Mechanisms and Translational Applications of Regeneration in Limbs: From Renewable Animals to Humans.

BACKGROUND: The regenerative capacity of organisms declines throughout evolution, and mammals lack the ability to regenerate limbs after injury. Past approaches to achieving successful restoration through pharmacological intervention, tissue engineering, and cell therapies have faced significant challenges. OBJECTIVES: This review aims to provide an overview of the current understanding of the mechanisms behind animal limb regeneration and the successful translation of these mechanisms for human tissue regeneration. RESULTS: Particular attention was paid to the Mexican axolotl (Ambystoma mexicanum), the only adult tetrapod capable of limb regeneration. We will explore fundamental questions surrounding limb regeneration, such as how amputation initiates regeneration, how the limb knows when to stop and which parts to regenerate, and how these findings can apply to mammalian systems. CONCLUSIONS: Given the urgent need for regenerative therapies to treat conditions like diabetic foot ulcers and trauma survivors, this review provides valuable insights and ideas for researchers, clinicians, and biomedical engineers seeking to facilitate the regeneration process or elicit full regeneration from partial regeneration events.

Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative ESKAPE pathogens.

Antibiotic resistance, especially in multidrug-resistant ESKAPE pathogens, remains a worldwide problem. Combination antimicrobial therapies may be an important strategy to overcome resistance and broaden the spectrum of existing antibiotics. However, this strategy is limited by the ability to efficiently screen large combinatorial chemical spaces. Here, we deployed a high-throughput combinatorial screening platform, DropArray, to evaluate the interactions of over 30,000 compounds with up to 22 antibiotics and 6 strains of Gram-negative ESKAPE pathogens, totaling to over 1.3 million unique strain-antibiotic-compound combinations. In this dataset, compounds more frequently exhibited synergy with known antibiotics than single-agent activity. We identified a compound, P2-56, and developed a more potent analog, P2-56-3, which potentiated rifampin (RIF) activity against Acinetobacter baumannii and Klebsiella pneumoniae. Using phenotypic assays, we showed P2-56-3 disrupts the outer membrane of A. baumannii. To identify pathways involved in the mechanism of synergy between P2-56-3 and RIF, we performed genetic screens in A. baumannii. CRISPRi-induced partial depletion of lipooligosaccharide transport genes (lptA-D, lptFG) resulted in hypersensitivity to P2-56-3/RIF treatment, demonstrating the genetic dependency of P2-56-3 activity and RIF sensitization on lpt genes in A. baumannii. Consistent with outer membrane homeostasis being an important determinant of P2-56-3/RIF tolerance, knockout of maintenance of lipid asymmetry complex genes and overexpression of certain resistance-nodulation-division efflux pumps - a phenotype associated with multidrug-resistance - resulted in hypersensitivity to P2-56-3. These findings demonstrate the immense scale of phenotypic antibiotic combination screens using DropArray and the potential for such approaches to discover new small molecule synergies against multidrug-resistant ESKAPE strains.

Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.

The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

Fertility issues in hypopituitarism.

Women with hypopituitarism have lower fertility rates and worse pregnancy outcomes than women with normal pituitary function. These disparities exist despite the use of assisted reproductive technologies and hormone replacement. In women with hypogonadotropic hypogonadism, administration of exogenous gonadotropins can be used to successfully induce ovulation. Growth hormone replacement in the setting of growth hormone deficiency has been suggested to potentiate reproductive function, but its routine use in hypopituitary women remains unclear and warrants further study. In this review, we will discuss the clinical approach to fertility in a woman with hypopituitarism.

Feasibility and Implementation Determinants of a Structured Goal Setting and Goal Management System.

IMPORTANCE: There is no evidence-based system to guide occupational therapists in implementing theory-based, client-engaged goal setting and goal management. A new system is needed to support high-quality goal setting and goal management. OBJECTIVE: To determine the acceptability, appropriateness, feasibility, credibility, and expectancy of a new structured theory-based, client-engaged goal setting and goal management system, called MyGoals, for occupational therapists. We explored MyGoals' implementation determinants, potential positive outcomes, and comparative advantages. DESIGN: This was a mixed-methods feasibility study. SETTING: Community. PARTICIPANTS: Occupational therapists (N = 7). OUTCOMES AND MEASURES: Acceptability, appropriateness, and feasibility were assessed using the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Credibility and expectancy were assessed with the Credibility and Expectancy Questionnaire (CEQ). Semistructured 1:1 interviews were conducted to explore occupational therapy perspectives on MyGoals and its implementation-related factors. RESULTS: MyGoals had high AIM (M = 18.1, SD = 1.9), IAM (M = 17.9, SD = 2.2), FIM (M = 17.3, SD = 2.1) scores and high CEQ Credibility (M = 22.1, SD = 5.0) and Expectancy (M = 20.6, SD = 4.3) scores. Interview data revealed suggestions to improve MyGoals, implementation determinants across the individuals involved, inner setting, and intervention characteristic domains, client- and clinician-related potential positive outcomes, and comparative advantages. CONCLUSIONS AND RELEVANCE: MyGoals is an acceptable, appropriate, feasible, credible, and promising system to guide occupational therapists in implementing theory-based, client-engaged goal setting and goal management for adults with chronic conditions in community-based rehabilitation. What This Article Adds: MyGoals is an easy-to-use, appealing, and helpful system to support occupational therapists in delivering theory-based goal setting and goal management components and to enable adults with chronic conditions to actively engage in their rehabilitation. This study supports the usefulness of MyGoals in community-based rehabilitation to improve goal setting and goal management quality and personally meaningful rehabilitation goal achievement in this population.

The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase.

Lysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels in monogenic and complex neurodegeneration suggest an essential function in human health. However, the site and mechanism responsible for BMP synthesis have been subject to debate for decades. Here, we report that the Batten disease gene product CLN5 is the elusive BMP synthase (BMPS). BMPS-deficient cells exhibited a massive accumulation of the BMP synthesis precursor lysophosphatidylglycerol (LPG), depletion of BMP species, and dysfunctional lipid metabolism. Mechanistically, we found that BMPS mediated synthesis through an energy-independent base exchange reaction between two LPG molecules with increased activity on BMP-laden vesicles. Our study elucidates BMP biosynthesis and reveals an anabolic function of late endosomes/lysosomes.

IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy.

Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.

Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance.

For a majority of patients with non-small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi. In this study, we tracked the origins and clonal evolution of drug-tolerant cells at a high resolution by using an expressed barcoding system coupled with single-cell RNA sequencing. This platform enabled longitudinal profiling of gene expression and drug sensitivity in response to EGFRi across a large number of clones. Drug-tolerant cells had higher expression of key survival pathways such as YAP and EMT at baseline and could also differentially adapt their gene expression following EGFRi treatment compared with sensitive cells. In addition, drug combinations targeting common downstream components (MAPK) or orthogonal factors (chemotherapy) showed greater efficacy than EGFRi alone, which is attributable to broader targeting of the heterogeneous EGFRi-tolerance mechanisms present in tumors. Overall, this approach facilitates thorough examination of clonal evolution in response to therapy that could inform the development of improved diagnostic approaches and treatment strategies for targeting drug-tolerant cells. SIGNIFICANCE: The evolution and heterogeneity of EGFR inhibitor tolerance are identified in a large number of clones at enhanced cellular and temporal resolution using an expressed barcode technology coupled with single-cell RNA sequencing.

Electrical stimulation alters DNA methylation and promotes neurite outgrowth.

Electrical stimulation (ES) influences neural regeneration and functionality. We here investigate whether ES regulates DNA demethylation, a critical epigenetic event known to influence nerve regeneration. Retinal ganglion cells (RGCs) have long served as a standard model for central nervous system neurons, whose growth and disease development are reportedly affected by DNA methylation. The current study focuses on the ability of ES to rescue RGCs and preserve vision by modulating DNA demethylation. To evaluate DNA demethylation pattern during development, RGCs from mice at different stages of development, were analyzed using qPCR for ten-eleven translocation (TETs) and immunostained for 5 hydroxymethylcytosine (5hmc) and 5 methylcytosine (5mc). To understand the effect of ES on neurite outgrowth and DNA demethylation, cells were subjected to ES at 75 µAmp biphasic ramp for 20 min and cultured for 5 days. ES increased TETs mediated neurite outgrowth, DNA demethylation, TET1 and growth associated protein 43 levels significantly. Immunostaining of PC12 cells following ES for histone 3 lysine 9 trimethylation showed cells attained an antiheterochromatin configuration. Cultured mouse and human retinal explants stained with ß-III tubulin exhibited increased neurite growth following ES. Finally, mice subjected to optic nerve crush injury followed by ES exhibited improved RGCs function and phenotype as validated using electroretinogram and immunohistochemistry. Our results point to a possible therapeutic regulation of DNA demethylation by ES in neurons.

Is there a causal relationship between hypothyroidism and hyponatremia?

Hyponatremia is one of the most common lab abnormalities seen in clinical practice. It has become widely accepted that hypothyroidism is a cause of euvolemic hyponatremia. The primary mechanism is thought to be due to impaired free water excretion and changes in sodium handling in the kidney. However, the clinical studies are conflicting and do not definitively confirm the association between hypothyroidism and hyponatremia. Therefore, if severe hyponatremia occurs in a patient without myxedema coma, other potential etiologies should be sought.

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

The Role of Gut Microbiota in Glaucoma Progression and Other Retinal Diseases.

As a rapidly growing field, microbiota research offers novel approaches to promoting ocular health and treating major retinal diseases, such as glaucoma. Gut microbiota changes throughout life; however, certain patterns of population changes have been increasingly associated with specific diseases. It has been well established that a disrupted microbiome contributes to central nervous system diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, and glioma, suggesting a prominent role of microbiome in neurodegenerative diseases. This review summarizes the progress in identifying significant changes in the microbial composition of patients with glaucoma by compiling studies on the association between microbiota and disease progression. Of interest is the relationship between increased Firmicutes/Bacteroidetes ratio in patients with primary open-angle glaucoma, increased taurocholic acid, decreased glutathione, and a reduction in retinal ganglion cell survival. Connecting these microbes to specific metabolites sheds light on the pathogenic mechanism and novel treatment strategies. In summary, the current review synthesizes the findings of several studies investigating the effects of shifting bacterial population in retinal diseases, particularly glaucoma, with the aim to identify the current direction of treatment and help direct future endeavors.

Feasibility, Client Engagement, and Person-Centeredness of Telehealth Goal Setting and Goal Management Intervention.

Telehealth-delivered goal setting and goal management may guide occupational therapists (OTs) to form a strong foundation of active client engagement and personally meaningful goals on which to base effective telehealth intervention. The objective was to determine the feasibility of a goal setting and goal management system, called MyGoals, delivered through telehealth and hybrid formats for adults with chronic conditions. This was a mixed-method feasibility study. The Credibility and Expectancy Questionnaire and Client Satisfaction Questionnaire-8 measured credibility, expectancy, and satisfaction. The Goals and Participation subscales of the Client-Centredness of Goal Setting Scale measured engagement and person-centeredness. Targeted self-ratings measured change objective achievement. Individuals' perspectives on MyGoals' feasibility were further explored in semi-structured interviews. In telehealth (N = 8) and hybrid (N = 9) groups, MyGoals had good credibility (M = 25.5, SD = 1.9), expectancy (M = 23.4, SD = 3.3), satisfaction (M = 31.3, SD = 0.9), client engagement (M = 29.4, SD = 1.5), person-centeredness (M = 19.5, SD = 1.2), and change objective achievement (M = 9.6, SD = 0.2). The interview data suggested improvements for MyGoals. In conclusion, telehealth delivery of MyGoals is feasible to support goal setting and goal management for adults with chronic conditions.

Towards a global partnership model in interprofessional education for cross-sector problem-solving.

OBJECTIVES: A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. METHODS: This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data. RESULTS: We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation. CONCLUSIONS: The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education.

Implementation strategies for occupational therapists to advance goal setting and goal management.

Background: There is a need for an effective evidence-based system to support high-quality goal setting and goal management implementation. We developed a new system for community-based rehabilitation, MyGoals, along with implementation strategies to support occupational therapists (OTs) in its administration. This study evaluates the acceptability, appropriateness, and feasibility of the implementation strategies, Clinician Education and Audit & Feedback. It also explores whether OTs achieve the change objectives of the MyGoals implementation strategies and MyGoals intervention fidelity. Methods: This mixed-methods case series study evaluated the MyGoals implementation strategies developed using Implementation Mapping (IM), specifically IM Task 5 - Implementation Outcome Evaluation. Seven OTs and 13 adults with chronic conditions participated in this study. OTs participated in two Clinician Education sessions, delivered two MyGoals interventions, and participated in two Audit & Feedback sessions. We evaluated the implementation strategies using the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), Feasibility of Intervention Measure (FIM), and semi-structured interviews and explored the OTs' self-rated MyGoals change objectives achievement and the intervention fidelity using quantitative MyGoals intervention fidelity measures and interviews. Quantitative data were analyzed using descriptive statistics. Qualitative data were analyzed by two independent coders using content analysis. Results: Seven OTs participated in this study (mean years of professional experience = 9.3, SD = 5.9). Clinician Education and Audit & Feedback had high AIM (M = 17.9, SD = 2.7), IAM (M = 17.3, SD = 3.60), and FIM scores (M = 17.3, SD = 3). The OTs also had high mean scores on self-perceived achievement of change objectives and intervention fidelity. Qualitative interviews suggested that the time commitment for Clinician Education is a key barrier to its acceptability, appropriateness, and feasibility. Participants also provided suggestions on how to improve the strategies (e.g., providing recorded Clinician Education, etc.). Conclusions: The MyGoals implementation strategies are acceptable, appropriate, and feasible to OTs working in community-based rehabilitation. They support OTs in achieving the change objectives necessary to deliver MyGoals completely and competently. Thus, the MyGoals implementation strategies may support clinicians in implementing a theory-based, client-engaged goal setting and goal management for adults with chronic conditions in community-based rehabilitation. This can ultimately help improve the integration of evidence-based interventions into practice.

Observed Interactions, Challenges, and Opportunities in Student-Led, Web-Based Near-Peer Teaching for Medical Students: Interview Study Among Peer Learners and Peer Teachers.

BACKGROUND: Near-peer teaching (NPT) is becoming an increasingly popular pedagogical tool in health professions education. Despite the shift in formal medical education from face-to-face teaching toward encompassing web-based learning activities, NPT has not experienced a similar transition. Apart from the few reports on NPT programs hastily converted to web-based learning in light of the COVID-19 pandemic, no studies to date have explored web-based learning in the specific context of NPT. OBJECTIVE: This qualitative study examined the nature of interactions among peer learners (PLs), peer teachers (PTs), and the learning content in a student-led, web-based NPT program for medical students. METHODS: A 5-month-long voluntary NPT program to support first- and second-year medical students' biomedical science learning in the undergraduate medical curriculum was designed by 2 senior-year medical students and delivered by 25 PTs with 84 PLs participating. In total, 9 PLs and 3 PTs underwent individual semistructured interviews at the end of the program to explore general NPT experience, reasons for joining NPT, the effectiveness of NPT, the demand and importance of NPT, and the feasibility of incorporating NPT in the formal curriculum. Interview transcripts were analyzed using a thematic analysis approach. RESULTS: The first general theme focused on the nature of student-student, student-teacher, and student-content interactions. Although PLs were engaged in web-based NPT, there was minimal interaction between students, as most PLs preferred to learn passively and remain anonymous. PLs believed the web-based NPT learning process to be a unidirectional transmission of knowledge from teacher to learner, with the teacher responsible for driving the interactions. This was in sharp contrast to PTs' expectation that both parties shared responsibility for learning in a collaborative effort. The second general theme identified the advantages and disadvantages of delivering NPT on a web platform, which were mainly convenience and teaching skills development and poor interactivity, respectively. CONCLUSIONS: Student-led, web-based NPT offers a flexible and comfortable means of delivering academic and nonacademic guidance to medical students. However, the web-based mode of delivery presents unique challenges in facilitating meaningful interactions among PLs, PTs, and subject content. A blended learning approach may be best suited for this form of student-led NPT program to optimize its efficacy.

Diagnostic accuracy of small-for-gestational-age status for infant mortality and school-age outcomes of live births <28 weeks' gestation: a cohort study.

OBJECTIVES: To determine the diagnostic accuracy of small-for-gestational-age (SGA; <10th centile) status for infant mortality and adverse school-age outcomes in infants born extremely preterm (EP; <28 weeks' gestation). DESIGN: Geographical cohort studies. SETTING: The state of Victoria, Australia. PATIENTS: For mortality, live births 22-27 weeks' gestation from 2009 to 2017 offered active care after birth. For school-age outcomes, survivors to 8 years' corrected age born in 1991-1992, 1997 or 2005. EXPOSURES: SGA <10th centile on four commonly used growth references: three derived from neonatal data (Fenton, UK-WHO and Intergrowth Newborn Size) and one from fetal data (Intergrowth Estimated Fetal Weight). MAIN OUTCOME MEASURES: (a) Infant mortality; (b) major neurodevelopmental disability, and poor performance on tests of IQ, academic achievement, motor function, and executive function. RESULTS: Infant mortality data were available for 2040 infants, and neurodevelopmental data for 499 children. Diagnostic accuracy of SGA status was low overall and varied with the growth reference. Positive predictive values for infant mortality ranged from 18% to 21%, only marginally higher than its 18% prevalence. Compared with a prevalence of 17%, positive predictive values for major neurodevelopmental disability ranged from 30% to 38% for the neonatal growth references but was only 20% for Intergrowth Estimated Fetal Weight. SGA status was also associated with lower IQ, poor academic achievement and poor motor performance. CONCLUSIONS: Among infants born EP, the diagnostic accuracy of SGA status was low for both infant mortality and adverse neurodevelopmental outcomes at school age, but importantly varied with the growth reference used to identify SGA status.

Health-related quality of life in Hong Kong physicians up to 20 years post-graduation: A cross-sectional survey.

BACKGROUND: Problems with health-related quality of life can affect physicians' ability to work effectively. This study compared the health-related quality of life of Hong Kong physicians to the general population and explored the factors associated with mental and physical health-related quality of life. METHODS: This cross-sectional study was conducted from January to April 2016. Medical graduates from the University of Hong Kong participated in a survey containing the Short Form-12 Item Health survey version 2, Patient Health Questionnaire-9, Copenhagen Burnout Inventory, and items on lifestyle behaviors, career satisfaction, and socio-demographics. RESULTS: 496 responses were received. The mean physical component summary score was 53.2 (SD = 7.6), similar to the general population. The mean mental component summary score was 43.6 (SD = 11.8), significantly worse than the general population (P<0.01). Compared to the general population, all Short-Form 12 Health Survey version 2 domains were worse in doctors, aside from bodily pain and general health. Regular exercise was positively associated with physical component summary scores (Coeff 2.024; P = 0.047); but having children and higher personal burnout scores were negatively associated with it (Coeff -1.890; P = 0.036; and Coeff -0.045; P = 0.027, respectively). Poorer mental component summary scores correlated with worse personal (Coeff -0.284; P< 0.001), work-related (Coeff -0.135; P = 0.040), and patient-related burnout (Coeff -0.060; P = 0.041), and higher Patient Health Questionnaire-9 scores (Coeff -9.170; P<0.001). There were significant differences in mental health (P = 0.042) and mental component summary scores (P = 0.012) across age groups, but not with gender. CONCLUSION: Hong Kong physicians are less impacted by physical health than mental health. Compared to the general population, doctors' mental health has a more significant impact on their lives. Interventions aimed to improve burnout and depression rates in physicians may improve physicians' mental health-related quality of life.

Predicting patient decompensation from continuous physiologic monitoring in the emergency department.

Anticipation of clinical decompensation is essential for effective emergency and critical care. In this study, we develop a multimodal machine learning approach to predict the onset of new vital sign abnormalities (tachycardia, hypotension, hypoxia) in ED patients with normal initial vital signs. Our method combines standard triage data (vital signs, demographics, chief complaint) with features derived from a brief period of continuous physiologic monitoring, extracted via both conventional signal processing and transformer-based deep learning on ECG and PPG waveforms. We study 19,847 adult ED visits, divided into training (75%), validation (12.5%), and a chronologically sequential held-out test set (12.5%). The best-performing models use a combination of engineered and transformer-derived features, predicting in a 90-minute window new tachycardia with AUROC of 0.836 (95% CI, 0.800-0.870), new hypotension with AUROC 0.802 (95% CI, 0.747-0.856), and new hypoxia with AUROC 0.713 (95% CI, 0.680-0.745), in all cases significantly outperforming models using only standard triage data. Salient features include vital sign trends, PPG perfusion index, and ECG waveforms. This approach could improve the triage of apparently stable patients and be applied continuously for the prediction of near-term clinical deterioration.