2023 Society for Academic Emergency Medicine Consensus Conference on Precision Emergency Medicine: Development of a policy-relevant, patient-centered research agenda.

OBJECTIVES: Precision medicine is data-driven health care tailored to individual patients based on their unique attributes, including biologic profiles, disease expressions, local environments, and socioeconomic conditions. Emergency medicine (EM) has been peripheral to the precision medicine discourse, lacking both a unified definition of precision medicine and a clear research agenda. We convened a national consensus conference to build a shared mental model and develop a research agenda for precision EM. METHODS: We held a conference to (1) define precision EM, (2) develop an evidence-based research agenda, and (3) identify educational gaps for current and future EM clinicians. Nine preconference workgroups (biomedical ethics, data science, health professions education, health care delivery and access, informatics, omics, population health, sex and gender, and technology and digital tools), comprising 84 individuals, garnered expert opinion, reviewed relevant literature, engaged with patients, and developed key research questions. During the conference, each workgroup shared how they defined precision EM within their domain, presented relevant conceptual frameworks, and engaged a broad set of stakeholders to refine precision EM research questions using a multistage consensus-building process. RESULTS: A total of 217 individuals participated in this initiative, of whom 115 were conference-day attendees. Consensus-building activities yielded a definition of precision EM and key research questions that comprised a new 10-year precision EM research agenda. The consensus process revealed three themes: (1) preeminence of data, (2) interconnectedness of research questions across domains, and (3) promises and pitfalls of advances in health technology and data science/artificial intelligence. The Health Professions Education Workgroup identified educational gaps in precision EM and discussed a training roadmap for the specialty. CONCLUSIONS: A research agenda for precision EM, developed with extensive stakeholder input, recognizes the potential and challenges of precision EM. Comprehensive clinician training in this field is essential to advance EM in this domain.

SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P.

SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1PA to mature S1PC form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1PA into its mature S1PC form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRINGKO cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1PA→C and trafficking of S1PC to the Golgi. However, despite reaching the Golgi in SPRINGKO cells, S1PC fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRINGKO cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.

Peer-reviewed publications in orthopaedic surgery from lower income countries: A comparative analysis.

INTRODUCTION: Musculoskeletal (MSK) disease is a substantial global burden, especially in lower income countries. However, limited research has been published on MSK health by scholars from these countries. We aimed to study the distribution of authorships, including trends in peer-reviewed orthopaedic publications based on each author's affiliated institution's country income status. METHODS: Based on a bibliometric search, 119 orthopaedic-related journals were identified using the Journal Citation Reports database. Details of all scientific articles published in these journals between 2012 and 2021 were used to study trends and association between each of the author's affiliated institution's country income status, using the World Bank Classification. RESULTS: Of the 133,718 unique articles, 87.6% had at least one author affiliation from a high-income country (HIC), 7.0% from an upper-middle income country (UMIC), 5.2% from a lower-middle income country (LMIC), and 0.2% from a low-income country (LIC). Overall, these articles were cited 1,825,365 times, with 92.5% of citations from HIC-affiliated authors and < 0.1% from LIC-affiliated authors. Over the 10-year study period, HIC-affiliated articles demonstrated the largest increase in the number of publications (9107-14,619), compared to UMIC-affiliated (495-1214), LMIC-affiliated (406-874), and LIC-affiliated articles (4-28). CONCLUSIONS: There are large and persistent disparities in orthopaedic research publications based on the country income status of the author's affiliated institution, especially in the higher impact orthopaedic journals. Efforts should be made to increase opportunities for scholars from LICs and LMICs to publish their research in high-impact orthopaedic journals.

The effects of psychosocial interventions using generic photos on social interaction, mood and quality of life of persons with dementia: a systematic review.

BACKGROUND: Although family photos are often used in the psychosocial care for people with dementia, little is known about the use and effectiveness of generic photos. This systematic literature review explored psychosocial interventions using generic photos for people with dementia, and the effects they have on their social interaction and/or mood and/or quality of life. In addition, it was investigated whether these interventions made use of technology in its implementation. METHODS: A systematic search on the following databases was performed: PubMed, Embase, APA PsychInfo, Cinahl, Web of Science, Scopus and Cochrane Central. Inclusion and exclusion criteria were based on the PICO model (Population, Intervention, Comparison, Outcome), and quality assessment was undertaken using the Weight of Evidence Framework. Narrative synthesis was undertaken to summarize study characteristics- settings and designs, type of psychosocial interventions identified, type of photos and technology used, outcome measures, and results. RESULTS: A total of 2,035 results were found, however after title, abstract and full-text screening, a total of 8 studies were included. The most common psychosocial intervention using generic photos was found to be reminiscence therapy, followed by art-viewing activities. In studies that used technology, it was reported that viewing digitalized photos were either similar or better to conventional printed photos. Despite photos being generic, it was found that generic photos could still hold personal significance to the person with dementia. Some positive and significant effects were found for the outcomes social interaction, mood and quality of life, though no study evaluated all three outcomes. Two studies were rated as having high overall quality, 4 were rated as fair, and 2 studies had a low quality assessment rating. CONCLUSION: Studies found using generic photos were limited, showing varying outcomes and methodological quality. Firm conclusions on the effectiveness of interventions using generic photos are not possible. However, the use of generic photos in psychosocial interventions is a promising area for future research. Researchers should consider studies with better methodological quality and larger samples; and qualitative studies where the intention is to get better insight into successful implementation and impact mechanisms of such psychosocial interventions. TRIAL REGISTRATION: n/a.

Control of murine brown adipocyte development by GATA6.

Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the identity of embryonic brown fat progenitor cells and regulators of adipogenic commitment are unclear. Here, we performed single-cell gene expression analyses of mesenchymal cells during mouse embryogenesis with a focus on BAT development. We identified cell populations associated with the development of BAT, including Dpp4+ cells that emerge at the onset of adipogenic commitment. Immunostaining and lineage-tracing studies show that Dpp4+ cells constitute the BAT fascia and contribute minorly as adipocyte progenitors. Additionally, we identified the transcription factor GATA6 as a marker of brown adipogenic progenitor cells. Deletion of Gata6 in the brown fat lineage resulted in a striking loss of BAT. Together, these results identify progenitor and transitional cells in the brown adipose lineage and define a crucial role for GATA6 in BAT development.

A Narrative Review Illustrating the Clinical Utility of Electroencephalogram-Guided Anesthesia Care in Children.

The major therapeutic end points of general anesthesia include hypnosis, amnesia, and immobility. There is a complex relationship between general anesthesia, responsiveness, hemodynamic stability, and reaction to noxious stimuli. This complexity is compounded in pediatric anesthesia, where clinicians manage children from a wide range of ages, developmental stages, and body sizes, with their concomitant differences in physiology and pharmacology. This renders anesthetic requirements difficult to predict based solely on a child's age, body weight, and vital signs. Electroencephalogram (EEG) monitoring provides a window into children's brain states and may be useful in guiding clinical anesthesia management. However, many clinicians are unfamiliar with EEG monitoring in children. Young children's EEGs differ substantially from those of older children and adults, and there is a lack of evidence-based guidance on how and when to use the EEG for anesthesia care in children. This narrative review begins by summarizing what is known about EEG monitoring in pediatric anesthesia care. A key knowledge gap in the literature relates to a lack of practical information illustrating the utility of the EEG in clinical management. To address this gap, this narrative review illustrates how the EEG spectrogram can be used to visualize, in real time, brain responses to anesthetic drugs in relation to hemodynamic stability, surgical stimulation, and other interventions such as cardiopulmonary bypass. This review discusses anesthetic management principles in a variety of clinical scenarios, including infants, children with altered conscious levels, children with atypical neurodevelopment, children with hemodynamic instability, children undergoing total intravenous anesthesia, and those undergoing cardiopulmonary bypass. Each scenario is accompanied by practical illustrations of how the EEG can be visualized to help titrate anesthetic dosage to avoid undersedation or oversedation when patients experience hypotension or other physiological challenges, when surgical stimulation increases, and when a child's anesthetic requirements are otherwise less predictable. Overall, this review illustrates how well-established clinical management principles in children can be significantly complemented by the addition of EEG monitoring, thus enabling personalized anesthesia care to enhance patient safety and experience.

Early Neurodevelopmental Outcomes Following Exposure to General Anesthesia in Infancy: EGAIN, a Prospective Cohort Study.

BACKGROUND: General anesthesia (GA) is known to worsen neural outcomes in animals, but human research assessing early-life GA exposure and neurodevelopment show inconsistent findings. We investigated the effects of a single GA exposure for minor surgery on the neurodevelopment of healthy children at multiple time-points, using clinical assessments along with behavioral and neurophysiological measures rarely used in human research. METHODS: GA-exposed children were a prospective cohort of 250 full-term, healthy infants who underwent GA for minor surgery before 15 months. Nonexposed children were from a separate cohort of similar age, sex, ethnicity, and maternal education. In both cohorts, clinical measures (Bayley Scales of Infant and Toddler Development-III [BSID-III] and Child Behavior Checklist [CBCL1½-5]) were assessed at 24 months, and experimental tests (memory and attentional) and neurophysiology (event-related potentials) at 6 and 18 months. RESULTS: At 24 months, there were no differences between GA-exposed and nonexposed children in the cognitive, language, motor, and socioemotional domains of the BSDI-III; however, GA-exposed children had poorer parental-reported scores in BSID-III general adaptability (94.2 vs. 99.0 [mean difference, 4.77; 97.3% confidence interval, -9.29, -0.24]; P =0.020) and poorer internalizing behavior scores on CBCL1½-5 (52.8 vs. 49.4 [mean difference, 3.35; 97.3% confidence interval, 0.15-6.55]; P =0.021). For experimental measures, GA-exposed children showed differences in 4 tests at 6 and 18 months. CONCLUSIONS: GA-exposed children did not differ from unexposed children in cognitive, language or motor outcomes at 24 months, but exhibited poorer parent-reported behavior scores. Differences in infant behavior and neurophysiology were detected at 6 and 18 months. Neurophysiological assessments may complement clinically relevant assessments to provide greater insights into neurodevelopment following early GA exposure.

Known in the nursing home: development and evaluation of a digital person-centered artistic photo-activity intervention to promote social interaction between residents with dementia, and their formal and informal carers.

BACKGROUND: To address the lack of social interaction and meaningful activities for persons with dementia (PWD) in nursing homes an artistic Photo-Activity was designed. The present study aims to develop a digital version of the Photo-Activity and to investigate its implementation and impact on nursing home residents with advanced dementia, and their (in)formal carers. METHODS: First, within a user-participatory design, a digital-app version of the Photo-Activity will be developed and pilot-tested, in co-creation with (in)formal carers and PWD. Next, the feasibility and effectiveness of the Photo-Activity versus a control activity will be explored in a randomized controlled trial with nursing home residents (N=90), and their (in)formal carers. Residents will be offered the Photo-Activity or the control activity by (in)formal carers during one month. Measurements will be conducted by independent assessors at baseline (T0), after one month (T1) and at follow up, two weeks after T1 (T2). Qualitative and quantitative methods will be used to investigate the effects of the intervention on mood, social interaction and quality of life of the PWD, sense of competence of informal carers, empathy and personal attitude of the formal carers, and quality of the relationship between the PWD, and their (in)formal carers. In addition, a process evaluation will be carried out by means of semi-structured interviews with the participating residents and (in)formal carers. Finally, an implementation package based on the process evaluation will be developed, allowing the scaling up of the intervention to other care institutions. DISCUSSION: Results of the trial will be available for dissemination by Spring 2023. The digital Photo-Activity is expected to promote meaningful connections between the resident with dementia, and their (in)formal carers through the facilitation of person-centered conversations. TRIAL REGISTRATION: Netherlands Trial Register: NL9219 ; registered (21 January 2021); NTR (trialregister.nl).

Interim Singapore guidelines for basic and advanced life support for paediatric patients with suspected or confirmed COVID-19.

The COVID-19 pandemic has resulted in significant challenges for the resuscitation of paediatric patients, especially for infants and children who are suspected or confirmed to be infected. Thus, the paediatric subcommittee of the Singapore Resuscitation and First Aid Council developed interim modifications to the current Singapore paediatric guidelines using extrapolated data from the available literature, local multidisciplinary expert consensus and institutional best practices. It is hoped that this it will provide a framework during the pandemic for improved outcomes in paediatric cardiac arrest patients in the local context, while taking into consideration the safety of all community first responders, medical frontline providers and healthcare workers.

Deuterium MRS of early treatment-induced changes in tumour lactate in vitro.

Elevated production of lactate is a key characteristic of aberrant tumour cell metabolism and can be non-invasively measured as an early marker of tumour response using deuterium (2 H) MRS. Following treatment, changes in the 2 H-labelled lactate signal could identify tumour cell death or impaired metabolic function, which precede morphological changes conventionally used to assess tumour response. In this work, the association between apoptotic cell death, extracellular lactate concentration, and early treatment-induced changes in the 2 H-labelled lactate signal was established in an in vitro tumour model. Experiments were conducted at 7 T on acute myeloid leukaemia (AML) cells, which had been treated with 10 µg/mL of the chemotherapeutic agent cisplatin. At 24 and 48 h after cisplatin treatment the cells were supplied with 20 mM of [6,6'-2 H2 ]glucose and scanned over 2 h using a two-dimensional 2 H MR spectroscopic imaging sequence. The resulting signals from 2 H-labelled glucose, lactate, and water were quantified using a spectral fitting algorithm implemented on the Oxford Spectroscopy Analysis MATLAB toolbox. After scanning, the cells were processed for histological stains (terminal deoxynucleotidyl transferase UTP nick end labelling and haematoxylin and eosin) to assess apoptotic area fraction and cell morphology respectively, while a colorimetric assay was used to measure extracellular lactate concentrations in the supernatant. Significantly lower levels of 2 H-labelled lactate were observed in the 48 h treated cells compared with the untreated and 24 h treated cells, and these changes were significantly correlated with an increase in apoptotic fraction and a decrease in extracellular lactate. By establishing the biological processes associated with treatment-induced changes in the 2 H-labelled lactate signal, these findings suggest that 2 H MRS of lactate may be valuable in evaluating early tumour response.

High frequency ultrasound nonlinear scattering from porphyrin nanobubbles.

Emerging contrast imaging studies have highlighted the potential of nanobubbles for both intravascular and extravascular applications. Reports to date on nanobubbles have generally utilized low frequencies (<12 MHz), high concentrations (>109 mL-1), and B-mode or contrast-mode on preclinical and clinical systems. However, none of these studies directly examined nanobubble acoustic signatures systematically to implement nonlinear imaging schemes in a methodical manner based on nanobubble behaviour. Here, nanobubble nonlinear behaviour is investigated at high frequencies (12.5, 25, 30 MHz) and low concentration (106 mL-1) in a channel phantom, with different pulse types in single- and multi-pulse sequences to examine behaviour under conditions relevant to high frequency imaging. Porphyrin nanobubbles are demonstrated to initiate nonlinear scattering at high frequencies in a pressure-threshold dependent manner, as previously observed at low frequencies. This threshold behaviour was then utilized to demonstrate enhanced nanobubble imaging with pulse inversion, amplitude modulation, and a combination of the two, progressing towards the improved sensitivity and expanded utility of these ultrasound contrast agents.

Singapore Paediatric Resuscitation Guidelines 2021.

We present the 2021 Singapore Paediatric Resuscitation Guidelines. The International Liaison Committee on Resuscitation's Pediatric Taskforce Consensus Statements on Science and Treatment Recommendations, which was published in October 2020, and the updated resuscitation guidelines from the American Heart Association and European Resuscitation Council, were reviewed and discussed by the committee. These recommendations were derived after deliberation of peer-reviewed evidence updates on paediatric resuscitation and took into consideration the local setting and clinical practice.

Association of anesthetic and surgical risk factors with outcomes of initial diagnostic biopsies in a current cohort of children with anterior mediastinal masses.

Background: Diagnostic biopsies of pediatric anterior mediastinal masses (AMMs) are high-risk procedures in which general anesthesia (GA) is traditionally avoided. However, awareness of historically recognized risk factors and corresponding perioperative management have improved over time and may now no longer strictly preclude the use of GA. Therefore, in this study, we examined the association of anesthetic and surgical risk factors and modalities with resulting procedural and survival outcomes in a current patient cohort. Methods: We retrospectively reviewed charts of 35 children with AMMs who underwent initial diagnostic biopsies between January 2001 and August 2019, and determined tracheal compression and deviation from archival CT scans and procedural and disease outcomes. Results: Twenty-three (65%) patients underwent GA while 12 (35%) received sedation. Among patients with available CT measurements, 13 of 25 (52%) had >50% anteroposterior tracheal diameter reduction. Patients with >50% anteroposterior tracheal compression received sedation more frequently (p=0.047) and were positioned upright (p=0.015) compared with patients with ≤50% compression, although 4 of 13 and 9 of 12, respectively, still received GA. Intraoperative adverse events (AEs) occurred in four (11.4%) patients: three received GA, and all were positioned supine or lateral. AEs were not associated with radiographic airway risk factors but were significantly associated with morphine and sevoflurane use (p<0.001) and with thoracoscopic biopsies (p=0.035). There were no on-table mortalities, but four delayed deaths occurred (three related to disease and one from late procedural complications). Conclusions: In a current cohort of pediatric AMM biopsies, patients with >50% anteroposterior tracheal compression were more frequently managed with a conservative perioperative management strategy, though not completely excluding GA. The corresponding reduction in frequency of procedural AEs in this traditionally high-risk group suggests that increased awareness of procedural risk factors and appropriate risk-guided perioperative management choices may obviate the procedural mortality historically associated with pediatric AMM biopsies.

The prevalence, risk factors, and psychosocial impacts of acne vulgaris in medical students: a literature review.

Affecting approximately 9.4% of the population worldwide, acne vulgaris is a common chronic inflammatory skin disease. Medical students are exposed to higher levels of stress and have a higher prevalence of acne. However, the risk factors and the impact of acne on medical students' mental health remains poorly understood. The aim of this literature review is to: (i) summarize the prevalence and risk factors of acne vulgaris in medical students and (ii) highlight the impact of psychological consequences of acne in medical students. A literature search was conducted using MEDLINE and EMBASE in OVID, using variations in the following search terms: acne vulgaris, medical students, self-esteem, psychology, psychiatry, suicide, suicidal thoughts, self-harm, positive and negative effects, psychological well-being, anxiety, and depression. Studies that stated the prevalence or risk factors of acne vulgaris and/or examined the association between psychosocial effects and acne vulgaris in medical students were included. Eleven cross-sectional studies were included. The prevalence of acne vulgaris in medical students ranged from 34.38% to 97.9% across nine studies. Review of these articles revealed that acne prevalence is associated with stress, gender differences, and lifestyle factors in medical students. Acne had many negative psychological and social impacts on medical students including negative self-image, lower confidence, embarrassment, depression, anxiety, social withdrawal, and impaired social behaviors. Further research on the intersection between acne vulgaris and the mental health of medical students is needed.

The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting.

The endothelial monolayer forms a barrier between the lumen of blood vessels and the underlying tissues. Stable VE-cadherin-based adherens junctions are essential for maintaining this barrier, whereas their remodeling is required for angiogenesis in health and disease. Here, we position the ERAD-associated ubiquitin ligase MARCH6 as a determinant of angiogenic sprouting and barrier integrity through its ability to promote the degradation of the rate-limiting cholesterol biosynthetic enzyme squalene epoxidase (SQLE). Accordingly, MARCHF6 ablation in endothelial cells increases SQLE protein and cholesterol load. This leads to altered membrane order, disorganized adherens junctions, decreased endothelial barrier function, and impaired SQLE-dependent sprouting angiogenesis. Akin to MARCHF6 silencing, the overexpression of SQLE impairs angiogenesis. However, angiogenesis is also attenuated when SQLE is silenced, indicating that fine-tuning cholesterol biosynthesis is a determinant of healthy endothelial function. In summary, we propose a mechanistic link between regulation of cholesterol homeostasis by the MARCH6-SQLE axis and endothelial integrity and angiogenesis.

Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism.

The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the SREBP Regulating Gene (SPRING/C12ORF49) as a determinant of the SREBP pathway. SPRING is a glycosylated Golgi-resident membrane protein and its ablation in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes reduces SREBP signaling. In mice, Spring deletion is embryonic lethal yet silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, attenuated SREBP signaling in SPRINGKO cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling and function. Moreover, in line with the role of SREBP in tumor growth, a wide range of tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized modulator of SREBP signaling.