INTRODUCTION: Discrimination in medical settings (DMS) contributes to health care disparities in the United States, but few studies have determined the extent of DMS in a large national sample and across different populations. This study estimated the national prevalence of DMS and described demographic and health-related characteristics associated with experiencing DMS in seven different situations. METHODS: Survey data from 41,875 adults participating in the All of Us Research Program collected in 2021-2022 and logistic regression were used to examine the association between sociodemographic and health-related characteristics and self-reported DMS among adults engaged with a health care provider within the past 12 months. Statistical analysis was performed in 2023-2024. RESULTS: About 36.89% of adults reported having experienced at least one DMS situation. Adults with relative social and medical disadvantages had higher prevalence of experiencing DMS. Compared to their counterparts, respondents with higher odds of experiencing DMS in at least one situation identified as female, non-Hispanic Black, having at least some college, living in the South, renter, having other living arrangement, being publicly insured, not having a usual source of care, having multiple chronic conditions, having any disability, and reporting fair or poor health, p<0.05. CONCLUSIONS: The findings indicate a high prevalence of DMS, particularly among some population groups. Characterizing DMS may be a valuable tool for identifying populations at risk within the health care system and optimizing the overall patient care experience. Implementing relevant policies remains an essential strategy for mitigating the prevalence of DMS and reducing health care disparities.
Prior research has established the psychometric properties of the Critical Warzone Experiences (CWE) scale among post-9/11 Iraq/Afghanistan-era veterans; however, the psychometric properties of the CWE among Gulf War I-era veterans have not yet been established. The first objective of the present study was to examine the psychometric properties of the CWE among Gulf War I-era veterans. The second objective was to test the hypothesis that the CWE would have a significant indirect effect on suicidal thoughts and behaviors via posttraumatic stress disorder (PTSD) and depressive symptoms. To test these hypotheses, a survey packet that included the CWE and measures of PTSD symptoms, depressive symptoms, and suicidal thoughts and behaviors was administered to 1,153 Gulf War I-era veterans. Consistent with prior research in post-9/11 Iraq/Afghanistan-era veterans, the CWE exhibited good internal consistency (α = .85), a unidimensional factor structure (RMSEA = .056, CFI = .959, SRMR = .033; average factor loading = .69), and good concurrent validity with PTSD (r = .47, p < .001) and depressive (r = .31, p < .001) symptoms among Gulf War I-era veterans. Additionally, as hypothesized, a significant indirect effect from the CWE to suicidal thoughts and behaviors via PTSD and depressive symptoms (ß = .35, p < .001) was also observed. Taken together, our findings provide strong support for using the CWE with Gulf War I-era veterans.
We report a cluster of nine isolates of Parengyodontium album recovered from four patients who had surgical tissue specimens processed after dilution with a multi-use diluent saline solution. P. album was also identified from a non-clinical sample on agar prepared with the same lot number of saline solution. Our epidemiological investigation revealed this to represent a pseudo-outbreak related to contaminated saline used to process specimens in the microbiology laboratory.
OBJECTIVES: Assessing listening difficulties and associated complaints can be challenging. Often, measures of peripheral auditory functions are within normal ranges, making clinicians feel unsure about proper management strategies. The range and nature of observed or experienced difficulties might be better captured using a qualitative measure. The Evaluation of Children's Listening and Processing Skills (ECLiPS) questionnaire was designed to broadly profile the auditory and cognitive problems often present in children with listening difficulties. This 38-item questionnaire was initially standardized in British children aged 6 to 11 years, was subsequently modified for use with North-American children, and was recently translated into Flemish-Dutch. This study aimed to compare typical scores of the Flemish version with the UK and US versions, and to evaluate and compare its psychometric quality based on Rasch analysis. DESIGN: We selected 112 Flemish children aged 6 to 11 years with verified normal hearing and typical development, and asked two caregivers of every child to fill out the ECLiPS. Data from two comparator samples were analyzed, including responses for 71 North-American children and 650 British children. Typical values for ECLiPS factors and aggregates were determined as a function of age and gender, and meaningful differences across samples were analyzed. Rasch analyses were performed to evaluate whether ECLiPS response categories work as intended, and whether item scores fit a linear equal interval measurement scale that works the same way for everyone. Item and person metrics were derived, including separation and reliability indices. We investigated whether items function similarly across linguistically and culturally different samples. RESULTS: ECLiPS scores were relatively invariant to age. Girls obtained higher scores compared with boys, mainly for items related to memory and attention, and pragmatic and social skills. Across ECLiPS versions, the most pronounced differences were found for items probing social skills. With respect to its psychometric quality, ECLiPS response categories work as intended, and ECLiPS items were found to fit the Rasch measurement scale. Cultural differences in responses were noted for some items, belonging to different factors. Item separation and reliability indices generally pointed toward sufficient variation in item difficulty. In general, person separation (and reliability) metrics, quantifying the instrument's ability to distinguish between poor and strong performers (in a reproducible manner), were low. This is expected from samples of typically developing children with homogeneous and high levels of listening ability. CONCLUSIONS: Across the languages assessed here, the ECLiPS caregiver questionnaire was verified to be a psychometrically valid qualitative measure to assess listening and processing skills, which can be used to support the assessment and management of elementary school children referred with LiD.
TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.
Survivors of adolescent and young adult (AYA, age 15-39 years at diagnosis) cancer are a growing population with the potential to live for many decades after treatment completion. Survivors of AYA cancer are at risk for adverse long-term outcomes including chronic conditions, secondary cancers, impaired fertility, poor psychosocial health and health behaviors, and financial toxicity. Further, survivors of AYA cancer from racially minoritized and low socio-economic status populations experience disparities in these outcomes, including lower long-term survival. Despite these known risks, most survivors of AYA cancer do not receive routine survivorship follow-up care, and research on delivering high-quality, evidence-based survivorship care to these patients is lacking. The need for survivorship care was initially advanced in 2006 by the Institute of Medicine. In 2019, the Quality of Cancer Survivorship Care Framework (QCSCF) was developed to provide an evidence-based framework to define key components of optimal survivorship care. In this commentary focused on survivors of AYA cancer, we apply the QCSCF framework to describe models of care that can be adapted for their unique needs, multi-level factors limiting equitable access to care, and opportunities to address these factors to improve short- and long-term outcomes in this vulnerable population.
BACKGROUND: Poor differentiation predicts adverse outcomes in cutaneous squamous cell carcinoma (CSCC), but there is no standardized, reliable grading system. OBJECTIVE: To explore which histologic features have the greatest impact on CSCC differentiation interrater agreement. MATERIALS AND METHODS: In a prior study, 40 raters graded differentiation for 45 squamous cell carcinomas, and percent interrater agreements were calculated. Cases graded as well/moderately differentiated with 100% agreement (10), those graded as poorly differentiated with ≥80% agreement (5), and those that received a variety of grades with ≤60% agreement (7) were pulled for the current study. Three raters graded individual histologic features for each case, and percent interrater agreements were calculated using both the well/moderately/poorly differentiated grading system and a dichotomized system. RESULTS: The percent interrater agreements were 34.8% for mitoses, 53% for pleomorphism, 59.1% for keratinization, 66.7% for cellular cohesion/intercellular bridges, and 78.8% for tumor edges. Percent agreements improved with dichotomous grading; the largest improvement was seen within the group of cases that had been graded as well/moderately differentiated with 100% agreement in the prior study. CONCLUSION: Future squamous cell carcinoma differentiation grading systems would benefit from eliminating mitotic rate, clearly defining how to grade other features, and dichotomous grading.
Introduction: The Global Strategy for Human Resources for Health 2030, requires member states to half their dependency on an international workforce by 2030. In order to design policies towards that goal, country-specific research on migration motivations of the health workforce is required. The United Kingdom (UK) is a net importer of health professionals and whilst there is a body of research on doctors' and nurses' migration, there is no research on the migration motivations of migrant dentists in the UK. This research explored the migration motivations of internationally qualified dentists (IQDs) in the UK and presents a typology to understand the global migration of dentists in the context of oral health workforce. Methods: The paper presents qualitative data from semi-structured interviews conducted between August 2014 and October 2017, of IQDs working in the United Kingdom. The topic guide for interviews was informed by the literature, with new themes added inductively. A phenomenological approach involving an epistemological stance of interpretivism, was used with framework analysis. Results: A total of 38 internationally qualified dentists (M = 18, F = 20), migrating from the five World Health Organization regions, and working in general practice, NHS hospitals and in community dental services across the four nations of the UK were interviewed. Seven types of internationally qualified dentists were identified working in the UK. They were livelihood migrants, career-orientated migrants, dependant migrants, backpacker migrants, commuter migrants, undocumented migrants, and education-tourist migrant. The categories were based on their migration motivations, which were complex, multifactorial, and included personal, professional, national, and international drivers. The typology, based on their migration motivations, offered a structured, comprehensive understanding of the migrant dental workforce. This typology involving dentists provides additional dimensions to commuter and undocumented migrants described in the context of other health professionals. The education-tourist migrant is a new category proposed as an extension to existing typology in health professional migration. Conclusions: The typology of internationally qualified dentists has congruency with other health professionals' typology in categories previously described and demonstrates that each of these categories are complex, fluid and change in response to policy changes. The new category of education-tourist migrant along with oral health dimensions of commuter and undocumented migrants adds to the existing typology in health professional migration.
Purpose: Competency-based medical education relies on feedback from workplace-based assessment (WBA) to direct learning. Unfortunately, WBAs often lack rich narrative feedback and show bias towards Medical Expert aspects of care. Building on research examining interactive assessment approaches, the Queen's University Internal Medicine residency program introduced a facilitated, team-based assessment initiative ("Feedback Fridays") in July 2017, aimed at improving holistic assessment of resident performance on the inpatient medicine teaching units. In this study, we aim to explore how Feedback Fridays contributed to formative assessment of Internal Medicine residents within our current model of competency-based training. Method: A total of 53 residents participated in facilitated, biweekly group assessment sessions during the 2017 and 2018 academic year. Each session was a 30-minute facilitated assessment discussion done with one inpatient team, which included medical students, residents, and their supervising attending. Feedback from the discussion was collected, summarized, and documented in narrative form in electronic WBA forms by the program's assessment officer for the residents. For research purposes, verbatim transcripts of feedback sessions were analyzed thematically. Results: The researchers identified four major themes for feedback: communication, intra- and inter-personal awareness, leadership and teamwork, and learning opportunities. Although feedback related to a broad range of activities, it showed strong emphasis on competencies within the intrinsic CanMEDS roles. Additionally, a clear formative focus in the feedback was another important finding. Conclusions: The introduction of facilitated team-based assessment in the Queen's Internal Medicine program filled an important gap in WBA by providing learners with detailed feedback across all CanMEDS roles and by providing constructive recommendations for identified areas for improvement.
Objectif: La formation médicale fondée sur les compétences s'appuie sur la rétroaction faite lors de l'évaluation des apprentissages par observation directe dans le milieu de travail. Malheureusement, les évaluations dans le milieu de travail omettent souvent de fournir une rétroaction narrative exhaustive et privilégient les aspects des soins relevant de l'expertise médicale. En se basant sur la recherche ayant étudié les approches d'évaluation interactive, le programme de résidence en médecine interne de l'Université Queen's a introduit en juillet 2017 une initiative d'évaluation facilitée et en équipe (« Les vendredis rétroaction ¼), visant à améliorer l'évaluation holistique du rendement des résidents dans les unités d'enseignement clinique en médecine interne. Dans cette étude, nous visons à explorer comment ces « vendredis rétroaction ¼ ont contribué à l'évaluation formative des résidents en médecine interne dans le cadre de notre modèle actuel de formation axée sur les compétences. Méthode: Au total, 53 résidents ont participé à des séances d'évaluation de groupe facilitées et bi-hebdomadaires au cours de l'année universitaire 2017-2018. Chaque séance consistait en une discussion d'évaluation facilitée de 30 minutes menée avec une équipe de l'unité de soins, qui comprenait des étudiants en médecine, des résidents et le médecin superviseur. Les commentaires issus de la discussion ont été recueillis, résumés et documentés sous forme narrative dans des formulaires électroniques d'observation directe dans le milieu de travail par le responsable de l'évaluation du programme de résidence. À des fins de recherche, les transcriptions verbatim des séances de rétroaction ont été analysées de façon thématique. Résultats: Les chercheurs ont identifié quatre thèmes principaux pour les commentaires : la communication, la conscience intra- et interpersonnelle, le leadership et le travail d'équipe, et les occasions d'apprentissage. Bien que la rétroaction concerne un large éventail d'activités, elle met fortement l'accent sur les compétences liées aux rôles intrinsèques de CanMEDS. De plus, le fait que la rétroaction avait un rôle clairement formatif est une autre constatation importante. Conclusions: L'introduction de l'évaluation en équipe facilitée dans le programme de médecine interne à Queen's a comblé une lacune importante dans l'apprentissage par observation directe dans le milieu de travail en fournissant aux apprenants une rétroaction détaillée sur tous les rôles CanMEDS et en formulant des recommandations constructives sur les domaines à améliorer.
Clinical Competence , Internal Medicine , Internship and Residency , Qualitative Research , Internal Medicine/education , Humans , Competency-Based Education/methods , Formative Feedback , Leadership , Feedback , Educational Measurement/methods , Communication
Deuterostomes are a monophyletic group of animals that includes Hemichordata, Echinodermata (together called Ambulacraria), and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of 2 hemichordate species, Ptychodera flava and Schizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N = 23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into 2 chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes and that maintenance of the clusters are likely due to lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of 3 pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.
Nerve growth factor (NGF) plays a crucial role in cellular growth and neurodifferentiation. To achieve significant neuronal regeneration and repair using in vitro NGF delivery, spatiotemporal control that follows the natural neuronal processes must be developed. Notably, a challenge hindering this is the uncontrolled burst release from the growth factor delivery systems. The rapid depletion of NGF reduces treatment efficacy, leading to poor cellular response. To address this, we developed a highly controllable system using graphene oxygen (GO) and GelMA hydrogels modulated by electrical stimulation. Our system showed superior control over the release kinetics, reducing the burst up 30-fold. We demonstrate that the system is also able to sequester and retain NGF up to 10-times more efficiently than GelMA hydrogels alone. Our controlled release system enabled neurodifferentiation, as revealed by gene expression and immunostaining analysis. The increased retention and reduced burst release from our system show a promising pathway for nerve tissue engineering research toward effective regeneration.
Background: There is a paucity of aggregate data documenting mid- to long-term outcomes of patients after hip arthroscopy with labral reconstruction. Purpose: To report mid- to long-term outcomes in patients after undergoing either primary or revision hip arthroscopy with labral reconstruction for the treatment of irreparable labral tears. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review of the PubMed, Cochrane, and Scopus databases in May 2022 was conducted with the following keywords: "hip arthroscopy,""labral reconstruction,""irreparable,""labrum,""reconstruction,""five-year,""midterm,""5 year,""long-term,""10 year," ten-year," and "femoroacetabular impingement" using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Midterm was defined as mean 5-year follow-up, and long-term was defined as mean 10-year or longer follow-up. For each included article, the demographic, radiographic, intraoperative, and surgical variables, as well as patient-reported outcomes (PROs), psychometric thresholds, and secondary surgeries were recorded. Forest plots were created for PROs that were reported in ≥3 studies; heterogeneity was assessed using I2 values. Results: Out of 463 initial articles, 5 studies including 178 hips with primary and 41 hips with revision surgeries were included. One study had an average 5-year follow-up, three studies had a minimum 5-year follow-up and one study had a minimum 10-year follow-up. The most common indications for hip arthroscopy with labral reconstruction were irreparable labral tears. The most common PRO was the modified Harris Hip Score (mHHS), which was reported in all 5 studies. The mean preoperative mHHS ranged from 58.9 to 66, and the mean postoperative mHHS at minimum 5-year follow-up ranged from 80.2 to 89. The preoperative and postoperative mHHSs for the single long-term follow-up study were 60 and 82, respectively. All 5 studies demonstrated significant improvements in reported PROs. All 5 studies reported secondary surgery rates, with 1 study reporting rates at both 5- and 10-year follow-up. Conversion to total hip arthroplasty ranged from 0% to 27%, while overall secondary surgery rates ranged from 0% to 36%. Conclusion: Findings demonstrated that patients undergoing primary and revision hip arthroscopy with labral reconstruction experienced favorable outcomes and high rates of clinical benefit and survivorship at mid- to long-term follow-up.
Meniscus allograft transplantation (MAT) is a technically challenging procedure. Bone plugs, slot techniques, and all-soft-tissue fixation techniques have been described in the past. Each technique comes with advantages and disadvantages. Native menisci have circumferential collagen fibers to help resist hoop stress during loading cycles. Although hoop stress resistance is a known function of the menisci, its recreation in MAT has only been targeted indirectly through anatomic root placement. The authors describe the use of a high-tensile suture tape (i.e. InternalBrace) to promote centralization by directly mitigating hoop stresses through recreation of peripheral meniscus tensioning in MAT.
OBJECTIVE: The purpose of this study was to examine factors correlated with psychological readiness to return to activity after ACLR. DESIGN: cross sectional study. SETTING: controlled laboratory. PARTICIPANTS: 164 patients (82 M/82 F, 22.5 ± 8.9yr, 171.6 ± 11.0 cm, 77.4 ± 18.6 kg, 8.6 ± 3.4 months post-ACLR) participated in this study after a primary, isolated, and uncomplicated ACLR. MAIN OUTCOME MEASURES: ACL Return to Sport Index (ACL-RSI). RESULTS: ACL-RSI scores demonstrated a weak positive correlation with activity level at the time of injury and a fair positive correlation with activity level at the time of post-operative testing (p-values: 0.004, <0.001). ACL-RSI scores showed a statistically significant fair negative correlation with pain and a moderate negative correlation with kinesiophobia during rehabilitation (p-values: <0.001, <0.001). There was no statistical significance between ACL-RSI and the surgical variables (p-value range: 0.10-0.61). CONCLUSIONS: Outcomes from testing during postoperative rehabilitation were most correlated with psychological readiness to return to activity after ACLR. Increased pain and kinesiophobia were associated with a decreased psychological readiness. Increased activity level prior to injury and activity level at the time of testing during rehabilitation were both correlated with increased psychological readiness. Psychological readiness to return to activity may need to be customized based on potentially modifiable patient-specific factors during the post-operative rehabilitation.
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Return to Sport , Humans , Anterior Cruciate Ligament Reconstruction/rehabilitation , Anterior Cruciate Ligament Reconstruction/psychology , Male , Female , Cross-Sectional Studies , Young Adult , Anterior Cruciate Ligament Injuries/surgery , Anterior Cruciate Ligament Injuries/psychology , Adult , Adolescent , Time Factors , Recovery of Function
Aim: The purpose is to determine the risk ratios (RR) for both major adverse foot events (MAFEs) and the presence of moderate and severe functional mobility deficits in participants with diabetic peripheral neuropathy across the stages of chronic kidney disease (CKD). Methods: We studied 284 participants with diabetes mellitus, peripheral neuropathy, and CKD. MAFEs including foot fracture, ulcerations, Charcot neuropathic arthropathy (CN), osteomyelitis, and minor foot amputations were collected from foot x-ray reports in the medical records of 152 participants; functional mobility deficits were assessed in 132 participants using the modified physical performance test (mPPT). Moderate mobility deficit was categorized as mPPT scores 22-29 and severe mobility deficit as < 22. Unadjusted and adjusted (age, body weight, race, HbA1c) RR were calculated across each stage of CKD, with stage 1 CKD used as the reference group. Results: The RR for neuropathic foot fracture, CN, and diabetic foot ulceration remained consistent across CKD stages. The RR of minor amputation is greater in CKD stages 4 and 5. The RR of moderate or severe mobility deficit is greater in CKD stages 3 and 5 and in CKD stages 3, 4, and 5, respectively. An inverse association was observed between MAFE prevalence and mPPT scores across CKD stages. Conclusion: Major adverse foot events and functional mobility deficits are prevalent in individuals with DPN and diabetic kidney disease. The risks for minor foot amputation and functional mobility deficits increase as early as stage 3 CKD and increase further in stages 4 and 5.
BACKGROUND: A subset of women with breast implants have reported a myriad of nonspecific systemic symptoms collectively termed systemic symptoms associated with breast implants (SSBI). SSBI symptoms are similar to manifestations associated with autoimmune and connective tissue disorders Breast tissue is rich in adipose cells, comprised of lipids. Insertion of an implant creates an oxidative environment leading to lipid oxidation. Oxylipins can influence immune responses and inflammatory processes. OBJECTIVES: This study explores the abundance of a spectrum of oxylipins in the peri-prosthetic tissue surrounding the breast implant. Since oxylipins are immunogenic, we sought to determine if they are associated with the SSBI subjects. We have also attempted to determine if the common manifestations exhibited by such subjects have any association with oxylipin abundance. METHODS: The study included 120 subjects divided in three cohorts. Forty-six subjects with breast implants exhibiting manifestation associated with SSBI, 29 in control cohort I subjects with breast implants not exhibiting manifestation associated with SSBI (non-SSBI) and 45 in control cohort II subjects without implants (normal tissue) were analyzed. Lipid extraction and oxylipin quantification was performed using LCMS. LC-MS/MS targeted analysis from the breast adipose tissue was performed. RESULTS: Of the fifteen oxylipins analyzed, four exhibited increased abundance in the SSBI cohort compared to the non-SSBI and normal cohorts. CONCLUSIONS: The study documents the association of the oxylipins with each manifestation reported by the subject. This study provides an objective assessment on the subjective questionnaire highlighting which symptoms could be more relevant than the others.
BACKGROUND: There is some evidence of an association between inflammation in the pathogenesis of mental disorders. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation, which provides a more stable index of systemic inflammation than more widely used biomarkers. This review aims to synthesise studies that measured suPAR concentrations in individuals with a psychiatric disorder, to determine if these concentrations are altered in comparison to healthy participants. METHOD: Comprehensive literature searches from inception to October 2023 were conducted of five relevant databases (PubMed, Web of Science, Embase, Scopus, APA PsychInfo). Random-effects meta-analyses were performed to compare the standardised mean difference of blood suPAR levels (i.e. plasma or serum) for individuals with any psychiatric disorder relative to controls. Separate meta-analyses of suPAR levels were conducted for individuals with schizophrenia or other psychotic disorder and depressive disorder. Risk of bias was assessed using the Newcastle Ottawa Scale. Post-hoc sensitivity analyses included excluding studies at high risk of bias, and analyses of studies that measured suPAR concentrations either in serum or in plasma separately. RESULTS: The literature search identified 149 records. Ten full-text studies were screened for eligibility and 9 studies were included for review. Primary analyses revealed no significant difference in suPAR levels between individuals with any psychiatric disorder compared to controls (kâ¯=â¯7, SMDâ¯=â¯0.42, 95â¯% CI [-0.20, 1.04]). However, those with depressive disorder had elevated suPAR levels relative to controls (kâ¯=â¯3, SMDâ¯=â¯0.61, 95â¯% CI [0.34, 0.87]). Similarly, secondary analyses showed no evidence of a significant difference in suPAR levels in individuals with any psychiatric disorder when studies at high risk of bias were excluded (kâ¯=â¯6, SMDâ¯=â¯0.54, 95â¯% CI [-0.14, 1.22]), but elevated suPAR concentrations for those with schizophrenia or other psychotic disorder were found (kâ¯=â¯3, SMDâ¯=â¯0.98, 95â¯% CI [0.39, 1.58]). Furthermore, studies that analysed plasma suPAR concentrations found elevated plasma suPAR levels in individuals with any psychiatric disorder relative to controls (kâ¯=â¯5, SMDâ¯=â¯0.84, 95â¯% CI [0.38, 1.29]), while studies measuring serum suPAR levels in any psychiatric disorder did not find a difference (kâ¯=â¯2, SMDâ¯=â¯-0.61, 95â¯% CI [-1.27, 0.04]). For plasma, elevated suPAR concentrations were also identified for those with schizophrenia or other psychotic disorder (kâ¯=â¯3, SMDâ¯=â¯0.98, 95â¯% CI [0.39, 1.58]). DISCUSSION: When studies measuring either only serum or only plasma suPAR were considered, no significant difference in suPAR levels were observed between psychiatric disorder groups, although significantly elevated suPAR levels were detected in those with moderate to severe depressive disorder. However, plasma suPAR levels were significantly elevated in those with any psychiatric disorder relative to controls, while no difference in serum samples was found. A similar finding was reported for schizophrenia or other psychotic disorder. The plasma findings suggest that chronic inflammatory dysregulation may contribute to the pathology of schizophrenia and depressive disorder. Future longitudinal studies are required to fully elucidate the role of this marker in the psychopathology of these disorders.
Methods for the targeted integration of genes in mammalian genomes suffer from low programmability, low efficiencies or low specificities. Here we show that phage-assisted continuous evolution enhances prime-editing-assisted site-specific integrase gene editing (PASSIGE), which couples the programmability of prime editing with the ability of recombinases to precisely integrate large DNA cargoes exceeding 10 kilobases. Evolved and engineered Bxb1 recombinase variants (evoBxb1 and eeBxb1) mediated up to 60% donor integration (3.2-fold that of wild-type Bxb1) in human cell lines with pre-installed recombinase landing sites. In single-transfection experiments at safe-harbour and therapeutically relevant sites, PASSIGE with eeBxb1 led to an average targeted-gene-integration efficiencies of 23% (4.2-fold that of wild-type Bxb1). Notably, integration efficiencies exceeded 30% at multiple sites in primary human fibroblasts. PASSIGE with evoBxb1 or eeBxb1 outperformed PASTE (for 'programmable addition via site-specific targeting elements', a method that uses prime editors fused to recombinases) on average by 9.1-fold and 16-fold, respectively. PASSIGE with continuously evolved recombinases is an unusually efficient method for the targeted integration of genes in mammalian cells.
The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5'-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.
Matrix Attachment Region Binding Proteins , Neocortex , Neurons , Protein Biosynthesis , Protein Serine-Threonine Kinases , Animals , Neocortex/metabolism , Neocortex/cytology , Neocortex/embryology , Neurons/metabolism , Neurons/cytology , Mice , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Matrix Attachment Region Binding Proteins/metabolism , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Gene Expression Regulation, Developmental , Proteostasis , Neurogenesis/genetics , RNA, Messenger/metabolism , RNA, Messenger/genetics , 5' Untranslated Regions/genetics , Ribosomes/metabolism , Ribosomes/genetics , Humans , Endoribonucleases/metabolism , Endoribonucleases/genetics , Cell Differentiation/genetics
