Extracellular vesicles (EVs) function as potent mediators of intercellular communication for many in vivo processes, contributing to both health and disease related conditions. Given their biological origins and diverse functionality from correspondingly unique “cargo” compositions, both endogenous and modified EVs are garnering attention as promising therapeutic modalities and vehicles for targeted therapeutic delivery applications. Their diversity in composition, however, has revealed a significant need for more comprehensive analytical-based characterization methods, and manufacturing processes that are consistent and scalable. In this review, we explore the dynamic landscape of EV research and development efforts, ranging from novel isolation approaches, to their analytical assessment through novel characterization techniques, and to their production by industrial-scale manufacturing process considerations. Expanding the horizon of these topics to EVs for in-human applications, we underscore the need for stringent development and adherence to Good Manufacturing Practice (GMP) guidelines. Wherein, the intricate interplay of raw materials, production in bioreactors, and isolation practices, along with analytical assessments compliant with the Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines, in conjunction with reference standard materials, collectively pave the way for standardized and consistent GMP production processes.

While Mek1/2 and Gsk3β inhibition ("2i") supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female "all-ESC" mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.
Male ; Animals ; Female ; Mice ; Mouse Embryonic Stem Cells ; Embryonic Stem Cells ; Genomic Instability ; Lipids ; DNA/metabolism* ; Cell Differentiation

Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions.
Adenomatous Polyps ; Endoscopy ; Humans ; Precancerous Conditions/therapy* ; Singapore ; Stomach Neoplasms/therapy*

Objective: Burnout is a common occurrence among healthcare providers and has been associated with provider wellness culture. However, this association has not been extensively studied among emergency medicine (EM) providers. We aim to determine the association between EM provider burnout and their culture of wellness, and to elicit the independent wellness culture domains most predictive of burnout prevention. Methods: This was a multi-center observational study. We enrolled EM physicians and advanced practice providers from sixteen different emergency departments (EDs). Provider wellness culture and burnout surveys were performed. The wellness culture domains included in this study are personal/organizational value alignment, provider appreciation, leadership quality, self-controlled scheduling, peer support, and family support. Correlations between each wellness culture domain and burnout were analyzed by Pearson correlation co-efficiency, and their associations were measured by multivariate logistic regression with adjustments of other confounders. Results: A total of 242 ED provider surveys were entered for final analysis. The overall burnout rate was 54% (130/242). Moderate correlations were found between burnout and two wellness culture domains (value alignment: r=-0.43, P<0.001 and provider appreciation: r=-0.49, P<0.001). The adjusted odds ratio of provider appreciation associated with burnout was 0.44 (95% confidence interval, 0.25–0.77; P=0.004), adjusted odds ratio of family support was 0.67 (95% confidence interval, 0.48–0.95; P=0.025). Conclusion ED providers have a relatively high burnout rate. Provider burnout might have certain associations with wellness culture domains. Provider appreciation and family support seem to play important roles in burnout protection.

Objective: Burnout is a common occurrence among healthcare providers and has been associated with provider wellness culture. However, this association has not been extensively studied among emergency medicine (EM) providers. We aim to determine the association between EM provider burnout and their culture of wellness, and to elicit the independent wellness culture domains most predictive of burnout prevention. Methods: This was a multi-center observational study. We enrolled EM physicians and advanced practice providers from sixteen different emergency departments (EDs). Provider wellness culture and burnout surveys were performed. The wellness culture domains included in this study are personal/organizational value alignment, provider appreciation, leadership quality, self-controlled scheduling, peer support, and family support. Correlations between each wellness culture domain and burnout were analyzed by Pearson correlation co-efficiency, and their associations were measured by multivariate logistic regression with adjustments of other confounders. Results: A total of 242 ED provider surveys were entered for final analysis. The overall burnout rate was 54% (130/242). Moderate correlations were found between burnout and two wellness culture domains (value alignment: r=-0.43, P<0.001 and provider appreciation: r=-0.49, P<0.001). The adjusted odds ratio of provider appreciation associated with burnout was 0.44 (95% confidence interval, 0.25–0.77; P=0.004), adjusted odds ratio of family support was 0.67 (95% confidence interval, 0.48–0.95; P=0.025). Conclusion ED providers have a relatively high burnout rate. Provider burnout might have certain associations with wellness culture domains. Provider appreciation and family support seem to play important roles in burnout protection.

Oligodontia is the congenital absence of six or more teeth and comprises the more severe forms of tooth agenesis. Many genes have been implicated in the etiology of tooth agenesis, which is highly variable in its clinical presentation. The purpose of this study was to identify associations between genetic mutations and clinical features of oligodontia patients. An online systematic search of papers published from January 1992 to June 2021 identified 381 oligodontia cases meeting the eligibility criteria of causative gene mutation, phenotype description, and radiographic records. Additionally, ten families with oligodontia were recruited and their genetic etiologies were determined by whole-exome sequence analyses. We identified a novel mutation in WNT10A (c.99_105dup) and eight previously reported mutations in WNT10A (c.433 G > A; c.682 T > A; c.318 C > G; c.511.C > T; c.321 C > A), EDAR (c.581 C > T), and LRP6 (c.1003 C > T, c.2747 G > T). Collectively, 20 different causative genes were implicated among those 393 cases with oligodontia. For each causative gene, the mean number of missing teeth per case and the frequency of teeth missing at each position were calculated. Genotype-phenotype correlation analysis indicated that molars agenesis is more likely linked to PAX9 mutations, mandibular first premolar agenesis is least associated with PAX9 mutations. Mandibular incisors and maxillary lateral incisor agenesis are most closely linked to EDA mutations.
Humans ; Phenotype ; Wnt Proteins

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.
Adult ; Allopurinol ; Anaphylaxis ; Anti-Bacterial Agents ; Asia ; Asian Continental Ancestry Group ; Aspirin ; Asthma ; Carbamazepine ; Child ; Cicatrix ; Contrast Media ; Coronary Artery Disease ; Diagnostic Tests, Routine ; Drug Hypersensitivity ; Ethnic Groups ; Humans ; Hypersensitivity ; Penicillins ; Percutaneous Coronary Intervention ; Phenotype ; Recurrence ; Skin Tests

Botany ; history ; China ; History, 20th Century ; History, 21st Century

Image-guided surgery potentially enhances intraoperative safety and outcomes in a variety of craniomaxillofacial procedures. We explore the efficiency of one intraoperative navigation system in a single complex craniofacial case, review the initial and recurring costs, and estimate the added cost (e.g., additional setup time, registration). We discuss the potential challenges and benefits of utilizing image-guided surgery in our specific case and its benefits in terms of educational and teaching purposes and compare this with traditional osteotomies that rely on a surgeon's thorough understanding of anatomy coupled with tactile feedback to blindly guide the osteotome during surgery. A 13-year-old presented with untreated syndromic multi-suture synostosis, brachycephaly, severe exorbitism, and midface hypoplasia. For now, initial costs are high, recurring costs are relatively low, and there are perceived benefits of imaged-guided surgery as an excellent teaching tool for visualizing difficult and often unseen anatomy through computerized software and multi-planar real-time images.
Adolescent ; Craniosynostoses ; Humans ; Osteotomy ; Surgery, Computer-Assisted* ; Synostosis