identification and were investigated by coupling the developed LC method with a QTOF instrument. Structures for the impurities were proposed based on gas-phase fragmentation patterns of the paromomycin reference standard. Impurity fragmentation pathways were proposed based on literature of other structurally related aminoglycoside compounds. CONCLUSIONS: Nine unknown paromomycin impurities were identified and the observed modifications included acetylation, carbamylation, gain of a hexose, and loss of glucosamine. The most abundant paromomycin modification was carbamylation by urea (a cream excipient) characterized by a 43 Da mass increase.

Validating a Measure of Friends' Responses to Self-Disclosure in Adolescent Obese and Public School Samples.

The goal of the current study was to validate a new measure of the friendship self-disclosure process that assesses the likelihood of disclosing a negative peer experience and expectations for friends' responses to disclosure (EFRD) of this experience. Participants for Study 1 were 572 adolescents (age M = 14.82; 53% female; 66% Caucasian) from a public school sample who completed the self-disclosure survey and a measures of depressive symptoms at one time point. Participants of Study 2 comprised 180 obese adolescents (age M = 12.78; 67% female; 58% African American) from an urban children's hospital. The obese sample completed the self-disclosure survey, as well as measures of friendship quality, peer victimization, and depressive symptoms at two time points, 6 months apart. For both studies, 3 dimensions of EFRD were examined: protection, blame, and negative responses. Each EFRD dimension was replicated across 2 samples, over time, and had good interitem reliability as well as convergent and discriminant validity. In Study 2, high rates of expected negativity (only for boys) and blame (for boys and girls) predicted increases in depressive symptoms. In addition, victimization led to increases in depression for obese adolescents who expected little in the way of protective responses from their friends. In contrast, changes in depression were not predictable from victimization for those who expected friends to use protective responses. EFRD are clearly important mechanisms in the self-disclosure process that may serve to protect against changes in adjustment in response to negative peer experiences, such as peer victimization.

A brief peer gatekeeper suicide prevention training: Results of an open pilot trial.

OBJECTIVE: The purpose of the present study was to test a 1-hour peer suicide gatekeeper training for students from the broad college community in the context of an open pilot trial. METHOD: Two-hundred and thirty-one college students were recruited university-wide, Mage  = 20.7, 65.4% female, and completed a peer suicide prevention gatekeeping training program. Assessments were completed at pre-training and post-training as well as 3-month follow-up. RESULTS: This brief peer suicide gatekeeper training program was associated with increases in suicide prevention knowledge. It was also associated with an increase in the number of students who identified suicidal youth and made mental health referrals, as well as total number of referrals made, over the course of three months. Females reported greater improvement in suicide prevention skills and knowledge post-training than males. CONCLUSIONS: Offering peer suicide gatekeeper training to students from the general college population may hold promise in suicide prevention efforts.

Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach.

Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

Topical paromomycin with or without gentamicin for cutaneous leishmaniasis.

BACKGROUND: There is a need for a simple and efficacious treatment for cutaneous leishmaniasis with an acceptable side-effect profile. METHODS: We conducted a randomized, vehicle-controlled phase 3 trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for cutaneous leishmaniasis caused by Leishmania major in Tunisia. We randomly assigned 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis to receive a cream containing 15% paromomycin-0.5% gentamicin (called WR 279,396), 15% paromomycin alone, or vehicle control (with the same base as the other two creams but containing neither paromomycin nor gentamicin). Each lesion was treated once daily for 20 days. The primary end point was the cure of the index lesion. Cure was defined as at least 50% reduction in the size of the index lesion by 42 days, complete reepithelialization by 98 days, and absence of relapse by the end of the trial (168 days). Any withdrawal from the trial was considered a treatment failure. RESULTS: The rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin-gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P<0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group. CONCLUSIONS: This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.).

How you look versus how you feel: Associations between BMI z-score, body dissatisfaction, peer victimization, and self-worth for African American and white adolescents.

Being overweight and having negative self-perceptions (body dissatisfaction) can have problematic consequences for adolescents physically, socially, and psychologically. Understanding associations between weight, self-perceptions, and peer experiences across ethnicities is particularly important given recent increases in obesity among ethnic minorities. The current study aimed to address these issues by examining Body Mass Index (BMI) z-scores and body dissatisfaction predicting change in general self-worth over time via peer victimization experiences in a diverse sample of 236 youth (ages 10-16 years). Body dissatisfaction predicted decreases in self-worth over time even after controlling for BMI z-score. BMI z-scores predicted decreases in self-worth over time only for white adolescents, whereas body dissatisfaction directly predicted decreases in self-worth for African American youth and indirectly via peer victimization for white youth. Associations were also considered by gender. Implications for intervention efforts for both white and African American adolescents are discussed.

The relation among sleep duration, homework burden, and sleep hygiene in chinese school-aged children.

Insufficient sleep in school-aged children is common in modern society, with homework burden being a potential risk factor. The aim of this article is to explore the effect of sleep hygiene on the association between homework and sleep duration. Children filled out the Chinese version of the Adolescent Sleep Hygiene Scale, and parents filled out a sociodemographic questionnaire. The final sample included 363 boys and 371 girls with a mean age of 10.82 ± 0.38 years. Children with more homework went to bed later and slept less. Better sleep hygiene was associated with earlier bedtimes and longer sleep duration. Findings suggest that homework burden had a larger effect on sleep duration than sleep hygiene. Fifth-grade children in Shanghai have an excessive homework burden, which overwrites the benefit of sleep hygiene on sleep duration.

Perspectives on Employer-Initiated Terminations Among Young Adults on the Autism Spectrum.

Job instability is high among autistic adults, with employer-initiated terminations a common reason for job loss. The current study used qualitative methods to code reasons that autistic adults identified for their employer-initiated termination. From 315 autistic individuals ages 18-35 who completed an online survey, 93 (29.5%) reported having been terminated from a job. These individuals were asked about the reasons for their termination and responses were coded into thematic categories. Common reasons included work performance, social difficulties, attendance, and mental health challenges. Adults were more likely to attribute terminations to internal causes (related to the individual) than to external causes (environment-related). A good fit between workplace, individual preferences, skills, and abilities is likely key to promoting job continuity for autistic adults.

Associations between social activities and depressive symptoms in adolescents and young adults with autism spectrum disorder: Testing the indirect effects of loneliness.

LAY ABSTRACT: Previous studies have found that social activities and depressive symptoms in adolescents and young adults with autism spectrum disorder are related. To better understand the relationship between these issues, this study examined the frequency of various types of social activities as well as if the participants felt that the frequency of time spent in the activity met their personal needs. In addition, the role of loneliness was tested as a possible way to understand the relationship between activities and depressive symptoms. To test these ideas, 321 participants who were recruited from the Simons Foundation Powering Autism Research for Knowledge (SPARK) research match registry and completed online measures of social activities, depressive symptoms, and loneliness. While the specific pattern was different for individual activities, it was found that those who felt that their current frequency of activities did not meet their needs had higher rates of depressive symptoms than those who felt they did meet their needs. Also, loneliness helps to understand relationship between social activities and depressive symptoms. The findings were discussed in light of previous study findings, interpersonal theories of depression, and clinical implications.

Associations between Social Experiences and Psychological Health for Autistic Youth with Low IQ.

PURPOSE: Social experiences are consistently associated with psychological health among autistic individuals. However, most extant studies on this topic exclude individuals with autism who have lower IQ or are otherwise unable to self-report. The current study addresses this gap by examining associations of negative peer experiences and social participation with psychological health among autistic youth with low IQ. METHODS: An online survey was collected from 268 parents of autistic adolescents and adults ages 15-25. Negative peer experiences included measures of peer victimization and being ignored. Social participation was assessed by the amount of participation and parents' perceptions of whether their youth felt the amount of participation was meeting their needs. Psychological health was assessed by parents' report of their youth's psychological quality of life, as well as whether they felt their son/daughter was currently depressed. RESULTS: Results suggested low rates of social participation in this sample, with relatively high rates of being ignored. Regression analysis found that lower rates of peer victimization and more activities in which parents perceived that the amount of time was meeting their youth's needs was associated with higher psychological quality of life and lower likelihood that parents felt their son/daughter was depressed. CONCLUSION: Though youth with autism and low IQ are often excluded from interventions aimed at improving social experiences, these findings suggest that promoting positive social experiences and ameliorating negative ones might be an avenue to improving psychological health in this group.

Use of Polyurethane-Covered Stents for Exclusion of Pulmonary Arteriovenous Malformations.

PURPOSE: To evaluate the safety, technical success and short-term effectiveness of polyurethane-covered stent (PK Papyrus, BioTronik, Berlin) in the treatment of pulmonary arteriovenous malformations (PAVMs) that are not amenable to embolotherapy. MATERIALS AND METHODS: In this IRB-approved, retrospective study, data from patients who received polyurethane-covered stents for exclusion of PAVMs were analyzed. The study included 5 patients (all women) with a median age of 40 years (range 25-60). Patients presented with hypoxemia, TIAs, and/or epistaxis; 4 were confirmed to have HHT. All had multiple PAVMs diagnosed on chest CT and underwent embolization with other devices in addition to the polyurethane-covered stent. The indication for stent placement in all cases was a short and/or tortuous feeding artery. Safety was assessed by immediate or short-term complications, e.g., migration, stent thrombosis, and fracture. Technical success was defined as the ability to accurately place the stent at the intended location. Effectiveness was defined as successful exclusion of PAVM with no perfusion across the AVM. RESULTS: Technical success of stent placement was 100%. AVM exclusion rate was 80% after single stent deployment; in the case of incomplete exclusion, success was achieved using an overlapping stent to completely cover a second feeding artery. During the median follow-up period of 5 months (range 2-10), all stents remained patent, and AVMs were excluded without other complications. CONCLUSION: Exclusion of PAVMs with polyurethane-covered stents is technically feasible, safe, and shows short-term effectiveness for PAVMs with a short/tortuous feeding artery when traditional embolization techniques are not possible.

Self-reported Everyday Sources of Happiness and Unhappiness in Autistic Adults.

PURPOSE: Daily mood can be influenced by a range of experiences. Identifying everyday life experiences that make autistic adults happy and unhappy holds potential to foster positive mood and tackle mental health problems amongst this group. METHODS: A total of 293 autistic adults between the ages of 18 to 35 years old (mean age of 26.51 years old (SD = 4.62); 43.3% female gender, 4.8% nonbinary) provided open-text responses regarding everyday sources of happiness and unhappiness. Using an iterative process of inductive coding, 14 happy themes and 22 unhappy themes of mood-changing life experiences were identified based on self-report qualitative data. RESULTS: Common themes across the happy and unhappy domain involved social partners, social interactions, and engagement in recreational and employment activities, with additional distinct themes specific to happy or unhappy mood. Top themes identified in the happy domain emphasizes encouraging quality relationships and positive interactions with others and cultivating supportive work/societal environments to build a sense of achievement and value. Meanwhile, emotional tolls accompanied negative relationships and interactions, underscoring the necessity to provide autistic adults with conflict resolution and coping skills to increase feelings of happiness. CONCLUSION: Overall, the wide range of sources of happy and unhappy everyday experiences highlights the importance of considering personal preferences in engagement with others and activities in treatment.

The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.