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Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its Minimal Information for Studies of Extracellular Vesicles, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteomes to genomes for 2812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We correctly linked 90-95% of proteomes to their correct genome and for 95-99% we identify the 1% most likely links. The linking accuracy in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. We also linked proteomes-to-proteomes and used the proteome only to determine features such as sex, ancestry, and first-degree relatives. When serial proteomes are available, the linking algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.

BackgroundThe molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status.MethodsAnonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated.ResultsA total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively).ConclusionPatients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.

Chronic obstructive pulmonary disease (COPD) is a disease with marked metabolic disturbance. Previous studies have shown the association between single metabolites and lung function for COPD, but whether a combination of metabolites could predict phenotype is unknown. We developed metabolomic severity scores using plasma metabolomics from the Metabolon platform from two US cohorts of ever-smokers: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) (n = 648; training/testing cohort; 72% non-Hispanic, white; average age 63 years) and the COPDGene Study (n = 1120; validation cohort; 92% non-Hispanic, white; average age 67 years). Separate adaptive LASSO (adaLASSO) models were used to model forced expiratory volume at one second (FEV1) and MESA-adjusted lung density using 762 metabolites common between studies. Metabolite coefficients selected by the adaLASSO procedure were used to create a metabolomic severity score (metSS) for each outcome. A total of 132 metabolites were selected to create a metSS for FEV1. The metSS-only models explained 64.8% and 31.7% of the variability in FEV1 in the training and validation cohorts, respectively. For MESA-adjusted lung density, 129 metabolites were selected, and metSS-only models explained 59.0% of the variability in the training cohort and 17.4% in the validation cohort. Regression models including both clinical covariates and the metSS explained more variability than either the clinical covariate or metSS-only models (53.4% vs. 46.4% and 31.6%) in the validation dataset. The metabolomic pathways for arginine biosynthesis; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine pathway were enriched by adaLASSO metabolites for FEV1. This is the first demonstration of a respiratory metabolomic severity score, which shows how a metSS can add explanation of variance to clinical predictors of FEV1 and MESA-adjusted lung density. The advantage of a comprehensive metSS is that it explains more disease than individual metabolites and can account for substantial collinearity among classes of metabolites. Future studies should be performed to determine whether metSSs are similar in younger, and more racially and ethnically diverse populations as well as whether a metabolomic severity score can predict disease development in individuals who do not yet have COPD.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (

ImportanceThe incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.ObservationsWithin the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and relevanceThe clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

ImportanceThe incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.ObservationsWithin the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and relevanceThe clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Are feelings of not mattering an antecedent of depressive symptoms, a consequence, or both? Most investigations focus exclusively on feelings of not mattering as an antecedent of depressive symptoms. Our current study examines a vulnerability model, a complication model, and a reciprocal relations model according to a cross-lagged panel model (CLPM) and a random-intercept cross-lagged panel model (RI-CLPM). A sample of 197 community adults completed the General Mattering Scale (GMS), the Anti-Mattering Scale (AMS), and a depression measure at three time points (i.e., baseline, 3 weeks, and 6 weeks). GMS and AMS scores were associated robustly with depressive symptoms at each time point. Other results highlighted the need to distinguish levels of anti-mattering and mattering. CLPM analyses supported a reciprocal relations model of anti-mattering (assessed by the AMS) and depressive symptoms and a complication model linking mattering (assessed by the GMS) and depressive symptoms. The RI-CLPM analyses provided tentative support only for a complication model of anti-mattering and depressive symptoms. Our findings highlight the differences between measures of the mattering construct and the need to adopt a temporal perspective that considers key nuances and the interplay among feelings of mattering, feelings of not mattering, and depression.

The COVID-19 pandemic forced the closure of schools in the UK and students had to study at home with limited access to the support they would have normally received. We designed this study to assess the experience of gifted and talented (GAT) students during this period and to identify factors related to their stress and self-regulation of learning. The factors we focused on were perfectionism and feelings of mattering. Three-hundred and eleven GAT students completed an online questionnaire when schools were closed and they were studying at home. Analyses revealed that striving for perfection was related to better effort regulation and better time and environment management. However, negative reactions to imperfection and feeling like they did not matter (anti-mattering) were related to higher academic stress, as well as worse effort regulation and worse time and environment management. The findings suggest aspects of both perfectionism and mattering may be important for GAT students' ability to study effectively during the COVID-19 pandemic.

Perfectionism has long been recognised as a psychological factor that can enhance or interfere with the healthy adjustment of young students who are academically gifted. However, it is apparent from existing research that a wide range of methods have been adopted to study perfectionism in this population. To identify what is currently known about perfectionism among these students and what future work needs to be undertaken, a systematic review of existing research is required. The aim of our study was to provide a first such review. In doing so, we utilised the two-factor perfectionism model which differentiates between perfectionistic strivings (PS) and perfectionistic concerns (PC). A systematic literature search returned 36 studies examining perfectionism in young students identified as academically gifted that varied in study characteristics, methodological quality, and findings. Of these studies, 24 adopted a variable-based approach to examining perfectionism (i.e., examined PS and PC) and 12 adopted a group-based approach to examining perfectionism (i.e., examined groups with varying levels of PS and PC). The findings show that the distinction between PS and PC is extremely important. Specifically, while PC are likely to be uniformly debilitating for students who are academically gifted, PS are associated with more mixed outcomes. This is also the case when the two dimensions of perfectionism are considered in combination, with levels of PC being the key factor in determining the outcomes associated with perfectionism. Future research needs to build on the existing evidence base in a systematic fashion and prioritise longitudinal research and intervention studies.

IntroductionPreventing tuberculosis (TB) disease requires treatment of latent TB infection (LTBI) as well as prevention of person-to-person transmission. We estimated the LTBI prevalence for the entire United States and for each state by medical risk factors, age, and race/ethnicity, both in the total population and stratified by nativity.MethodsWe created a mathematical model using all incident TB disease cases during 2013-2017 reported to the National Tuberculosis Surveillance System that were classified using genotype-based methods or imputation as not attributed to recent TB transmission. Using the annual average number of TB cases among US-born and non-US-born persons by medical risk factor, age group, and race/ethnicity, we applied population-specific reactivation rates (and corresponding 95% confidence intervals [CI]) to back-calculate the estimated prevalence of untreated LTBI in each population for the United States and for each of the 50 states and the District of Columbia in 2015.ResultsWe estimated that 2.7% (CI: 2.6%-2.8%) of the U.S. population, or 8.6 (CI: 8.3-8.8) million people, were living with LTBI in 2015. Estimated LTBI prevalence among US-born persons was 1.0% (CI: 1.0%-1.1%) and among non-US-born persons was 13.9% (CI: 13.5%-14.3%). Among US-born persons, the highest LTBI prevalence was in persons aged ≥65 years (2.1%) and in persons of non-Hispanic Black race/ethnicity (3.1%). Among non-US-born persons, the highest LTBI prevalence was estimated in persons aged 45-64 years (16.3%) and persons of Asian and other racial/ethnic groups (19.1%).ConclusionsOur estimations of the prevalence of LTBI by medical risk factors and demographic characteristics for each state could facilitate planning for testing and treatment interventions to eliminate TB in the United States. Our back-calculation method feasibly estimates untreated LTBI prevalence and can be updated using future TB disease case counts at the state or national level.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

StatementThe International Society for Cellular and Gene Therapies (ISCT) and the International Society for Extracellular Vesicles (ISEV) recognize the potential of extracellular vesicles (EVs, including exosomes) from mesenchymal stromal cells (MSCs) and possibly other cell sources as treatments for COVID-19. Research and trials in this area are encouraged. However, ISEV and ISCT do not currently endorse the use of EVs or exosomes for any purpose in COVID-19, including but not limited to reducing cytokine storm, exerting regenerative effects or delivering drugs, pending the generation of appropriate manufacturing and quality control provisions, pre-clinical safety and efficacy data, rational clinical trial design and proper regulatory oversight.

Teacher performance pay is often introduced with the goal of reducing gaps in test scores across groups, yet little is known about how well they achieve this aim. We ask, "Do test score-based teacher incentives impact the Black-White test score gap?" Using student-teacher matched data and a difference-in-differences approach in which the performance of a teacher's students before and after the policy is compared, we find that performance pay increases the conditional Black-White gap. The effect is particularly evident when bonuses are large, consistent with a causal response to performance pay.

Self-esteem, academic self-efficacy, perceived stress, and preferred learning styles have been linked to academic performance. Investigation of the relationships between these variables has mainly occurred with medical and dental tertiary students in Saudi Arabia, but no previous study has focused on psychology students. The main purpose of the current study was to assess stress levels and preferred learning styles, and examine the relationships between self-esteem, academic self-efficacy, perceived stress, and academic performance among a cohort of psychology students in Saudi Arabia. Participants were 214 psychology students from Taif University and King Abdulaziz University, who completed online measures including the VARK, the Perceived Stress Scale (PSS), the Academic Self-Efficacy (ASE), and the Rosenberg Self-Esteem Scale (RSES). Prevalence of stress was overwhelming, with 71% being highly stressed (PSS= 27-40). Most of the sample preferred a multimodal learning style. Furthermore, low yet significant correlations between academic performance and academic self-efficacy, rs(212)= 0.188, p= 0.003, and self-esteem, rs(212)= 0.121, p= 0.039, were identified. However, academic performance was not correlated with perceived stress levels.