Causal association of genetically determined caffeine intake from tea or coffee with bone health: a two-sample Mendelian randomization study.

BACKGROUND: Relationship of caffeine intake and consumption of caffeinated beverages, such as tea and coffee, with bone health remains controversial. This study aimed to evaluate whether genetically determined caffeine intake from tea or coffee has causal effects on overall total body bone mineral density (TB-BMD) and fracture. We also assessed the association with TB-BMD in five age strata. METHODS: Using two-sample Mendelian randomization approach, summary statistics were retrieved from genome-wide association studies (GWAS)/GWAS meta-analyses of caffeine intake from tea (n = 395 866)/coffee (n = 373 522), TB-BMD (n = 66 628), and fracture (n = 426 795). Inverse variance weighted method was adopted as the main univariable analysis. Multivariable analysis was conducted to evaluate whether the causal effect is independent. RESULTS: In univariable analysis, genetically determined caffeine intake from tea had positive association with overall TB-BMD (per SD increase in genetically determined caffeine intake, beta of TB-BMD [in SD]: 0.166; 95% confidence interval (CI): 0.006-0.326) and inverse association with fracture (OR = 0.79; 95% CI: 0.654-0.954). Genetically determined caffeine intake from coffee was also positively associated with overall TB-BMD (beta = 0.231; 95% CI: 0.093-0.369). The association remained significant after adjustment for smoking in multivariable analysis. Genetically determined caffeine intake from tea or coffee was both positively associated with TB-BMD in the age strata of 45-60 years, but we lacked evidence of association in other strata. CONCLUSIONS: Genetically, caffeine intake from tea or coffee may be beneficial to bone health. Due to the ascertainment method of caffeine intake from tea, our study also implied genetically higher tea consumption may improve TB-BMD and lower fracture risk.

Predicting factors for acute encephalopathy in febrile seizure children with SARS-CoV-2 omicron variant: a retrospective study.

BACKGROUND: SARS-CoV-2 posed a threat to children during the early phase of Omicron wave because many patients presented with febrile seizures. The study aimed to investigate predicting factors for acute encephalopathy of children infected by SARS-CoV-2 Omicron variant presenting with febrile seizures. METHODS: The retrospective study analyzed data from pediatric patients who visited the emergency department of Chang Gung Memorial Hospital in Taiwan between April and July 2022. We specifically focused on children with COVID-19 who presented with febrile seizures, collecting demographic, clinical, and laboratory data at the pediatric emergency department, as well as final discharge diagnoses. Subsequently, we conducted a comparative analysis of the clinical and laboratory characteristics between patients diagnosed with acute encephalopathy and those with other causes of febrile seizures. RESULTS: Overall, 10,878 children were included, of which 260 patients presented with febrile seizures. Among them, 116 individuals tested positive for SARS-CoV-2 and of them, 14 subsequently developed acute encephalopathy (12%). Those with acute encephalopathy displayed distinctive features, including older age (5.1 vs. 2.6 years old), longer fever duration preceding the first seizure (1.6 vs. 0.9 days), cluster seizure (50% vs. 16.7%), status epilepticus (50% vs. 13.7%) and occurrences of bradycardia (26.8% vs. 0%) and hypotension (14.3% vs. 0%) in the encephalopathy group. Besides, the laboratory findings in the encephalopathy group are characterized by hyperglycemia (mean (95% CI) 146 mg/dL (95% CI 109-157) vs. 108 mg/dL (95% CI 103-114) and metabolic acidosis (mean (95% CI) pH 7.29(95% CI 7.22-7.36) vs. 7.39 (95%CI 7.37-7.41)). CONCLUSIONS: In pediatric patients with COVID-19-related febrile seizures, the occurrence of seizures beyond the first day of fever, bradycardia, clustered seizures, status epilepticus, hyperglycemia, and metabolic acidosis should raise concerns about acute encephalitis/encephalopathy. However, the highest body temperature and the severity of leukocytosis or C-reactive protein levels were not associated with poor outcomes.

Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. METHODS: The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. RESULTS: The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. CONCLUSION: FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.

COVID-19 and cognitive performance: a Mendelian randomization study.

Background: A substantial proportion of individuals with COVID-19 experienced cognitive impairment after resolution of SARS-CoV-2 infection. We aimed to evaluate whether genetic liability to SARS-CoV-2 infection per se, or more severe COVID-19, is causally linked to cognitive deficit. Methods: We firstly performed univariable Mendelian randomization (MR) analysis to examine whether genetic liability to SARS-CoV-2 infection, hospitalized and severe COVID-19 is causally associated with cognitive performance. To dissect the causal pathway, multivariable MR (MVMR) analysis was conducted by adjusting for five inflammatory markers [C-reactive protein, interleukin (IL)-1ß, IL-6, IL-8, and tumour necrosis factor α, as proxies of systemic inflammation]. Results: In univariable MR analysis, host genetic liability to SARS-CoV-2 infection was associated with lower cognitive performance [inverse variance weighted (IVW) analysis, estimate: -0.023; 95% Confidence Interval (CI): -0.038 to -0.009]. Such causal association was attenuated in MVMR analysis when we adjusted for the five correlated inflammatory markers in one analysis (IVW analysis, estimate: -0.022; 95% CI: -0.049 to 0.004). There was insufficient evidence of association for genetic liability to hospitalized and severe COVID-19 with cognitive performance. Conclusion: The causal effect of host genetic liability to SARS-CoV-2 infection on reduced cognitive performance may be mediated by systemic inflammation. Future studies examining whether anti-inflammatory agents could alleviate cognitive impairment in SARS-CoV-2-infected individuals are warranted.

Social cognitive theory to improve symptom appraisal and help-seeking among patients with autoimmune rheumatic diseases: A qualitative study.

AIM: Social cognitive theory (SCT) has been successfully employed to improve symptom appraisal and help-seeking among patients with various conditions but is yet to be applied in the context of autoimmune rheumatic diseases (ARDs). This study aimed to explore the applicability of SCT in and possible approaches to improving symptom appraisal and help-seeking of patients with ARDs, one of the key barriers to earlier diagnosis. METHODS: Semi-structured interviews were conducted with 33 ARD patients with a prolonged pre-diagnosis interval (>3 months). We coded the transcripts deductively using SCT as the overarching framework and inductively for approaches identified from the interviews. RESULTS: All six main concepts of SCT (behavioral capacity, expectations, self-efficacy, observational learning, reinforcements, and reciprocal determinism) were observed in the three stages of symptom appraisal and help-seeking (detection, interpretation, and response) of patients with ARDs. While many participants reported that they were able and confident to detect their symptoms, they lacked the behavioral capacity and self-efficacy to interpret symptoms correctly, which resulted in delayed help-seeking and diagnosis. Possible approaches to address this suggested by participants (such as education of the general population) could improve behavioral capacity and self-efficacy in symptom interpretation and enhance expectations, observational learning, reinforcements, and reciprocal determinism in symptom response. CONCLUSION: Lack of behavioral capacity and self-efficacy was observed in symptom interpretation of patients with ARDs, which resulted in delayed help-seeking. Approaches could target the behavioral capacity and self-efficacy for symptom interpretation to facilitate early help-seeking and, in turn, earlier diagnosis among individuals with possible ARDs.

Healthcare professionals' experiences of interprofessional collaboration in patient education: A systematic review.

OBJECTIVES: This study explores interprofessional collaboration amongst healthcare professionals in patient education. METHODS: A systematic review was conducted. A search in seven databases was conducted from 2011 to 2022 and screened against the inclusion criteria. Quality appraisal was done independently by two reviewers. Studies were extracted and synthesised using the data-based convergent synthesis design. RESULTS: Twenty-one studies were included. Five themes on factors affecting interprofessional collaboration in patient education emerged: 1) role clarification, 2) communication infrastructure, 3) shared space for collaboration, 4) interprofessional trust, and 5) organisational support. CONCLUSION: Findings highlighted the importance of developing trustful relationships within the multidisciplinary team in delivering patient education. Channels for additional infrastructural support, guidelines and training in patient education delivery is required. Future research could explore patients' perspectives on how their learning needs in patient education may be optimised through a multidisciplinary approach. PRACTICE IMPLICATIONS: Healthcare leaders could promote shared goals within the team by facilitating a common space and time for interprofessional team rounding, and by developing shared patient education resources and documentation processes. Interprofessional education focusing on the delivery of team-based patient education could be implemented to foster understanding of the interdependent role of multidisciplinary healthcare professionals.

Symptom Appraisal and Help-Seeking Among Patients With Autoimmune Rheumatic Diseases: A Qualitative Study.

OBJECTIVE: Long diagnostic delay remains an unsolved problem in many autoimmune rheumatic diseases (ARDs). One of the major contributing factors is poor symptom appraisal and the resulting delays in help-seeking by patients themselves. We therefore aimed to understand the symptom appraisal and help-seeking experience among patients with ARDs in a multiethnic urban Asian population and to explore its influencing factors. METHODS: Semistructured interviews with 33 patients with ARDs were audio recorded and transcribed verbatim. We coded the transcripts deductively using the reported 3 stages of symptom appraisal (detection, interpretation, and response) as the framework, and inductively for newly emerging themes and subthemes. RESULTS: All 3 stages of the symptom appraisal and help-seeking journey (ie, symptom detection [by self and by others], symptom interpretation [causes, consequences, and required actions] and symptom response [no action, self-management, seeking help from nonhealthcare professionals, and seeking help from healthcare professionals]) were observed among patients. Interactions among these 3 stages were also observed: symptom interpretation was found to influence subsequent symptom detection, and the outcome of symptom response was found to influence both subsequent symptom detection and symptom interpretation. Various personal and socioenvironmental factors (eg, knowledge and cultural beliefs about the symptom) that influenced symptom appraisal and help-seeking were identified from the interviews. CONCLUSION: The symptom appraisal and help-seeking journey of patients with ARDs is an iterative process of detection, interpretation, and response, and is influenced by various personal and socioenvironmental factors. Addressing modifiable factors could shorten the symptom appraisal and help-seeking interval and improve patient outcomes.

Leukocyte 8-hydroxy-2'-deoxyguanosine as an oxidative stress marker to predict cardiovascular events and death in chronic hemodialysis patients.

BACKGROUND: Hemodialysis patients have a markedly increased risk of cardiovascular (CV) morbidity and mortality. Oxidative stress plays a pathogenic role in the progression of atherosclerosis and CV disease among chronic hemodialysis patients. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) content in leukocyte deoxyribonucleic acid (DNA) has been shown as a sensitive and well-known biomarker of oxidant-induced DNA damage in chronic hemodialysis patients. METHODS: We conducted a retrospective cohort study to investigate the association of leukocyte 8-OHdG and CV events and deaths in patients of chronic hemodialysis. In this study, 217 chronic hemodialysis patients were recruited from 2016 to 2021. The 8-OHdG content of leukocyte DNA was measured by a high-performance liquid chromatography electrochemical detection method. Study outcomes were CV events as well as CV and all-cause deaths. The patients were followed until May 2021. RESULTS: The median follow-up period was 34.8 months. At the end of May 2021, 57 first CV events and 89 all-CV events occurred. Among the first and all CV events, 17 (29.8%) and 32 (36.0%) were fatal, respectively. Multivariate Cox regression analysis showed per 1/10 5 dG increment in leukocyte 8-OHdG values increased risk of CV events (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.10-1.41; p < 0.001), CV death (aHR, 1.27; 95% CI, 1.03-1.72; p = 0.034), and all-cause death (aHR, 1.11; 95% CI, 1.01-1.30; p = 0.038). CONCLUSION: This is the first study to demonstrate that oxidative stress assessed by 8-OHdG levels of leukocyte DNA predicted CV events as well as CV and all-cause deaths among chronic hemodialysis patients.

Artificial Intelligence Versus Human-Controlled Doctor in Virtual Reality Simulation for Sepsis Team Training: Randomized Controlled Study.

BACKGROUND: Interprofessional communication is needed to enhance the early recognition and management of patients with sepsis. Preparing medical and nursing students using virtual reality simulation has been shown to be an effective learning approach for sepsis team training. However, its scalability is constrained by unequal cohort sizes between medical and nursing students. An artificial intelligence (AI) medical team member can be implemented in a virtual reality simulation to engage nursing students in sepsis team training. OBJECTIVE: This study aimed to evaluate the effectiveness of an AI-powered doctor versus a human-controlled doctor in training nursing students for sepsis care and interprofessional communication. METHODS: A randomized controlled trial study was conducted with 64 nursing students who were randomly assigned to undertake sepsis team training with an AI-powered doctor (AI-powered group) or with medical students using virtual reality simulation (human-controlled group). Participants from both groups were tested on their sepsis and communication performance through simulation-based assessments (posttest). Participants' sepsis knowledge and self-efficacy in interprofessional communication were also evaluated before and after the study interventions. RESULTS: A total of 32 nursing students from each group completed the simulation-based assessment, sepsis and communication knowledge test, and self-efficacy questionnaire. Compared with the baseline scores, both the AI-powered and human-controlled groups demonstrated significant improvements in communication knowledge (P=.001) and self-efficacy in interprofessional communication (P<.001) in posttest scores. For sepsis care knowledge, a significant improvement in sepsis care knowledge from the baseline was observed in the AI-powered group (P<.001) but not in the human-controlled group (P=.16). Although no significant differences were found in sepsis care performance between the groups (AI-powered group: mean 13.63, SD 4.23, vs human-controlled group: mean 12.75, SD 3.85, P=.39), the AI-powered group (mean 9.06, SD 1.78) had statistically significantly higher sepsis posttest knowledge scores (P=.009) than the human-controlled group (mean 7.75, SD 2.08). No significant differences were found in interprofessional communication performance between the 2 groups (AI-powered group: mean 29.34, SD 8.37, vs human-controlled group: mean 27.06, SD 5.69, P=.21). However, the human-controlled group (mean 69.6, SD 14.4) reported a significantly higher level of self-efficacy in interprofessional communication (P=.008) than the AI-powered group (mean 60.1, SD 13.3). CONCLUSIONS: Our study suggested that AI-powered doctors are not inferior to human-controlled virtual reality simulations with respect to sepsis care and interprofessional communication performance, which supports the viability of implementing AI-powered doctors to achieve scalability in sepsis team training. Our findings also suggested that future innovations should focus on the sociability of AI-powered doctors to enhance users' interprofessional communication training. Perhaps in the nearer term, future studies should examine how to best blend AI-powered training with human-controlled virtual reality simulation to optimize clinical performance in sepsis care and interprofessional communication. TRIAL REGISTRATION: ClinicalTrials.gov NCT05953441; https://clinicaltrials.gov/study/NCT05953441.

Outcomes After Endovascular Aortic Intervention in Patients With Connective Tissue Disease.

Importance: Endovascular treatment is not recommended for aortic pathologies in patients with connective tissue diseases (CTDs) other than in redo operations and as bridging procedures in emergencies. However, recent developments in endovascular technology may challenge this dogma. Objective: To assess the midterm outcomes of endovascular aortic repair in patients with CTD. Design, Setting, and Participants: For this descriptive retrospective study, data on demographics, interventions, and short-term and midterm outcomes were collected from 18 aortic centers in Europe, Asia, North America, and New Zealand. Patients with CTD who had undergone endovascular aortic repair from 2005 to 2020 were included. Data were analyzed from December 2021 to November 2022. Exposure: All principal endovascular aortic repairs, including redo surgery and complex repairs of the aortic arch and visceral aorta. Main Outcomes and Measures: Short-term and midterm survival, rates of secondary procedures, and conversion to open repair. Results: In total, 171 patients were included: 142 with Marfan syndrome, 17 with Loeys-Dietz syndrome, and 12 with vascular Ehlers-Danlos syndrome (vEDS). Median (IQR) age was 49.9 years (37.9-59.0), and 107 patients (62.6%) were male. One hundred fifty-two (88.9%) were treated for aortic dissections and 19 (11.1%) for degenerative aneurysms. One hundred thirty-six patients (79.5%) had undergone open aortic surgery before the index endovascular repair. In 74 patients (43.3%), arch and/or visceral branches were included in the repair. Primary technical success was achieved in 168 patients (98.2%), and 30-day mortality was 2.9% (5 patients). Survival at 1 and 5 years was 96.2% and 80.6% for Marfan syndrome, 93.8% and 85.2% for Loeys-Dietz syndrome, and 75.0% and 43.8% for vEDS, respectively. After a median (IQR) follow-up of 4.7 years (1.9-9.2), 91 patients (53.2%) had undergone secondary procedures, of which 14 (8.2%) were open conversions. Conclusions and Relevance: This study found that endovascular aortic interventions, including redo procedures and complex repairs of the aortic arch and visceral aorta, in patients with CTD had a high rate of early technical success, low perioperative mortality, and a midterm survival rate comparable with reports of open aortic surgery in patients with CTD. The rate of secondary procedures was high, but few patients required conversion to open repair. Improvements in devices and techniques, as well as ongoing follow-up, may result in endovascular treatment for patients with CTD being included in guideline recommendations.

Lifetime Enhancement and Degradation Study of Blue OLEDs Using Deuterated Materials.

Significant lifetime enhancement, up to an eight-fold increase in T90, has been demonstrated in blue organic light-emitting diode (OLED) devices through the deuteration of host and hole transport materials. We observed a progressive increase in T90 using a series of anthracene-based hydrocarbon hosts with incremental deuteration in the emitting layer. In addition, we realized further lifetime improvement using a deuterated hole-transport layer along with the deuterated emitting layer. To elucidate the deuteration effects, we utilized laser desorption/ionization-time-of-flight (LDI-TOF) mass spectrometry for in situ UV irradiation to induce photodegradation and immediate chemical analysis of the resultant photodegradation species. Adducts between the host and moieties from transport materials were identified in UV-degraded films comprising a mixture of host and transport materials, indicating that similar species could be produced in OLED devices using these materials. Deuteration, in effect, mediated the formation of these adduct species, presumably electroluminescence quenchers, and thus improved the device lifetime. An approximate agreement was obtained between the kinetic isotope effect of the photodegradation reactions and the enhancement in device lifetime with deuteration.

Cost-effectiveness of selective bone densitometry using the osteoporosis self-assessment tool for Asians in multi-ethnic Asian population.

Early detection and treatment of osteoporosis can help to prevent debilitating fractures in the elderly. The osteoporosis self-assessment tool for Asians can be used as a screening tool to stratify patients for bone densitometry. It is most cost-effective for post-menopausal women aged 70 and males aged 75. PURPOSE: To determine the cost-effectiveness of selective bone densitometry (SBD) using the Osteoporosis Self-Assessment Tool for Asians (OSTA) as a risk-stratifying tool for the three predominant races (Chinese, Malay and Indian) in Singapore. METHODS: Decision analytical models were developed using a Markov model. Three scenarios were compared: no bone densitometry, SBD using the OSTA as a pre-screening tool and universal bone densitometry. Those diagnosed with osteoporosis were treated with five years of alendronate therapy. Data sources were from Singapore epidemiological studies, healthcare cost figures and published literature. Measurements include life years, quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratios (ICER). RESULTS: Compared to no bone densitometry, SBD using the OSTA would cost between $40,679 and $73,909 per QALY gained for men aged 75-80 and $22,386 to $58,185 per QALY gained for post-menopausal women aged 70-80. Universal bone densitometry would cost $157,955 to $177,127 per QALY gained for men aged 75-80 and $40,179 to $66,112 per QALY gained for post-menopausal women aged 70 to 80 compared to SBD. CONCLUSION: In general, osteoporosis screening was the most cost-effective for Malays and the least cost-effective for Indians. However, a general guideline should still be applied to the Singaporean population, as further explained later. Overall, the most cost-effective strategy for males would be using OSTA as a risk-stratifying tool at age 75. For post-menopausal women, SBD should be used for women aged 70, while universal bone densitometry should be used for women aged 75-80.

Navigating nursing curriculum change during COVID-19 pandemic: A systematic review and meta-synthesis.

AIM: To consolidate the evidence around the experiences of nursing undergraduates and faculty members navigating through remote and online education during the COVID-19 pandemic. BACKGROUND: The Coronavirus disease 2019 caused by the SARS-CoV-2 Virus (COVID-19) has placed massive pressure on healthcare, economic and education systems globally. Restrictive social distancing policies and public health measures necessitated educational institutions to switch from face-to-face to remote and online education to sustain the learning process. These changes have created an uncertain path and undue stress for healthcare learners and faculty, especially for professional roles that traditionally require more hands-on and access to clinical practice particularly pre-licensure nursing students. As such, there is an urgent need to consolidate evidence on the experiences of nursing undergraduates and faculty members as they navigate the rapid transition from face-to-face to remote and online education to ensure continuity of learning in achieving optimal learning outcomes and to support them during current and future public health crises. DESIGN: A systematic review and meta-synthesis of the qualitative literature was undertaken using Sandelowski and Barroso's approach. METHODS: Six electronic databases, CINAHL, Embase, ERIC, PsycINFO, PubMed and Scopus, were searched systematically using the eligibility criteria from December 2019 to September 2022. The Critical Appraisal Skills Program checklist for qualitative studies was used to conduct the critical appraisal of the selected articles. RESULTS: Forty-seven studies were included in this review, which encapsulates the experiences of 3052 undergraduates and 241 faculty members. An overarching meta-theme 'Remote and online education: a rollercoaster ride', emerged along with three main meta-themes: (1) Transition to remote and online education: A turbulent road, (2) Acceptance of the untravelled road, (3) Hopes and recommendations for the road ahead. CONCLUSION: To improve nursing undergraduates' and faculty member's navigation of remote and online education, more institutions should move towards establishing hybrid education as the new 'normal' and exercise prudence in the organisation and delivery of curriculum, teaching, well-being and clinical attachment contingencies of their healthcare courses.

Approaches to improving symptom appraisal: a systematic literature review.

OBJECTIVES: Poor symptom appraisal (detection, interpretation and response to symptoms) plays a major role in prolonged prediagnosis interval in various health conditions. Theories and models have been proposed to study the symptom appraisal process but how they could be employed to improve symptom appraisal remains unclear. We therefore aimed to review approaches to improving symptom appraisal in the literature and to develop a theoretical framework that could guide the development of approaches to improving symptom appraisal among individuals in the general population. DESIGN: Systematic review. DATA SOURCES: Medline, Web of Science, PsycINFO, Embase, CINAHL and Scopus were searched from inception to 30 March 2021. ELIGIBILITY CRITERIA: We included original articles in English in which approaches to improve the detection, interpretation or response to symptoms for symptomatic individuals were described. We excluded articles in which approaches were developed to improve symptom appraisal among healthcare professionals. DATA EXTRACTION AND SYNTHESIS: A predefined data extraction form was used to extract the development, characteristics and evaluation of approaches to improving symptom appraisal. This formed the basis for the narrative synthesis. RESULTS: Of 19 046 publications identified from the literature search, 112 were selected for full-text review and 29 approaches comprising provision of knowledge of symptoms/signs and additional components (eg, symptom self-examination and comparison) for symptom appraisal were included in the synthesis. Less than half (41.4%) of these approaches were developed based on theories/models. Interestingly, despite the variety of theories/models adopted in developing these approaches, the components of these approaches were similar. CONCLUSION: Symptom appraisal is an essential process in a patient's journey that can be targeted to facilitate early diagnosis but is largely unstudied. Building on the literature, we proposed a theoretical framework and approaches to improving symptom appraisal. This could facilitate early identification of a variety of health conditions in the general population. TRIAL REGISTRATION NUMBER: CRD42021279500.

Glycolipid-peptide conjugate vaccines elicit CD8+ T-cell responses and prevent breast cancer metastasis.

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple-negative breast cancer (TNBC). Certain glycolipids can act as vaccine adjuvants by specifically stimulating natural killer T (NKT) cells to provide a universal form of T-cell help. Methods: We designed and made a series of conjugate vaccines comprising a prodrug of the NKT cell-activating glycolipid α-galactosylceramide covalently linked to tumor-expressed peptides, and assessed these using E0771- and 4T1-based breast cancer models in vivo. We employed peptides from the model antigen ovalbumin and from clinically relevant breast cancer antigens HER2 and NY-ESO-1. Results: Glycolipid-peptide conjugate vaccines that activate NKT cells led to antigen-presenting cell activation, induced inflammatory cytokines, and, compared with peptide alone or admixed peptide and α-galactosylceramide, specifically enhanced CD8+ T-cell responses against tumor-associated peptides. Primary tumor growth was delayed by vaccination in all tumor models. Using 4T1-based cell lines expressing HER2 or NY-ESO-1, a single administration of the relevant conjugate vaccine prevented tumor colonisation of the lung following intravenous inoculation of tumor cells or spontaneous metastasis from breast, respectively. Conclusion: Glycolipid-peptide conjugate vaccines that activate NKT cells prevent lung metastasis in breast cancer models and warrant investigation as adjuvant therapies for high-risk breast cancer.

Using Full-Spectrum Flow Cytometry to Phenotype Memory T and NKT Cell Subsets with Optimized Tissue-Specific Preparation Protocols.

Full-spectrum flow cytometry is now routinely used in many laboratories internationally, and the demand for this technology is rapidly increasing. With capacity to use larger and more complex staining panels, standardized protocols are required for optimal panel design and analysis. Importantly, for ex vivo analysis, tissue preparation methods also need to be optimized to ensure samples are truly representative of tissues in situ. This is particularly relevant given the recent interest in adaptive immune cells that form residency in specific organs. Here we provide optimized protocols for tissue processing and phenotyping of memory T cells and natural killer T (NKT) cell subsets from liver, lung, spleen, and lymph node using full-spectrum flow cytometry. We provide a 21-color antibody panel for identification of different memory subsets, including tissue-resident memory T (TRM ) cells, which are increasingly regarded as important effectors in adaptive immunity. We show that processing procedures can affect outcomes, with liver TRM cells particularly sensitive to heat, such that accurate evaluation requires fast processing at defined temperatures. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Processing mouse liver for flow cytometric analysis of memory T and NKT cell subsets Basic Protocol 2: Processing mouse spleen for flow cytometric analysis of memory T and NKT cell subsets Basic Protocol 3: Processing mouse lungs for flow cytometric analysis of memory T and NKT cell subsets Basic Protocol 4: Processing mouse lymph nodes for flow cytometric analysis of memory T and NKT cell subsets Basic Protocol 5: Staining and flow cytometric analysis of samples for memory T and NKT cell subsets Support Protocol: Obtaining cell counts from flow cytometry data.

COVID-19 and Thyroid Function: A Bi-Directional Two-Sample Mendelian Randomization Study.

Background: Thyroid dysfunction has been observed among some patients with coronavirus disease (COVID-19). It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (or its severity) leads to the development of thyroid dysfunction, or vice versa. In this study, we examined the bi-directional causal relationship between host genetic liability to three COVID-19 phenotypes (including SARS-CoV-2 infection, hospitalized and severe COVID-19) and three thyroid dysfunction traits (including hyperthyroidism, hypothyroidism, and autoimmune thyroid disease [AITD]) and three continuous traits of thyroid hormones (including thyrotropin [TSH] and free thyroxine [fT4] within reference range, and TSH in full range). Methods: Summary statistics from the largest available meta-analyses of human genome-wide association studies were retrieved for the following variables: SARS-CoV-2 infection (n = 1,348,701), COVID-19 hospitalization (n = 1,557,411), severe COVID-19 (n = 1,059,456), hyperthyroidism (n = 51,823), hypothyroidism (n = 53,423), AITD (n = 755,406), TSH within reference range (n = 54,288), fT4 within reference range (n = 49,269), and TSH in full range (n = 119,715). Using a two-sample Mendelian randomization (MR) approach, the inverse-variance weighted (IVW) method was adopted as the main MR analysis. Weighted median, contamination mixture, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied as sensitivity analyses. Results: Host genetic susceptibility to SARS-CoV-2 infection was causally associated with hypothyroidism in the main IVW analysis (per doubling in prevalence of SARS-CoV-2 infection, odds ratio [OR] = 1.335; 95% confidence interval [CI]: 1.167-1.526; p = 2.4 × 10-5, surpassing the Bonferroni multiple-testing threshold). Similar causal estimates were observed in the sensitivity analyses (weighted median: OR = 1.296; CI: 1.066-1.575; p = 9 × 10-3; contamination mixture: OR = 1.356; CI: 1.095-1.818; p = 0.013; MR-Egger: OR = 1.712; CI: 1.202-2.439; p = 2.92 × 10-3, and MR-PRESSO: OR = 1.335; CI: 1.156-1.542; p = 5.73 × 10-4). Host genetic liability to hospitalized or severe COVID-19 was not associated with thyroid dysfunction or thyroid hormone levels. In the reverse direction, there was no evidence to suggest that genetic predisposition to thyroid dysfunction or genetically determined thyroid hormone levels altered the risk of the COVID-19 outcomes. Conclusions: This bi-directional MR study supports that host response to SARS-CoV-2 viral infection plays a role in the causal association with increased risk of hypothyroidism. Long-term follow-up studies are needed to confirm the expected increased hypothyroidism risk.

The Effect of a Sepsis Interprofessional Education Using Virtual Patient Telesimulation on Sepsis Team Care in Clinical Practice: Mixed Methods Study.

BACKGROUND: Improving interprofessional communication and collaboration is necessary to facilitate the early identification and treatment of patients with sepsis. Preparing undergraduate medical and nursing students for the knowledge and skills required to assess, escalate, and manage patients with sepsis is crucial for their entry into clinical practice. However, the COVID-19 pandemic and social distancing measures have created the need for interactive distance learning to support collaborative learning. OBJECTIVE: This study aimed to evaluate the effect of sepsis interprofessional education on medical and nursing students' sepsis knowledge, team communication skills, and skill use in clinical practice. METHODS: A mixed methods design using a 1-group pretest-posttest design and focus group discussions was used. This study involved 415 undergraduate medical and nursing students from a university in Singapore. After a baseline evaluation of the participants' sepsis knowledge and team communication skills, they underwent didactic e-learning followed by virtual telesimulation on early recognition and management of sepsis and team communication strategies. The participants' sepsis knowledge and team communication skills were evaluated immediately and 2 months after the telesimulation. In total, 4 focus group discussions were conducted using a purposive sample of 18 medical and nursing students to explore their transfer of learning to clinical practice. RESULTS: Compared with the baseline scores, both the medical and nursing students demonstrated a significant improvement in sepsis knowledge (P<.001) and team communication skills (P<.001) in immediate posttest scores. At the 2-month follow-up, the nursing students continued to have statistically significantly higher sepsis knowledge (P<.001) and communication scores (P<.001) than the pretest scores, whereas the medical students had no significant changes in test scores between the 2-month follow-up and pretest time points (P=.99). A total of three themes emerged from the qualitative findings: greater understanding of each other's roles, application of mental models in clinical practice, and theory-practice gaps. The sepsis interprofessional education-particularly the use of virtual telesimulation-fostered participants' understanding and appreciation of each other's interprofessional roles when caring for patients with sepsis. Despite noting some incongruities with the real-world clinical practice and not encountering many sepsis scenarios in clinical settings, participants shared the application of mental models using interprofessional communication strategies and the patient assessment framework in their daily clinical practice. CONCLUSIONS: Although the study did not show long-term knowledge retention, the use of virtual telesimulation played a critical role in facilitating the application of mental models for learning transfer and therefore could serve as a promising education modality for sepsis training. For a greater clinical effect, future studies could complement virtual telesimulation with a mannequin-based simulation and provide more evidence on the long-term retention of sepsis knowledge and clinical skills performance.

Longitudinal Metabolomic Analysis Reveals Gut Microbial-Derived Metabolites Related to Formula Feeding and Milk Sensitization Development in Infancy.

Early exposure to formula milk increases the likelihood of cow's milk sensitization and food allergies in the later childhood. However, the underlying mechanisms are multifactorial and unclear. Fifty-five children from a follow-up birth cohort study were grouped into exclusive breastfeeding (EBF, n = 33) and formula feeding (EFF, n = 22) in the first six months of life. Urinary metabolites were longitudinally assessed and analyzed at 6 months, 1, and 2 years of age using 1H-nuclear magnetic resonance (NMR) spectroscopy. Integrated analysis of metabolic profiling associated with formula feeding and milk sensitization related to IgE reactions was also investigated. Twenty-two metabolites were significantly obtained in the EFF set at age 0.5, whereas nine metabolites were predominantly obtained in the milk sensitization set at age 1. A subsequent analysis of metabolic change from 6 months to age 1 identified eight metabolites, including 3-methyl-2-oxovaleric acid, glutarate, lysine, N-phenylacetylglycine, N,N-dimethylglycine, 3-indoxysulfate, 2-oxoglutaric acid, and pantothenate associated with formula feeding and milk sensitization with same trend variation. Among them, 3-indoxysulfate, N-phenylacetylglycine, and N,N-dimethylglycine were gut microbial-derived without IgE association. By contrast, 3-methyl-2-oxovaleric acid, glutarate, and lysine were IgE related associated with formula feeding contributing to milk sensitization (p < 0.05). Longitudinal urinary metabolomic analysis provides molecular insight into the mechanism of formula feeding associated with milk sensitization. Gut microbial-derived metabolites associated with formula feeding and IgE associated metabolites related to branched-chain amino acid metabolism play roles in developing sensitization and allergic symptoms in response to formula feeding.